WO2021170504A1

WO2021170504A1 - Dna methylation level of specific cpg sites for prediction of glycemic response and tolerance to metformin treatment in type 2 diabetic patients

Info

Publication number: WO2021170504A1
Application number: PCT/EP2021/054183
Authority: WO
Inventors: Charlotte LING; Sonia GARCÍA-CALZÓN; Alexander PERFILYEV
Original assignee: Ling Charlotte; Garcia Calzon Sonia; Perfilyev Alexander
Priority date: 2020-02-25
Filing date: 2021-02-19
Publication date: 2021-09-02

Abstract

The present invention relates to methods and arrays for determining the methylation status of DNA. The present invention also relates to methods and arrays for determining if a type 2 diabetic individual is able to respond to and/or tolerate a particular treatment regime, e.g. metformin treatment.

Description

DNA methylation level of specific CpG sites for prediction of glycemic response and tolerance to metformin treatment in type 2 diabetic patients

Technical field

Background

Metformin is first-line treatment for type 2 diabetes (T2D) (Inzucchi et al.

2015). Metformin has also been associated with cancer treatment, but has not been approved for treatment of any type of cancer. In diabetes, metformin is used to lower the blood sugar levels in T2D patient. In particular, metformin decreases hepatic glucose production, and may also lower blood sugar in T2D patients through additional mechanisms. However, about 30% of T2D patients do not respond to metformin and about 20-30% experience intolerable adverse effects, including gastrointestinal symptoms, which warrant discontinuation of metformin treatment in about 5% of patients (Cook et al. 2007; Kahn et al. 2006). There are no phenotypes that successfully predict the glycemic response or intolerance to metformin (Donnelly et al. 2006). Genetics explain a modest proportion of metformin response and intolerance (Dujic et al. 2015; Dujic et al. 2016; Jablonski et al. 2010; Zhou et al 2014). Therefore, additional studies are needed to find biomarkers that predict whether T2D patients will respond to and/or tolerate metformin or whether other therapies should be prioritized.

So far, no pharmacoepigenetics study has explored if epigenetic biomarkers may be used for precision medicine in T2D. Studies have demonstrated that epigenetics e.g. DNA methylation, contribute to T2D (Dayeh et al. 2014; Nilsson et al. 2014; Nilsson et al. 2015; Bacos et al. 2016; Volkov et al. 2017; Chambers et al. 2015). Blood-based epigenetic markers that mirror the methylation pattern in human islets and predict insulin secretion and T2D have been identified (Bacos et al. 2016).

Summary

The present invention provides blood-based epigenetic biomarkers which are able to predict drug response and intolerance in type 2 diabetes (T2D) patients. Such epigenetic markers could provide a valuable tool for personalized medicine. The present inventors have in fact found that DNA methylation in blood is able to predict glycemic response and intolerance to metformin therapy in drug-naive T2D patients. In other words, they have investigated DNA methylation in vivo and shown that it predicts the response and tolerance of treatment with metformin in T2D patients which have not yet received metformin therapy. Such in vivo approach to investigate DNA methylation is different from in vitro approaches, where methylation patterns are studied in cell lines. In in vitro studies, methylation patterns may for example be affected by culture conditions. Furthermore, cancerous cell lines have been shown to display higher frequencies of CpG island methylation than primary tumours, and to not represent the full spectrum of disease subtypes observed clinically (Lindsey et al., 2005).

One aspect of the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not and/or whether an individual is able to tolerate metformin treatment or not, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, wherein the normal methylation level is the average methylation level of said CpG site as observed in at least 15 individuals suffering from type 2 diabetes and known to be able to respond to and/or tolerate metformin; d) Identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of sequences, wherein a methylation level of the majority of the CpG sites being higher than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being equal or lower than the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and wherein said individual suffers from or is at risk of developing type 2 diabetes.

Another aspect of the present disclosure relates to a method for treating a patient suffering from type 2 diabetes, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being equal or lower than the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin, and administering to the responder and tolerant individuals a therapeutically effective amount of a medicament that comprises metformin.

Another aspect of the present disclosure relates to a method for identifying a patient for treatment with an anti-diabetic medicament which does not comprise metformin, wherein said patient suffers from type 2 diabetes, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin.

Another aspect of the present disclosure relates to an array comprising a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

A further aspect of the present disclosure relates to a use of an array as disclosed herein, for determining the methylation level of a DNA molecule of an individual.

An even further aspect of the present disclosure relates to a method of determining the methylation level of DNA of an individual, the method comprising the steps of: a) Providing a sample obtained from said individual, wherein said sample comprises one or more DNA molecules; b) Treating said sample with an agent that modifies unmethylated cytosines in said one or more DNA molecules; c) Contacting said sample with an array comprising a plurality of DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.; d) Determining the methylation level of the DNA by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the plurality of DNA sequences in the panel.

An even further aspect of the present disclosure relates to a use of the methylation level of blood DNA of an individual for the manufacture of a diagnostic agent for predicting whether said individual is able to respond to metformin treatment or not and/or whether said individual is able to tolerate metformin treatment or not, wherein said diagnostic agent is manufactured to measure the methylation level of a panel of CpG sites, wherein said measured methylation level is compared to a normal methylation level of each of said CpG sites, and wherein a measured methylation level of the majority of the CpG sites being higher than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment.

Detailed description Definitions

“Methylation level” as used herein refers to the degree of cytosine methylation of a certain CpG site comprised in an amplified nucleotide sequence, wherein “0% or 0” corresponds to a completely non-methylated CpG site and “100% or 1” to a completely methylated CpG site in an analysed DNA sample obtained from one or more cells. A completely methylated CpG site is a site that is methylated on every allele in an analysed DNA sample of cell(s). A completely non-methylated CpG site is a site that is methylated on none of the alleles in an analysed DNA sample of cell(s). “CpG site” or “CG sites” as used herein is a region of DNA where a cytosine (C) nucleotide is followed by a guanine (G) nucleotide in the linear sequence of bases along its 5' 3' direction.

A “normal methylation level” of a CpG site, as used herein, is the average methylation level of said CpG site as observed in at least 15 individuals suffering from T2D and known to be able to respond to and/or tolerate metformin. Hence, the normal methylation level of a certain CpG site can also be called normal methylation level. In order to compare the measured methylation level of a CpG site with the normal methylation level of said CpG site, both the measured and the normal methylation levels have to be determined in the same type of sample. In some embodiments, the present disclosure relates to methylation levels determined in blood samples.

“Methylation Risk Score (MRS)” as used herein refers to a parameter calculated from the methylation level of each of a panel of CpG sites, to obtain a single value (the MRS) representing the methylation level of a plurality of CpG sites. The MRS is calculated as the sum of the standardized methylation values at each CpG site weighted by the CpG-specific effect size, wherein: the standardized methylation values are ((Beta values - average) / SD), wherein the beta values are the degree of DNA methylation, and average and SD refer to the average and standard deviation, respectively, of beta values for a specific CpG site in the tested subjects; the CpG specific effect size is the B-coefficient obtained from the following logistic models:

I) response ~ methylation + basal HbA1c + eGFr + time gap methylation + time gap

HbA1c for response, and

II) tolerance ~ methylation + eGFr + time gap methylation for tolerance,

Wherein:

HbA1c is glycated haemoglobin; eGFr is the estimated glomerular filtration rate (or creatinine clearance) calculated with the Cockcroft-Gault equation [eGFR= (140-age)*(weight in kg)*(0.85 if female) / (72*creatinine in mg/dL)]; time gap methylation is a time gap in baseline methylation defined as the number of days between the measurement of DNA methylation in blood and the start of metformin treatment; and time gap HbA1c is a time gap in baseline HbA1c defined as the number of days between the measurement of baseline HbA1c and the start of metformin treatment.

A “cut-point” of the MRS, as used herein, refers to a point within the MRS, which better separates subjects based on (i) whether they respond to or do not respond to metformin treatment; or (ii) based on whether they tolerate or do not tolerate metformin treatment. A cut-point used for the prediction of responder/non-responder is also referred to as response cut-point. A cut-point used for the prediction of tolerant/intolerant is also referred to as tolerance cut-point. In some embodiments, the response cut-point differs from the tolerance cut-point. In some embodiments, the response cut-point differs from the tolerance cut-point as they may be calculated based on a different set of CpG sites. The optimal cut-point may be calculated based on the best sensitivity and specificity in: i) a Receiver-Operating-Characteristic (ROC) curve for metformin response including at least 100 individuals, such as at least 150 individuals, for example in at least 200 individuals suffering from T2D which includes both responders and non-responders to metformin; and ii) in a ROC curve for metformin intolerance including at least 100 individuals, such as at least 150 individuals suffering from T2D which includes both tolerant and intolerant to metformin.

“Responder individuals” as used herein refers to subjects obtaining a reduction in HbA1 c to below 53 mmol/mol (<7%) if their basal HbA1 c was ³ 53, or to below 48 mmol/mol (<6.5%) if their basal HbA1c was ³ 48, after about 3 months to 24 months with metformin therapy, or a decrease of 8 mmol/mol or more, such as of 11 mmol/mol or more from baseline (corresponding to a reduction of ³ 0.7%, such as ³ 1% from baseline) in HbA1c levels within a three months period of metformin treatment. “Non responders individuals” as used herein refers to subjects who do not achieve the goal of < 53 mmol/mol (<7%) or <48 mmol/mol (<6.5%), depending on their basal HbA1c, after about 3 months to 24 months with metformin therapy, or who obtain a reduction in HbA1c of less than 11 mmol/mol, such as of less than 8 mmol/mol from baseline (corresponding to a reduction of < 1% from baseline), or even maintained or increased their HbA1c levels after about 3 months to 24 months with metformin therapy. “Non-tolerant individuals” as used herein refers to subjects with T2D who are not able to follow a metformin treatment at any dose because it gives them severe adverse effects, mostly in the form of gastrointestinal problems.

Method for predicting whether an individual is able to respond to and/or tolerate metformin treatment or not

One aspect of the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not and/or whether an individual is able to tolerate metformin treatment or not, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) Identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of sequences, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being about equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment.

The inventors have surprisingly found that the methylation level of a panel of CpG sites found in DNA, for example in blood DNA, of an individual correlate with the capability of said individual to respond to metformin treatment. In particular, if the methylation level of the majority of the CpG sites of the panel is higher, such as statistically significantly higher, or lower, such as statistically significantly lower, than the normal methylation level of said CpG sites, the individual is not able to respond to metformin treatment. Example of statistical methods that may be used to determine whether the difference between a measured methylation level and the normal methylation is significant are described herein. If instead the methylation level of the majority of the CpG sites of the panel is about the same, such as essentially the same, such as equal to, the normal methylation level of said CpG sites, the individual is able to respond to metformin treatment. “The majority of the CpG sites” as used herein refers to 75% of the CpG sites of the panel or more, such as 80% of the CpG sites of the panel or more, such as 85% of the CpG sites of the panel or more, such as 90% of the CpG sites of the panel or more, such as 95% of the CpG sites of the panel or more, such as 96% of the CpG sites of the panel or more, such as 97% of the CpG sites of the panel or more, such as 98% of the CpG sites of the panel or more, such as 99% of the CpG sites of the panel or more, such as about all of the CpG sites of the panel, wherein the panel is as defined herein.

Likewise, the present inventors have surprisingly found that the methylation level of a panel of CpG sites found in DNA, for example in blood DNA, of an individual correlate with the capability of said individual to tolerate metformin treatment. In particular, if the methylation level of the majority of the CpG sites of the panel is higher, such as statistically significantly higher, or lower, such as statistically significantly lower, than the normal methylation level of said CpG sites, the individual is not able to tolerate metformin treatment. If instead the methylation level of the majority of the CpG sites of the panel is about the same, such as equal to, the normal methylation level of said CpG sites, the individual is able to tolerate metformin treatment.

In some embodiments, the methods of the present disclosure are conducted in vitro. The CpG sites that can be used for predicting response/non-response to metformin treatment are different from the CpG sites that can be used for predicting tolerance/non-tolerance to metformin treatment.

In particular, the panel of CpG sites having a methylation level that correlates with the capability of an individual to respond or not respond to metformin treatment corresponds to the CpG sites represented in List 1 herein, as well as their surrounding genomic regions, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1.

The panel of CpG sites having a methylation level that correlates with the capability of an individual to tolerate or not tolerate metformin treatment correspond to the CpG sites represented in List 2 herein, as well as their surrounding genomic regions, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2.

In some embodiments, the panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being about equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being about equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

In some embodiments of the present disclosure, the panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

In some embodiments of the present disclosure, the panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

In some embodiments the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as disclosed herein, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

In some embodiments, the panel of CpG sites comprises or consists of at least 1 CpG site, such at least 4 CpG sites, such as at least 7 CpG sites, such as at least 10 CpG sites, for example at least 11 CpG sites, such as at least 20 CpG sites, for example at least 50 CpG sites, such of at least 100 CpG sites, for example at least 150 CpG sites, such as more than 200 CpG sites, for example more than 500 CpG sites, for example at the most 7916 CpG sites for example at the most 9676 CpG sites. In some embodiments, the panel of CpG sites comprises or consists of in the range of 5 to 50 CpG sites, such as in the range of 7 to 100 CpG sites, such of in the range of 5 to 200 CpG sites, such as in the range of 5 to 1000 CpG sites, such as in the range of 5 to 1500 CpG sites, such as in the range of 5 to 3000 CpG sites, such as in the range of 5 to 5000 CpG sites, such as in the range of 5 to 7000 CpG sites, such as in the range of 1 to 10.000 CpG sites. The panel of CpG sites can comprise or consist of any possible combination of any one of the CpG sites of List 1 and/or List 2, such as of any possible combination of any one of the CpG sites of table A and/or Table B.

In some embodiments, the panel of CpG sites comprises or consists of 4 CpG sites.

In some embodiments, the panel of CpG sites comprises or consists of 11 CpG sites.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 4 CpG sites, such as at least 7 CpG sites, such at least 10 CpG sites, for example at least 11 CpG sites, such as at least 25 CpG sites, for example 50 CpG sites, such of at least 100 CpG sites, for example at least 150 CpG sites, for example in the range of 5 to 200 CpG sites, such as in the range of 7 to 500 CpG sites, such as in the range of 7 to 1000 CpG sites, such as in the range of 7 to 3000 CpG sites, such as in the range of 7 to 5000 CpG sites, such as in the range of 7 to 7000 CpG sites, for example at the most 7916 CpG sites, for example at the most 8000 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to than the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 4 CpG sites, such as at least 7 CpG sites, such at least 10 CpG sites, for example at least 11 CpG sites, such as at least 25 CpG sites, for example 50 CpG sites, such of at least 100 CpG sites, for example at least 500 CpG sites, for example at least 1000 CpG sites, for example in the range of 1 to 33 CpG sites, for example in the range of 1 to 100 CpG sites, for example in the range of 1 to 500 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 4 CpG sites, such as at least 7 CpG sites, such at least 10 CpG sites, for example at the most 11 CpG sites, for example in the range of 1 to 11 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 4 CpG sites, such as at least 7 CpG sites, such at least 10 CpG sites, for example at least 11 CpG sites, for example in the range of 5 to 20 CpG sites, such as in the range of 7 to 11 , such as at least 25 CpG sites, for example 50 CpG sites, such of at least 100 CpG sites, for example at least 150 CpG sites, for example in the range of 50 to 200 CpG sites, such as in the range of 7 to 500 CpG sites, such as in the range of 7 to 1000 CpG sites, such as in the range of 7 to 3000 CpG sites, such as in the range of 7 to 5000 CpG sites, such as in the range of 7 to 7000 CpG sites, for example at the most 9976 CpG sites, for example at the most 10000 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the nucleotide sequences of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the nucleotide sequences of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the nucleotide sequences of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the nucleotide sequences of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 4 CpG sites, such as at least 7 CpG sites, such at least 10 CpG sites, for example at least 11 CpG sites, such as at least 25 CpG sites, for example 50 CpG sites, such of at least 100 CpG sites, for example at least 150 CpG sites, for example at least 500 CpG sites, for example in the range of 1 to 200 CpG sites, for example in the range of 1 to 500 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the nucleotide sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the nucleotide sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not as defined herein, wherein the panel of CpG sites comprises or consists of at least 1 CpG site, for example at least 2 CpG sites, such as at least 3 CpG sites, for example at the most 4 CpG sites, , for example in the range of 1 to 4 CpG sites, wherein each said CpG site is located on one or more DNA sequence selected from a group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment.

An aspect of the present disclosure relates to a use of the methylation level of blood DNA of an individual for the manufacture of a diagnostic agent for predicting whether said individual is able to respond to metformin treatment or not and/or whether said individual is able to tolerate metformin treatment or not, wherein said diagnostic agent is manufactured to measure the methylation level of a panel of CpG sites, wherein said measured methylation level is compared to a normal methylation level, and wherein a measured methylation level of the majority of the CpG sites being higher or lower than the normal methylation level indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment.

In some embodiments, the present disclosure relates to using the methylation level of blood DNA of an individual for the manufacture of a diagnostic agent suitable for predicting whether the individual is able to respond to metformin treatment or not and/or whether the individual is able to tolerate metformin treatment or not, wherein the diagnostic agent is manufactured to measure the methylation level of a panel of CpG sites as defined herein.

In some embodiments, the method of predicting whether an individual is able to respond to metformin treatment or not according to the present disclosure comprises in step b) a further calculation, namely the calculation of a weighted methylation risk score (MRS) based on the determined methylation level of a panel of CpG sites. In particular, the method of the present disclosure may further comprise a step of calculating a weighted response methylation risk score (rMRS) and/or a weighted tolerance methylation risk score (tMRS). When an rMRS and/or a tMRS are calculated, than the rMRS and/or a tMRS may be compared to a predetermined response cut-point and a predetermined tolerance cut-point, respectively.

An rMRS higher than or essentially equal to the response cut-point is indicative of non response (non-responder individual) to metformin treatment. An rMRS lower than or essentially equal to the response cut-point is indicative of response (responder individual) to metformin treatment.

A tMRS higher than or essentially equal to the tolerance cut-point is indicative of non tolerance (non-tolerant individual) to metformin treatment. A tMRS lower than or essentially equal to the tolerance cut-point is indicative of tolerance (tolerant individual) to metformin treatment.

Methods for calculating a MRS, as well as a definition of the response and tolerance cut-points, are further explained herein in the present disclosure.

Methylation level

The methods of the present disclosure are based on determining the methylation level of one or more CpG sites, such as of a panel of CpG sites, and comparing the so- determined methylation level of each CpG site to a normal methylation level of each said CpG site. In some embodiments, the methods of the present disclosure are based on determining an rMRS and/or a tMRS based on the determined methylation level of one or more CpG sites, such as of a panel of CpG sites, and comparing the so- determined rMRS and/or a tMRS to a response cut-point and/or to a tolerance cut- point, respectively.

Several methods for determining the methylation level of a CpG site are known in the state of the art. In some embodiments, the methylation level of a CpG site is analysed by pyrosequencing, PCR based methods, methylation-based methods, microarray- based methods, MALDI-TOF mass spectrometry (Tost et al. 2003), or combinations thereof. See for example Yang et al., 2011 for a description of methylation analysis based on pyrosequencing and/or microarrays. Moreover, MassARRAY Epi-TYPER®, by Sequenom, is an example of a method for automatic and quantitative analysis of DNA methylation based on PCR and MALDI_TOF mass spectrometry. The methods of the present disclosure comprise determining the methylation level of a panel of CpG sites in a sample. In same embodiments, the sample is a body cell, a body tissue or a body fluid, wherein the body fluid is selected from blood, serum, plasma, saliva, amniotic fluid or urine sample. The sample comprises DNA sequences.

For example, the body tissue is a homogenized body tissue.

One aspect of the present disclosure relates to a method of determining the methylation level of DNA of an individual, the method comprising the steps of: a) Providing a sample obtained from said individual, wherein said sample comprises one or more DNA molecules; b) Treating said sample with an agent that modifies unmethylated cytosines in said one or more DNA molecules; c) Contacting said sample with an array comprising a plurality of DNA sequences selected from the group consisting of:

DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.; d) Determining the methylation level of the DNA by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the plurality of DNA sequences in the panel. In some embodiments, the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

It may be particularly preferred that said CpG sites are selected so that they have a high specific effect size. As described herein below, the beta-coefficient is a useful value for determining the effect size. Accordingly, it is preferred that the beta-coefficient (non-responders vs. responders) is less than 1, preferably less than 0.7, more preferably less than 0.5, yet more preferably less than 0.4. Said beta-coefficient should be calculated between a group of at least 10, preferably at least 100, even more preferably at least 1000 individuals non responding to metformin treatment (non responders) versus a group of at least 10, preferably at least 100, even more preferably at least 1000 individuals responding to metformin treatment (responders). Preferably, said beta-coefficient is calculated essentially as described in Example 3 herein below. The skilled person will understand that blood samples from a different group of individuals may be used for the calculations, as long as samples from both tolerant and intolerant individuals are included.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

It may be particularly preferred that said CpG sites are selected so that they have a high specific effect size. As described herein below, the beta-coefficient is a useful value for determining the effect size. Accordingly, it is preferred that the beta-coefficient (intolerant vs. tolerant) is less than 1, preferably less than 0.7, more preferably less than 0.5, yet more preferably less than 0.4. Said beta-coefficient should be calculated between a group of at least 10, preferably at least 100, even more preferably at least 1000 intolerant individuals versus a group of at least 10, preferably at least 100, even more preferably at least 1000 tolerant individuals. Preferably, said beta-coefficient is calculated essentially as described in Example 3 herein below. The skilled person will understand that blood samples from a different group of individuals may be used for the calculations, as long as samples from both tolerant and intolerant individuals are included.

In some embodiments, the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to respond to metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

In some embodiments, the present disclosure relates to a method of predicting whether an individual is able to tolerate metformin treatment or not, wherein the methylation level is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

In some embodiments, the sample is treated with an agent that modifies unmethylated cytosines prior to determining the methylation level.

In some embodiments, the present disclosure relates to a method comprising determining the methylation level of a panel of CpG sites as defined herein, wherein the methylation level is determined on one or more single-stranded DNA sequences.

In some embodiments of the present disclosure, the methylation level is determined by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the one or more DNA sequences in the panel. In some embodiments, the normal methylation level is the average methylation level of a CpG site of said panel of CpG sites in at least 15 individuals, such as in at least 20 individuals, such as in at least 25 individuals, such as in at least 30 individuals, such as in at least 40 individuals, such as in at least 50 individuals, such as in at least 75 individuals, such as in at least 100 individuals, such as in at least 120 individuals suffering from T2D and that are able to respond to and tolerate metformin treatment.

The methylation level of the panel of CpG sites may be used to calculate a weighted methylation risk score (MRS), such as a response MRS and/or a tolerance MRS, so that instead of comparing the methylation level of each CpG site of the panel to the respective normal methylation level, the comparison is made between the response MRS and/or a tolerance MRS calculated on a panel of CpG sites as defined herein and predefined response and/or tolerance cut-point.

The MRS may be calculated based on the methylation level of at least two CpG sites, such as of at least 5 CpG sites, for example of at least 7 CpG sites, such as of at least 10 CpG sites, for example of at least 20 CpG sites, such as of at least 28 CpG sites, for example of at least 33 CpG sites, such as of at least 40 CpG sites, such as of more than 50 CpG sites.

In some embodiments, the method of predicting whether an individual is able to respond to metformin treatment or not as defined herein, further comprises calculating a response weighted methylation risk score (rMRS) for the panel of CpG sites as defined herein, wherein said rMRS is the sum of the standardized methylation values at each CpG site, weighted by CpG-specific effect size, and wherein the panel of CpG sites is as defined herein.

In some embodiments of the present disclosure, the response methylation risk score (rMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of:

DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments of the present disclosure, the response methylation risk score (rMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments of the present disclosure, the response methylation risk score (rMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

In some embodiments, the method of predicting whether an individual is able to tolerate metformin treatment or not as defined herein, further comprises calculating a tolerance weighted methylation risk score (tMRS) for the panel of CpG sites, wherein said tMRS is the sum of the standardized methylation values at each CpG site, weighted by CpG-specific effect size, and wherein the panel of CpG sites is as defined herein.

In some embodiments of the present disclosure, the tolerance methylation risk score (tMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.

In some embodiments of the present disclosure, the tolerance methylation risk score (tMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i.

In some embodiments of the present disclosure, the tolerance methylation risk score (tMRS) is calculated for a panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

The MRS, such as the rMRS and/or the tMRS, may then be compared to cut-point, such as to a response cut-point and/or a tolerance cut-point, respectively. The response cut-point and/or the tolerance cut-point are calculated based on the best sensitivity and specificity in a Receiver-Operating-Characteristic (ROC) curve for metformin response including at least 15, such as at least 20 individuals suffering from T2D who are able to respond/not-respond, and a ROC curve for metformin intolerance including individuals suffering from T2D who are able to tolerate/not-tolerate metformin.

It is preferred that the ROC curve used for determining the cut-point has an area under the curve (AUC) as close to 1 as possible, for example and AUC of at least 0.7, such as an AUC of at least 0.8.

Thus, in some embodiments, the method of predicting whether an individual is able to respond to metformin treatment or not as defined herein, further comprises comparing the rMRS with a predefined response cut-point, wherein a rMRS being equal or higher than the predefined response cut-point indicates that the individual is not able to respond to metformin treatment, and wherein a rMRS being lower than the predefined response cut-point indicates that the individual is able to respond to metformin treatment.

Similarly, in some embodiments, the method of predicting whether an individual is able to tolerate metformin treatment or not as defined herein, further comprises comparing the tMRS with a predefined tolerance cut-point, wherein a tMRS being equal or higher than the predefined tolerance cut-point indicates that the individual is not able to tolerate metformin treatment, and wherein a tMRS being lower than the predefined tolerance cut-point indicates that the individual is able to tolerate metformin treatment.

In some embodiments of the present disclosure, step c) of comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, comprises or consists of comparing the rMRS with a predefined response cut- point calculated for said panel of CpG sites, wherein a rMRS being equal or higher than the predefined response cut-point indicates that the individual is not able to respond to metformin treatment, and wherein a rMRS being lower than the predefined response cut-point indicates that the individual is able to respond to metformin treatment.

Similarly, in some embodiments of the present disclosure, step c) of comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, comprises or consists of comparing the tMRS with a predefined tolerance cut-point calculated for said panel of CpG sites, wherein a tMRS being equal or higher than the predefined tolerance cut-point indicates that the individual is not able to tolerate metformin treatment, and wherein a tMRS being lower than the predefined response cut-point indicates that the individual is able to tolerate metformin treatment.

The predefined response and tolerance cut-point are calculated based on the best sensitivity and specificity in: i) a ROC curve for metformin response (rMRS) including at least 15, such as at least 20 individuals suffering from T2D which includes both responders and non-responders to metformin; and ii) ii) in a ROC curve for metformin intolerance (tMRS) including at least 15, such as at least 20 individuals suffering from T2D which includes both tolerant and intolerant to metformin.

In one embodiment of the present disclosure, the predefined response cut-point is determined from a Receiver-Operating-Characteristic (ROC) curve for metformin response including at least 100 individuals suffering from T2D, wherein at least a portion of the individuals are responders and at least a portion of the individuals are non-responders to metformin.

In one embodiment of the present disclosure, the predefined tolerance cut-point is determined from a Receiver-Operating-Characteristic (ROC) curve for metformin tolerance including at least 100 individuals suffering from T2D, wherein at least a portion of the individuals are tolerant and at least a portion of the individuals are intolerant to metformin.

Method for treating a patient suffering from type 2 diabetes

One aspect of the present disclosure relates to a method for treating a patient suffering from type 2 diabetes (T2D), the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin, and administering to the responder and tolerant individuals a therapeutically effective amount of a medicament that comprises metformin.

In another aspect, the present disclosure relates to a method for identifying a patient for treatment with an anti-diabetic medicament which does not comprise metformin, wherein said patient suffers from T2D, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin.

The methods of the present disclosure allow to identify individuals that are not able to respond to and/or to tolerate metformin treatment even before a metformin treatment is started, and thus the method of the present disclosure allow to administer an appropriate treatment, which does not comprise metformin, to individuals diagnosed with T2D and who are not able to respond to and/or tolerate metformin. In some embodiments, administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin comprises administering a therapeutically effective amount of a medicament selected from the group consisting of sulfonylureas, pioglitazone, alpha- glucosidase inhibitors, gliptins, Bromocriptine, colesevalam, SGLT2 inhibitors, GLP1 analogues, insulin and/or any other glycemic lowering drugs that can be used as second-line treatments according to the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and/or International Diabetes Federation (IDF).

An individual is able to respond to metformin if the hemoglobin A1c (HbA1c) is reduced to:

- below 53 mmol/mol, if the basal HbAlcwas equal to or higher than 53 mmol/mol, or

- below 48 mmol/mol if the basal HbA1 c was equal to or higher than 48 mmol/mol, upon treating the individual with metformin for in the range of 3 months to 24 months.

An individual is able to respond to metformin if the hemoglobin A1c (HbA1c) is reduced of 8 mmol/mol or more, such as of 11 mmol/mol or more from baseline, upon treating the individual with metformin for in the range of 3 months to 24 months.

An individual is able to respond to metformin if, upon treating the individual with metformin for in the range of 3 months to 24 months, the hemoglobin A1c (HbA1c) is reduced of 0.7% or more, such as of 1% or more from baseline.

An individual is not able to tolerate metformin, if the individual suffers from severe adverse effects when administered with a daily dose of metformin of 500 mg or more, wherein said severe adverse effects are frequently gastrointestinal adverse effects.

Individual

The inventors have shown that it is possible to predict whether or not an individual is or is not able to respond to and/or to tolerate metformin treatment. In particular, they have shown that it is possible to predict whether or not a human is or is not able to respond to and/or to tolerate metformin treatment, wherein said human suffers from or is at risk of developing T2D. In other words, said metformin treatment is preferably metformin treatment of T2D. Thus, in some embodiments of the present disclosure, the individual is a human.

In some embodiments of the present disclosure, the individual is a patient who suffers from or is at risk of developing T2D.ln some embodiments of the present disclosure, the sample is obtained from an individual who suffers from or is at risk of developing T2D.

In some embodiments of the present disclosure, the sample is obtained from an individual who has not been treated with metformin for at least 6 months prior to obtaining a sample, such as for at least 12 months, for example for at least 2 years, such as wherein the individual has never been treated with metformin prior to obtaining the sample.

In some embodiments of the present disclosure, the sample is obtained from a metformin-naive individual.

Array

One aspect of the resent disclosure relates to an array comprising a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The array of the present disclosure thus allows to determine the methylation level of a panel of CpG sites as defined herein and is suitable for use in a method of predicting whether an individual is able to respond to metformin treatment or not and/or tolerate metformin treatment or not.

In some embodiments, the array comprises a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein said consecutive sequence comprises at least one CpG site, and wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein said consecutive sequence comprises at least one CpG site, and wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

In some embodiments, the array comprises a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said consecutive sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises at least one CpG site.

It is known to the person of skills in the art how to make arrays comprising up to 900.000 DNA sequences.

In some embodiments, the array of the present disclosure comprises between 1 and 900.000 DNA sequences, for example between 10 and 900.000 DNA sequences, for example between 50 and 900.000 DNA sequences, for example between 500 and 900.000 DNA sequences, for example between 1000 and 900.000 DNA sequences, for example between 10.000 and 900.000 DNA sequences.

In some embodiments, the array of the present disclosure is fixed to a carrier material.

In some embodiments, one or more DNA sequences comprised in the array of the present disclosure are labelled, such as labelled with a fluorescent moiety.

One aspect of the present disclosure relates to the use of the array of the present disclosure for determining the methylation level of a DNA molecule of an individual.

References

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Chambers JC, Loh M, Lehne B, et al. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study. Lancet Diabetes Endocrinol 2015;3:526-34. Cook MN, Girman CJ, Stein PP, Alexander CM. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with Type 2 diabetes in UK primary care. Diabet Med 2007;24:350-8.

Dayeh T, Volkov P, Salo S, et al. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 2014;10:e1004160.

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Examples

Example 1 - Genome-wide DNA methylation analysis

Study populations

All new diabetics in Scania (ANDIS) started the 1st of January 2008 and it is an ongoing clinical study counting about 18,700 patients in November 2018 (Ahlqvist et al. 2018). ANDIS gives access to baseline information from disease debut and prospective outcome measures e.g. glycemic response.

All new diabetics in Uppsala County (ANDiU) started for inclusion between 2011 and 2016 (http://www.andiu.se/). Anyone who is diagnosed with diabetes according to the WHO classification and resides in the County of Uppsala, Sweden, is eligible to participate. Blood tests (fasting plasma glucose, HbA1c, GAD antibodies, c-peptide, etc.) will appear in the patients’ electronic medical protocol (EMR).

The prospective OPTIMED cohort was launched in 2010 in the framework of the Latvian National Research Programme BIOMEDICINE in collaboration with endocrinologists and family doctors from the leading health care centers in Latvia, ensuring recruitment of newly diagnosed drug naive patients with E11 (ICD-11) diagnosis (fasting blood glucose ³7mmol/l and/or OGTT ³11mmol/l) and follow-up data collection.

Genome-wide DNA methylation analysis

DNA was extracted from whole blood using Gentra Puregene Blood kit (Qiagen,

Hilden, Germany) according to the manufacturer’s instructions. Nucleic acid concentration and purity were assessed by NanoDrop 1000 spectrophotometer (NanoDrop Technologies). Genome-wide DNA methylation analysis of the ANDIS discovery cohort and European replication cohorts (ANDiU + OPTIMED) was carried out at CRC at Lund University Diabetes Centre (LUDC) in Malmo while DNA methylation of the ANDIS replication cohorts was analyzed at SCIBLU genomics facility at Lund University, Sweden. A total of 1000ng or 500ng, respectively, of genomic DNA was bisulfite treated by the EZ DNA methylation kit (Zymo Research, Orange, CA, USA). Genome-wide DNA methylation was analyzed in whole blood using Infinium MethylationEPIC BeadChip microarray (850K array, lllumina, Inc., CA, USA) which interrogates 853,307 CpG sites of which 333,265 CpG sites are located in regulatory regions, 2,880 are non-CpG sites, 59 SNP sites, and covers 99% of all RefSeq genes and 96% of CpG islands. There are 439,562 CpGs from the 450K Infinium array (lllumina) also present on the 850K array (91%).

Samples of bisulfite converted human blood DNA were randomized across the chips and the DNA was amplified, fragmented and hybridized to the BeadChips with the Infinium HD assay methylation protocol. BeadChips were imaged with the lllumina iScan, after single base extension and staining. Raw fluorescence intensities of the scanned images were extracted using GenomeStudio methylation module software for obtaining the raw methylation score for each DNA methylation site. This methylation score is presented as a b-value which is calculated with the following equation: b-value = intensity of the Methylated allele (M) / (intensity of the Unmethylated allele (U) + intensity of the Methylated allele (M) +100).

DNA methylation b-values go from 0 (completely unmethylated) to 1 (completely methylated). All samples passed GenomeStudio quality control steps based on built-in control probes for staining, hybridization, extension and specificity, and showed a high- quality bisulfite conversion efficiency (intensity signal >4,000).

DNA methylation data was then exported from GenomeStudio and subsequently analyzed using Bioconductor. The following probes were filtered away: rs-probes, cross-reactive probes and polymorphic probes based on annotation from McCartney et al. (2016), Y chromosome probes, non-CpG probes as well as individual probes that did not pass our quality control based on a mean detection p-value >0.01. b-values were converted into M-values for further analysis to remove heteroscedasticity in the date distribution. Furthermore, quantile normalization was used to correct for intra-array variation and the data was further background corrected (Du et al. 2008). Next, probe type bias was corrected using BMIQ and then ComBat was used to remove batch effect and center effect in case of the European replication cohort for metformin response. Batch was included in the linear model for the European replication cohort for metformin intolerance. Since whole blood contains multiple cell types, we used the reference-free Houseman method to correct for potential effects of cellular heterogeneity (Houseman et al. 2014). To easier interpret the results biologically, M- values were reconverted into b-values and these were then used when describing the data. Statistical analysis

Statistical analyses were performed using R Statistical Software. The ROC curves and C statistics were generated with the use of the ROCR package for R (www.r- project.org).

To assess if DNA methylation could predict metformin response in the selected case- control cohort and for the replication cohorts for metformin response after about 1 to 1.5 year of metformin therapy, a linear regression model was fit including the following covariates: baseline HbA1c, eGFR, time gap in baseline HbA1c, time gap in baseline methylation. Age, sex and weight were used to calculate eGFR and thereby we correct for these variables in the linear model. Due to multicollinearity, age, sex and weight were not included as individual variables in the linear model. To test if DNA methylation in blood may predict metformin intolerance, a linear regression model was performed with eGFR and time gap in baseline methylation as covariates. DNA methylation was used as the dependent variable in all models. Baseline HbA1c and both time gaps were rank transformed in all models whereas eGFR was log transformed in the ANDIS and European replication cohorts for metformin response and in the European replication cohort for metformin intolerance to achieve normality.

Statistics for selection of individual methylation markers associated with future metformin response or intolerance and risk assessment The pre-specified criterion for taking methylation markers through from the discovery stage to replication testing was FDR below 5% (q<0.05) based on the Benjamini- Hochberg procedure. Next, methylation markers were considered to be associated with metformin response or intolerance if p<0.05 in the replication cohorts with directional consistency. Finally, we performed combined analyses of discovery and replication data using inverse variance fixed meta-analysis and here we required epigenome-wide significance after Bonferroni correction (p<6.1 ^c 10-8, 0.05/816000). The risk of not responding or not tolerating metformin based on significant individual methylation markers was assessed by logistic regression models and presented with odds ratios (OR).

Calculation of methylation risk scores (MRS) to discriminate metformin response or intolerance

To integrate epigenetic information across CpG sites in each cohort, we calculated weighted Methylation Risk Scores (MRS). We required genome-wide significance in the meta-analyses for individual methylation markers to be included in the MRS. The scores were calculated as the sum of standardized methylation values at each site significantly associated with metformin response or intolerance, weighted by CpG- specific effect size (21). The effect size was estimated using logistic regression models where the binary outcome was either response to metformin (1 non-responder, 0 responder) or intolerance to metformin (1 intolerant, 0 tolerant) with CpG sites as the predictors, adjusting for baseline HbA1c, eGFR, and time gaps for metformin response and for eGFR and time methylation gap for metformin intolerance. Thus, the weight (effect size) for each CpG site used to calculate the MRS was its beta-coefficient.

We next evaluated whether MRS could discriminate between glycemic responders and non-responders, as well as, between tolerant and intolerant subjects to metformin. To validate our findings and control for overfitting, we performed three evaluations, calculating the MRS using CpG-specific effect sizes (beta-coefficients from the logistic models) estimated from one cohort and evaluating it in the other two using ROC curves and the AUC. Specifically, we used the CpG-specific effect sizes (beta-coefficients from the logistic models) estimated from the ANDIS discovery cohort to calculate and evaluate the MRS in the two replication cohorts (ANDIS and European replication cohorts). Next, we used CpG-specific effect sizes estimated from the ANDIS replication cohort to calculate and evaluate these new MRS in the ANDIS discovery cohort and the European replication cohort. Finally, we used CpG-specific effect sizes estimated from the European replication cohort to calculate and evaluate these new MRS in the ANDIS discovery cohort and the ANDIS replication cohort.

Example 2 - Results relative to response to metformin treatment Summary of the study

We carried out the first pharmacoepigenetic study for diabetes to identify blood-based epigenetic biomarkers that predict metformin response in drug-naive T2D patients. We assessed if methylation before taking metformin i.e. epigenetic biomarkers could discriminate between non-responders and responders to metformin in patients that fulfil these criteria, which would be clinically useful.

Methodology

Genome-wide DNA methylation analysis was conducted as described in Example 1 herein and the statistical analysis of the obtained data was conducted as outlined in Example 1 herein. Results

We selected two well-defined groups of 26 glycemic responders (HbA1c after about 1.5 years < 6.5-7% or <48-53 mmol/mol and reduction in HbA1c³1% or³11 mmol/mol) and 21 non-responders (HbA1c after about 1.5 years ³ 6.5-7% or ³48-53 mmol/mol and reduction in HbA1c <1% or <11 mmol/mol) to metformin treatment from the discovery cohort for metformin response, and tested whether baseline methylation may be used as a biomarker to discriminate metformin responders from non-responders. These two groups were balanced for baseline HbA1c, eGFR, age, sex and BMI. After performing the linear regression model including the dichotomous response variable instead of AHbAlc, 7,973 sites showed significant differences in methylation between glycemic responders and non-responders (FDR< 5%). DNA methylation of 7,916 sites (List 1 below) remained significant when adjusting for cell composition (Houseman et al.

2014).

We then performed replication testing of sites significantly associated with glycemic response (List 1 below) using two independent cohorts of 48 responders and 39 non responders selected from the ANDIS replication cohort for metformin response as well as 47 responders and 31 non-responders from the European replication cohort for metformin response. Methylation of 33 sites was associated with glycemic metformin response in the discovery cohort (FDR<0.05) and in the two replication cohorts (p<0.05, Table S10). In a combined meta-analysis of the discovery and replication data, 11 out of these 33 methylation markers reached epigenome-wide significance after Bonferroni correction (p<6.1 ^c 10-8, 0.05/816000) for the association with glycemic metformin response. Next, we proceeded to generate combined weighted methylation risk scores (MRS) based on these 11 sites (Table A) associated with metformin response in both the discovery and the two replication cohorts, to examine if these scores could better discriminate responders from non-responders to metformin. First, using the CpG-specific effect sizes (beta-coefficients from logistic models) from the ANDIS discovery cohort we calculated and evaluated the MRS in the two replication cohorts, and were able to adequately discriminate metformin responders from non-responders. ROC curves were then generated describing the extent to which these MRSs discriminate between groups of metformin responders and non responders. Here, the area under the curve (AUC) was 0.80 for the ANDIS replication cohort and 0.89 for the European replication cohort. We next used the CpG-specific effect sizes from the ANDIS replication cohort or the European replication cohort to calculate and evaluate MRS in the other two cohorts. These MRS also allowed adequate discrimination of metformin responders and non-responders; the AUCs ranged between 0.80-0.98. In addition, these MRS explained 68-73% in the ANDIS discovery cohort, 19-20% in the ANDIS replication cohort and 38-42% in the European replication cohorts (based on R-squared McFadden) of the variation in glycemic response to metformin in these cohorts. All these data support the notion that blood- based epigenetic biomarkers may be used for stratification of metformin response in drug-naive T2D patients. Table A. CpG sites with DNA methylation associated with response to metformin in the ANDIS discovery cohort and in both the ANDIS and the European replication cohorts for metformin response, which were used for the methylation risk score. The CpG sites and nucleotide sequences are defined by the lllumina Probe ID based on genome build 37/ hg19 assembly. Each probe ID number listed corresponds to the DNA sequence corresponding to the lllumina MethylationEPIC Beadchip target id annotation. A q-value <0.05 was the first criteria to select the CpG sites associated with response/tolerance since it is more restrictive than p-value. Q-value was therefore only measured in the discovery cohort.

Table A. Continuation.

ANDIS replication cohort for metformin response (n=87)

Example 3 - Results relative to tolerance of metformin treatment

Summary of the study We evaluated if methylation in blood taken before treatment could discriminate those T2D subjects who had intolerable adverse effects (metformin-intolerant) and those who tolerated metformin (metformin-tolerant). Methylation of about 850,000 sites was analyzed in blood of the discovery and replication cohorts for metformin intolerance including drug-naive T2D subjects.

Methodology

Genome-wide DNA methylation analysis was conducted as described in Example 1 herein and the statistical analysis of the obtained data was conducted as outlined in example 1 herein.

Results

We evaluated if methylation in blood taken before treatment could discriminate those T2D subjects who had intolerable side effects (metformin-intolerant) and those who tolerated metformin (metformin-tolerant). Methylation of about 850000 sites was analyzed in blood of the discovery and replication cohorts for metformin intolerance including drug-naive T2D subjects. To test whether methylation of individual sites predicts metformin intolerance, a linear model was performed adjusting for eGFR and time gap in baseline methylation. DNA methylation of 12,579 sites was associated with intolerable adverse effects in 83 T2D subjects receiving metformin (FDR<5%). DNA methylation of 9,676 CpG sites (List 2) remained significant after adjusting for cell composition (Houseman et al. 2014). Interestingly, most sites showed higher methylation (7,865 CpGs out of 9,676) in metformin-intolerant versus -tolerant patients.

We next performed replication testing of sites significantly associated with metformin intolerance (List 2 below) in two independent cohorts of 37 tolerant and 11 intolerant patients to metformin, the ANDIS replication cohort for metformin intolerance and 15 tolerant and 5 intolerant patients to metformin, the European replication cohort for metformin intolerance.

Overall, 7 methylation markers were associated with metformin intolerance in the discovery cohort (FDR<0.05) and in both two replication cohorts (p<0.05). In a combined meta-analysis of the discovery and replication data, 4 out of these 7 methylation markers reached epigenome-wide significance after Bonferroni correction (p<6.1 x 10-8, 0.05/816000) for the association with metformin intolerance. We then generated a combined MRS (Wahl et al. 2017) based on these 4 CpG sites (Table B), to assess if these scores could discriminate metformin tolerant from intolerant drug- naive T2D subjects. First, using the CpG-specific effect sizes (beta-coefficients from logistic models) from the ANDIS discovery cohort, we calculated and evaluated MRS in the two replication cohorts, and found a very good separation between metformin tolerant and intolerant subjects. We then generated ROC curves using these MRS and having metformin intolerance as outcome. Here, the AUC was 0.94 for the ANDIS replication cohort and 0.87 for the European replication cohort. We next used CpG- specific effect sizes from the ANDIS replication cohort or the European replication cohort to calculate and evaluate MRS in the other two cohorts. These MRS did also give a good separation between metformin intolerant and tolerant subjects, and AUCs that ranged between 0.85-0.93, supporting further development of epigenetic biomarkers that may predict metformin intolerance. In addition, these MRS explained 50-51% in the ANDIS discovery cohort, 51-54% in the ANDIS replication cohort and 32-33% in the European replication cohorts (based on R-squared McFadden) of the variation in metformin intolerance in these cohorts.

Table B. CpG sites with DNA methylation associated with intolerance to metformin in the discovery cohort and in both the ANDIS and the European replication cohorts for metformin intolerance, which were used for the methylation risk score. The CpG sites and nucleotide sequences are defined by the lllumina Probe ID based on genome build

37/ hg19 assembly. Each probe ID number listed correspond to the DNA sequence corresponding to the lllumina MethylationEPIC Beadchip target id annotation.

Table B. Continuation.

Table B. Continuation.

Table B. Continuation

Example 4 - Sequences

DNA sequence/CpG site (lllumina Probe ID based on genome build 37/hg19):

SEQ ID NO: 2: DNA sequence/CpG site (lllumina Probe ID based on genome build

37/hg19):

Example 5 - List 1 and List 2

“List 1” is a list of the target ID number of the 7,916 CpG sites identified as significant for DNA methylation predicting glycemic response to metformin treatment. “List 2” is a list of the target ID number of the 9,676 CpG sites identified as significant for DNA methylation predicting tolerance to metformin treatment. Each target ID number listed in “List 1 and “List 2” correspond to the CpG sites/DNA sequence corresponding to the lllumina MethylationEPIC Beadchip target ID annotation which has used genome reference build 37/hg19 assembly.

List 1 "response_7,916 sites"

(G RCh37/hg 19) . cg20256649, cg01427362, eg 13810707, cg00301033, eg 17065020, cg22 188627, cg11038627, cg20201929, cg26096887,cg08105471 , eg 12004003, eg 17872357, cg24159142, cg07394411,cg14847588,cg03354616,cg24662247,cg24389597,cg07126 469, cg17121907, cg13420975, cg02937751 ,cg09164206, cg14214913, cg25005374,cg2 4206781 , eg 10662995, cg26257240,cg09800748,cg06721031 , cg00786408, eg 10442735 ,cg22586493,cg13446918, cg04068975,cg15054536, cg13041355,cg23081193,cg0574 6092 , cg07114151, cg20697575, cg23190146, eg 19069952, cg07349094, eg 12937337, eg 01266880,cg05703749,cg18595515, cg11194440, eg 17025484,cg17868893, cg2223366 7, cg21686851 , cg10630129, cg03606931 ,cg21579920, cg04706200,cg19894498, cg042 91404, cg02931650,cg01358444, cg12182940, cg25887715, cg12782408,cg19016768, c g01062564, cg04898167, cg05235844,cg23892924,cg05337549,cg09361461,cg079579 53, cg13412659,cg17328472, cg15305643, cg27055759,cg09468177, cg13392953, cg13 183211,cg26611184, cg11584519, cg24289219, eg 14968371 ,cg02430990, eg 15985891 , cg12260808, cg24754199, cg24280483,cg22579631,cg27284428,cg27342801 ,cg21358 741 ,cg14007156,cg13459812,cg09312564,cg22012759,cg24965026,cg05746500,cg0 5339114, eg 14344147, eg 10772991 , eg 17312152, eg 16236626, cg26968187, cg02105087 , cg07346604, eg 10057033, eg 11727198, eg 17413625, cg04578029, cg09692952, eg 1166 2242,cg09181008,cg08366931 ,cg14918119,cg08295400,cg25013443, cg10733196, eg 19888246, cg01525244, cg10208319, cg13620814, cg02764745,cg20745910, eg 1447044 8, cg09003678,cg05583033, eg 11451801 ,cg15597140,cg06095814,cg06077359,cg125 70256, cg07620621 , eg 17768039, cg01307529, cg27609550,cg05959346, cg15052214, c g22392793,cg03014264, cg11672225, cg05336056,cg25565504,cg08650900,cg215754 65, cg00653081 , cg09641663, eg01173794, cg23317115, cg22842444, cg25899135, cg25 057591,cg00904612, cg13252104, cg13636533, eg 13696550, cg08764421 ,cg 13276631 , cg06139720, cg07622648,cg26182253, cg12550020, cg14527441, cg01170387, cg07926 620, cg13254203, cg16721427,cg25974365,cg06530633,cg25989392,cg20461275,cg0 4434491 , cg21650076, cg02138813, eg 15750705, cg24245297, eg 10305409, eg 13294185 ,cg14600648, cg27597325,cg09761915, cg13027851 , eg 17096328, eg 15838553, eg 1791 2633, cg25880347, cg03485311 , cg22364932 ,cg00833487,cg 18139426, cg02567750, eg 03700457, cg03658066, cg14614792, cg10062298, eg 18880946, cg09009869, eg 1261745

6, cg16181099, cg12297970, cg19665756, cg19467508, cg14770351 ,cg03395846,cg207 25021,cg21006536, cg02951847, cg05235016, cg23551827, cg20278075,cg01066179, c g 13252516 , cg21890813 , cg03796943 , cg21664256 , eg 16648265, cg00434151 , eg 198062 92 , eg 10625354, cg06222885, cg00127991 , cg21928427, cg03790967, eg 17440386, cg20 880080, eg01688211 , eg 14938730, eg 18539608, cg01460882 ,cg02601200,cg00883712 , eg 14432322, cg06605685 , cg22156046 , eg 13087557 , eg 17666994 , eg 14446494 , eg 17671 177,cg24475731 ,cg00750169,cg06284231 ,cg08551333,cg07258627,cg25021532,cg0 3515927, cg07962360,cg14325813, cg18596369, cg20963529,cg01354137, cg22846109 , cg01931742, cg12426325, cg16577533, cg14025606, cg21191574, cg20386759,cg1582 4449, cg00255726, cg05734020, eg 14829953, cg20472032, cg06960356, cg24001985, eg 09483734, cg25828097, eg 13175786, eg 15639330, eg 17481411 ,cg22100868, cg0795039

7, cg02423285, cg25228282,cg01793178, cg18685639, cg24785606,cg26129675,cg027 69522, eg 16798247, cg04010586, cg16018488, cg02400735,cg03191943, cg14173006, c g26718929, cg03899098,cg10884975, cg18769770, cg02121517, eg 18527276, eg 150732 48, eg 19505184, eg01327965, eg 10912806, eg 18986305, eg01777672, cg07684587, eg 13 854860, cg20598211 , eg 11369599, eg 12742501 , eg 13808626, eg 14664875, eg 10617058, cg20975835,cg23239637,cg08583780,cg21695906, cg23880855,cg00080252 , eg 18727 742, cg02271180, cg11427880, cg05660308,cg02908756,cg25599473,cg08456852,cg2 7184729, cg06830971 ,cg11708694, cg19991558,cg27260624,cg21112452, cg03104937 , cg02067222 ,cg03493932, cg08366534, cg09850248, eg 13336249, eg 12279119, eg 1215 0131 ,cg11874613,cg12174129,cg16048915,cg01173733, cg01623639, cg22643740, eg 05533706, cg13077796, cg12417385, cg13848056, cg25955365, eg 11672710,cg0013311 6, cg15697652, cg23820245,cg06060185, cg07787248,cg04887210,cg06536608,cg067 38867, cg04145065 , eg 14122403 , cg24223733 , eg 15209738 , eg 18948646 , cg26713664, c g27615363, cg04453624,cg09075515, cg18118535, cg24405068,cg10408467, cg001490 95, eg 16847107, eg 19178853, egOO019351 , eg 11896246, cg00902691 , eg 11579758, eg01 214376, cg20319147, cg03428703 , cg04594399 , eg 10176692 , eg 16703934 , cg04762004 , cg14288066, cg22480441, cg12133731, cg11718135, cg16818286, cg05338083,cg02285 278, cg08200419, cg20917946, cg15658978, cg14463305, cg18140479, cg02953897,cg1 9478426, eg 16782184, cg23460663, eg 16319140, eg 15079869, cg07693631, eg 10392817 , cg08951301 , cg06787422, eg 14831128, cg03386320, eg 11673594, eg 14030785, eg 1997 6410, cg00508950, cg04369443, cg08998953, eg 17971841, cg04519626, cg02031712, eg 08468375, cg20348189, cg25347698, cg27525295, cg22670759,cg 18823832 ,cg0499021 0,cg13485939, cg14061359, cg08721599, cg25934944,cg18218829, cg05717123, cg066 86029, eg 19690306, cg08174206, eg 17087741 ,cg01221209,cg05640189,cg20889930,c g14353278,cg06501070,cg09607047,cg26684131 ,cg05605564,cg00153082,cg062927 09, cg18454299, cg23130385, cg16757886, cg03138560, cg21025551, cg25278456,cg05 468212, cg08620804, eg 17002156, cg01695620, cg04289959,cg20754305, eg 13250203 cg06791979, cg04923627,cg09069073,cg04474190, cg10054838, cg26381175, cg22675 550,cg01204513,cg26336235,cg19171307,cg21546915,cg05506448,cg08316558,cg2 3570618, cg24344404 , eg 15102057, cg09023351 , eg 11158613 , eg 16880210 , cg26646203 , cg07864906, cg07716322, eg 10383380, cg04773977, cg05964667, cg22416376, eg 1713 2963, cg03738438, eg 13721560, eg 19399653, eg01744926, cg24285545, cg07343885, eg 17282428, eg 18096787, cg07242776, eg 10684985, eg 15664596, cg08829299, cg2283440 9, cg12687181 ,cg11215901 ,cg03690528,cg06205364,cg22498223,cg08462952,cg183 43870, cg26257641 , eg 15069620, cg07715138, cg26847409,cg09261791 ,cg17475733, c g22608492,cg14288106,cg02882018,cg25323690,cg22717328,cg06500727,cg104764 73,cg10309178,cg15469171 ,cg12141064,cg13082318,cg03225671 ,cg22969400,cg08 288545, cg24251145, cg26996760,cg20468476,cg11733155, eg 10582929, cg05011467, cg10983470, cg07007080,cg07135629, cg10617617, cg08238539,cg17258607, cg12901 910, cg16139227, cg18551548, cg08958168, cg08964099,cg05615439, cg02896317, cg1 0305469, cg24045875, eg 16412142, eg 19029700, cg04717777, cg02709068, cg07748807 , cg26205698,cg04442311 , cg09270225, cg21187535, eg 12580461 , cg05556461 , eg 1670 4073, eg 12276329, cg23678322, cg02067801 , cg07588194, eg 15098410, cg05510339, eg 09148630, eg 16949623, cg09343360, eg01738854, cg22491193, cg24682776,cg0649328 9, eg 14800868 , cg24473616 , eg 16483096 , eg 10021749 , eg 10582808 , cg22220796 , cg062 54588, cg07063274,cg07537605, eg 16677367, cg22102964, cg09902029,cg09706324,c g18121601, cg06360465,cg03761346, cg03660538,cg15629006, cg13627714, cg237858 59, cg15556873, cg24828603,cg02684740,cg05761813, eg 17536586, cg05090553,cg08 720478, cg26764579, eg 10740488, cg02138348, cg05035332 , eg 13455774, cg22298524, cg22677757, cg04028140,cg18470307, cg05972770,cg13569779, cg24755006,cg15426 660, cg13440393, cg27313776, cg16888293, cg04267953,cg10592944, cg04189679, egO 9577317, eg 16000321 , eg 18423391 , cg00328381 , cg02245875, cg03935044, eg 11890753 , eg 14810242, eg 18757565, eg 19194753, cg25751787, eg 13288621 , eg 14678550, eg 1716 7045, cg00137264, cg03227481,cg03916756,cg14218747, cg21751047, cg25370180, eg 26585779, cg12722589,cg18391972,cg20147224,cg23398323,cg00010506,cg1516121 8, cg17356750, cg01352705, cg23116684, cg03648895,cg07230698, cg11798489, cg184 22853, eg 19465484, cg26287827,cg08746611 ,cg14907310,cg26120489,cg01216623,c g02742294,cg03267321 ,cg07176294, cg19915007, cg24295487,cg25423732,cg256877 77,cg03743413,cg04529611,cg13986618,cg20267897,cg06338016,cg05474370,cg06 657975,cg20284096,cg01923616,cg02018921,cg02561451 ,cg11130515, cg19247005, cg06844864,cg26920757,cg12170514, cg14095607,cg14354418, cg14747825, cg16534 698,cg20899615,cg26287546,cg27091865,cg02867046,cg04667945,cg27125645,cg0 0752577, eg01143454, eg01310881, cg06322639, cg24721647, cg25515269, cg03275084 , eg 14134616, eg 16377998, cg24681901 , eg 13926833, eg 16780652 , cg03826578, eg 1048 6069, cg11079255, cg15900624, cg22746765,cg01013171 , eg 16607799, cg01642246, eg 04726653, cg06194050, cg06939307,cg07039885, eg 17228073, cg01948218, cg0659394 0, cg07516148, cg14057435, cg14632180, cg18240186, cg23002384,cg10730816, cg173 44749, eg 19659271 ,cg26975787, cg04515132, eg 13663572, eg 14864302, eg 15294934, c g26209899,cg26973354,cg02168806,cg03960952,cg11114579, cg16192774,cg236150 12,cg13771612,cg01357846,cg01894192,cg06953270,cg00929878,cg06641624,cg01 070242, cg09027658,cg10473842, cg22524864,cg02584802,cg05365729,cg07823305, eg 14320593, eg 17766699, cg21419489, cg26595336 , cg04591228 , cg06197356 , eg 16561 911,cg02244697, cg20289897,cg21528393, eg 11749420, eg 19437852, cg22344617, cg2 4337829, cg06443772, cg09295300, cg08416661, cg09907968, eg 10382346, cg05410948 ,cg09235031,cg13026838, cg00541421, cg08539752, cg12495731 , cg14923188, cg2271 8431 , cg02143656, cg07130621 , eg 14857368, eg 16573044, cg24959793, cg25782835, eg 00379002, cg01902584, cg03125765, cg09786333, eg 14534327, cg22309086,cg0002636

3, cg09462274, cg14287089, cg17895698, cg18450582, cg04055539,cg04392554,cg096 14218, eg 14959425, cg26531371 ,cg02307288,cg07533515,cg16441943,cg21513991,c g23434264,cg24969222,cg25465603,cg25493454,cg03147470,cg02367655,cg029150 52 , cg22867315, cg07538364, cg08993197, eg 16568918, cg24596244, cg08483501 , cg09 830747, eg 12693595, eg 16377351 , cg22003804, cg00489066, eg 14918650, eg 17533847, eg 19274676, cg27653595, eg 10723906, eg 11716258, cg24529508,cg02844324, eg 13634 653, eg 15563735 , cg21516670 , eg 16699843 , cg22062306 , eg 13680613 , eg 17526323 , cg2 6058161 ,cg12378615,cg20131941 ,cg04549489,cg15212570,cg20895818,cg04963177 , cg05630607,cg09152548, cg09635874, eg 11380366, eg 14741811 , eg 13864356, cg2537 0756, eg 10410970, eg01029047, cg07967246, cg02710813, cg03085618, cg06359077, eg 06664147, cg23092576,cg00545918, cg06940690, eg 13290643, eg 14888407, eg 1833155

4,cg27523417,cg03028472,cg04323785,cg13131840,cg14368297,cg16487399,cg237 04107, cg00268735,cg02556497, eg 12635841 , eg 16685327, cg25287372,cg01527581, c g07520687, cg10850522, cg11552873, cg14284248, cg16684290, cg24511062, cg266299 69, cg02291472, cg22711621, cg06449313, cg00172794, cg14974262, cg16372786, cg17 389218, cg17795629, cg17945140,cg26062472,cg08227227,cg10141839, cg22253401 , cg24207410,cg25853624,cg12006206,cg00121868,cg05237114,cg04837902,cg09214 369, eg 10006969 , eg 10047115 , eg 19249874 , cg20046743 , cg05823768 , eg 17499324 , eg 1 8199386, cg21828027, cg23104549, cg26300760,cg20778776,cg01673301 ,cg08870893 , eg 10125865, eg 10484120, eg 18355176, eg 19751300,cg27360206,cg05999769,cg1137 6570,cg25151270,cg03524219,cg17151054, cg17439967, cg18653750, cg10143323, eg 20398378, cg26766364,cg00001791, cg06300880,cg07340660, eg 13545926, eg 1745521 2, cg21449256, cg27212760, cg27539405,cg07377290,cg16207671 , cg16594958,cg169 50129,cg18484870,cg21152077, cg21480319, cg24356707,cg02829992,cg20228985,c g04364060,cg11954852, cg14247126, cg21872822, cg08681365, cg14746369, cg171787 77, eg 18865127, cg23725024, cg26647771 , cg21080034, cg21198875, cg22104725, cg22 935317, cg26683025,cg06168007, cg13510584, cg20112453, cg02957086,cg05068449, eg 19680048, eg01099024, eg 10931539, cg22481950, cg23251056,cg05607222 ,cg09808 211,cg00081104, cg04796986,cg09997530,cg26242772, cg16416383, cg00172614, egO 0844202 , cg06103657 , eg 13680696 , eg 14735587, eg 19882179, eg 17991812 , eg 19306368 , cg21997510, cg24983998, cg05286615, eg 12433623, eg 14219059, cg00986053, cg0572 3107, cg06276981,cg20395773,cg09193751, cg14144977, cg02085805,cg18126791, eg 26919256, cg13714938,cg19260967, cg07665458,cg25127214, cg02190897, cg0812215 6,cg14014665,cg24091698,cg27417798,cg05086873,cg12847382,cg14884347,cg223 53755, cg24479928,cg02354388,cg11106802, cg00596521 ,cg01473228,cg03181514,c g08048970,cg10668512,cg11261403, cg17556976,cg07292334,cg10411146, cg104803 28, cg18897026, cg03027437,cg03741118, cg11354699, cg15225779, cg01668383, cg04 962528, cg24699857,cg00335908,cg00475745,cg03204140, cg21034311 ,cg01549115, cg03900856, cg07468830, cg10261205, cg15749661, cg06921803, cg11256364, cg13810 113, cg13876853, cg27626037,cg00418087, cg00594880,cg06943544,cg10633779, cg2 1570866, cg06106653, eg 12528609, cg26336078, cg27333099, cg05684054, cg06906980 , cg08343540, cg08855742, cg00035583, cg00040663, eg01618697, eg 12825303, eg 1299 4911 , eg 13354969, cg20249492, cg21208580, eg 10841124, eg 11714554, eg 16170467, eg 22883502, cg25049631,cg00625752,cg00782223,cg08392212, cg23298829,cg2698148 4,cg03693486,cg05260733,cg07879942,cg09446247,cg15081334,cg04797958,cg129 30338, cg23549571 ,cg26522786,cg01170247, cg04825263,cg10271422, cg24614741,c g00874694, cg03420245,cg15613148, cg21702128, cg05422920,cg13951624, cg172768 63, eg 17443440, cg21047884, eg01479190, cg03166732, eg 17438468, cg27627570, eg 14 543433, cg26025944, cg08418635, eg 15232654, cg20347626,cg05964212 ,cg07371029, cg13396619,cg15791180, cg22191376, cg02018010, cg10328471 , cg13855364, cg15606 745, eg 18449050, eg 19892433, cg25653802,cg27095776,cg06827850,cg11673850, cg2 6958078, cg27274718, eg01606576, cg02835343, cg03525786, cg03649047, eg 14691808 , eg 16010122, eg 16681157, eg 19012958, eg 19764588, eg 15635024, cg22078460, cg2694 5226, cg03196115, cg05243747,cg21006542, cg23469522,cg24428565,cg05206802, eg 13776620, cg20847586, cg25029657, cg25061146, cg05880385,cg06723012 ,cg0818807 6,cg12256233,cg27205898,cg05816924,cg05873865,cg14476845,cg22538355,cg264 70958, cg05524962, eg 11097777, eg 14477768, cg22598432,cg03387256,cg04467034,c g12951726,cg15370783,cg25970447,cg13825977,cg19835227,cg20322564,cg242740 90, cg00049709, eg 16900740, cg26952572, cg00560558, eg01616906, cg04522633, eg 19 240552, cg22791478, cg25924761,cg18273593, cg21149302, cg26617298, cg03619352, cg09113477, cg18087023, cg00799637,cg07985309,cg08329931 ,cg00377953,cg15001 904, cg24240534,cg12336209, cg17115258, cg20324502,cg23113308, cg25065836,cg0 1158367, cg06018029, cg07405919, eg 14100242, cg23491387, eg 13525170, eg 15433159 ,cg00063503,cg05983127,cg08911133, cg16976508, cg19638060, cg22295983,cg0183 9742,cg01525194,cg07140366,cg13922745,cg26277069,cg07130826,cg13425294, eg 16531181, cg25261208,cg00509120,cg03417466,cg15997127,cg17301506,cg0115244 1, cg13019512, cg14322040, cg14020285, cg14316148, cg16092904, cg20176093, cg032 21596, cg12049067,cg00939649,cg02274974,cg09675743,cg12716445,cg22028624,c g22850508,cg24656125, cg07531268, cg17063742, cg22436253,cg24810741, cg263448 59, cg03015610, cg04194677, cg05877788, eg 12684767, eg 14862502, eg 18656667, cg03 542197,cg06804411,cg24701934, cg02746852,cg09612929, cg23001084, cg27188891 , cg27569525, cg03529510, cg03990551 , cg06970471 , eg 10813240 , eg 13992360 , cg20077 718,cg25266170,cg02675173,cg04865575,cg17273961 ,cg25651662,cg01555330, egO 3427619, eg 13028768, eg 14394678, eg 10488314, eg 10886901 , cg23509574, cg25353026 , eg 16639307, cg02986643, eg 10590376, eg 10721706, eg 19932984, cg06935361 , cg0982 9263 , cg26341661, cg03947651 , eg 16466899 , eg 15970686 , eg 18365142 , cg25524233, eg 05977900, cg08670367,cg24370375,cg00299257,cg10766866,cg19164175,cg2085109 7, cg20927731 , cg19145240, cg26073181 ,cg05652933,cg23824502,cg01077058, cg219 10736,cg07287107, eg 10269948, cg00250454,cg07242890,cg07056507,cg09474714,c g12849710,cg00379266,cg09019526,cg17739260,cg24507384,cg20703523,cg271969 25, eg01020413, cg04920474, cg07775433, cg23666833, cg21825586, cg04105876, cg23 415712,cg01395265,cg25980539,cg02424637,cg12508795,cg02517871 , eg 10805565, cg20823922,cg02347367,cg23071623,cg26484667,cg02951883,cg27489994,cg01878 839, cg02208820,cg26610808, cg08384819, cg10075828, cg13074686, cg18898185, cg2 0776758, cg23652442,cg01228854,cg01294836,cg13104335, cg21154985, cg23852531 ,cg26011900,cg06532493,cg25663170,cg10379517,cg12393716,cg20424036,cg0012 7037, cg00325528, cg04141487, cg20584925, cg26488256, eg01655210, cg05471295, eg 14809121, cg17359407, cg16672277, cg19939130, cg01912838, cg03427120, cg0898498 5, eg 11588566, eg 12319618, eg 12940886, cg23384017, cg04175885, cg04284245,cg011 89168, cg08823287,cg12784272, cg12940040, cg08593626,cg08694418, cg17172507, c g19753650, cg19952228, cg00767544, cg12271223, cg15481754, cg00263759,cg122621 81 , cg00590134, eg01780490, cg06484065, eg 10433625, eg 19880074, cg20798726, cg21 813377, cg04701785, cg09853514, cg12406628, cg00216200, cg17081684, cg22028284, cg23689129,cg04439113,cg26661718,cg00247830,cg04192014,cg17871510,cg06794 398, cg15133444, cg03055693, cg16481469, cg25829488,cg06658146, cg15218589, egO 0882709, eg 11477847, eg 18539768, eg 19964927, cg23083516, cg00503537, cg02057621 , cg02174225, cg02609338, eg 19165652, cg25271479, eg 19278098, eg01837272, eg 1845 4774, eg 18679976, cg23683501 , cg07381436, cg26720909, cg03863692, cg08413347, eg 17004737, cg06398881,cg15590338, cg05062935,cg09289181 , eg 12441680, eg 1989804 3,cg20228289,cg24854963,cg10831324, cg15076218, cg16635863, cg08025954,cg107 86481, eg 13860980, eg 15922821 ,cg 19752551 ,cg21215149,cg02498382,cg09564749,c g10371412, cg26246467,cg06077949,cg08457872,cg08476806,cg09907658,cg141463 78,cg24789424,cg02854730,cg24137511 ,cg03455716,cg13451597, eg 15223345, cg27 260418, cg05648367 , eg 19680388 , cg20485411 , eg 12664730 , eg 17403084 , eg 18550312 , cg22004955,cg24433530,cg06575843,cg23297661,cg00412805, cg09532261 ,cg13685 273, cg17027626, cg17280284, cg18895867, cg20249949,cg02291664,cg05588757,cg1 0777128,cg14220502,cg 15141853, cg25177305, cg09443182,cg11326613,cg 15625573 , cg02696346, cg02794962 , eg 11977691 , eg 13920100, eg 14990438, cg25217053, cg0837 8790, eg 12725590, eg 16623922, cg27252406, eg 16466690, cg25885978, cg02513946, eg 05496603, cg10503854, cg21504624, cg23100668, eg 14303079, eg 19093260, cg2561517 4, cg00174986, cg01016203, cg02948188, cg10233539, cg19501502, cg19710386, cg045 06625, cg22703115, cg26436821 , cg08047417, eg 10561983, eg 16605743, cg17204018, c g17295864, cg22164539, cg09038676, cg16384189, cg26079073,cg08870845,cg218987 34, cg05850431,cg11727132, eg 15966441 ,cg23497879,cg00382230,cg06460333,cg22 999830, cg24921795, cg01945501, cg02075590,cg02154914, cg09788125, cg12173462, cg21213571, cg22226342,cg01293164,cg16278329,cg26192503, cg06126149, cg10465 202, cg17151604, cg07640296,cg19053142, cg24826236,cg04241095, cg24280851 ,cg0 7263960, eg 14673729, cg20796357,cg21647932, cg26261298, eg 13409997, cg21429492 , cg23923425,cg02863817, cg07581739, eg01113412, cg04036009, cg04249634, eg 1167 7430, cg18296495, cg22966316, cg26654702,cg13431902, cg23142004, cg00961222, eg 01781118,cg08550615,cg13134514,cg05576925,cg10194632, cg17011181 ,cg2121707 0,cg00650856,cg02360340, cg13956954, cg15346493, cg20587889,cg12600550,cg254 53841, cg24876012,cg24153085,cg24880818,cg04387788,cg07874294,cg01051701,c g22197934, cg05406954, cg12819470, cg13184841 , cg13237147, cg15411871, cg225725 60, cg27521151, cg07265786, cg23871952, cg04159908, cg06018739, cg08858787, cg09 886009, cg11806172, cg08039193,cg20170147,cg24012157,cg07588442,cg08800326, cg12953827, cg18276368, cg07538849,cg07732421,cg19785559, cg01306579, cg03338 123, cg04211829, cg06853506,cg11227598, cg16085094, cg22386965,cg06409665,cg1 9694099, cg25007572, cg02438408, cg05528782, cg25981801 , eg 15511785, cg07121155 , eg 11967074, eg01704246, cg03139475, cg06501407, cg09796911 , cg20288916, cg2126 2120, cg24854606, eg 10034572, cg21128319, cg22788080, eg 13210566, eg 16421090, eg 24898643, cg26770051 , eg01656421 , cg06247666, cg09780150, eg 10892268 , cg2661443 6, cg00556715, cg01733568, cg04100395, cg02540212, cg03226571 ,cg21624165, cg226 63895, cg22737478,cg24049838,cg25814743, cg01316047, cg01911745, cg12606401, c g25964067,cg06811801 ,cg08231949,cg04699394,cg08483912,cg14012362,cg144338 47, cg27602981 , cg00380408, cg03197758, cg09915984, cg00882832, cg03885119, cg08 413381, cg08527065, cg09892426, cg08077846, cg08472142 ,cg22246344,cg08182162, cg08596591, cg21973719, cg02879784,cg24694743, cg13337958, cg16055185, cg21261 403, cg00710955, cg02089787,cg00177923, cg01229973, cg06008302,cg26398332,cg2 7089352, eg 16318688, cg21370976, eg 10096536, eg 14796679, cg05255580, cg08834429 , cg03090734,cg23813270, cg02155957, eg 19921389, eg 16334849, cg08890080, eg 1109 1615, cg06312696,cg16090912, cg17770541, cg24792113, cg01727585, cg09689279, eg 17532626, cg22960185, cg02760912, cg12955459, eg 19694945, eg 15622170, eg 1932786 3,cg26791197, cg00851299,cg03080605,cg03774957,cg16711837, eg 19099034, cg006 01124,cg13464117, cg18599996, cg00545462,cg06183267, cg15312290, cg05819188, c g14216694,cg15406637,cg16528372,cg08300343,cg22611089,cg00923719,cg041003 86, cg06124683, cg13558452, cg21709842, cg14425869, cg26199552, cg04892724,cg05 949268, cg06618958, cg08565176, cg24851364, cg27129984, cg01575096,cg11807600, cg01542384, cg09314225, cg09318453, cg18133076, cg19964454, cg02620694,cg04508 136, eg 11845411 , eg 13584329 , cg26281633 , cg26513818 , cg00621029 , eg 14062002 , egO 0865537, cg03263002, eg 15086256, eg 17299902, cg24919806, cg05821186, cg07087674 , cg23964342,cg25404031 , eg 19015511 , cg23300746, cg00076216, cg03483654, cg0410 3122,cg03256335,cg07342325,cg25775493,cg10498798,cg13544294,cg24268443,cg 13590943, cg26820559,cg13424617, cg13985436, cg14610958, cg06373817, cg2199832 5,cg02033540,cg02285155,cg07322079,cg10819689,cg12307716,cg03142551 ,cg262 50886, cg08091970, cg07203893,cg08821879, eg 10776232, cg20057103, cg00125601, c g02957569, cg01225838, cg06750897,cg00413196, cg02753187, cg11710086, cg012445 14, eg 16530730, cg09261289, eg 15730087, eg 17860546, cg22278224, cg00866813, cg09 171565,cg15283982,cg23623781,cg08006263,cg11267683, eg 13642237, eg 15196697, cg16297907, cg01622919, cg08406714, cg16399506,cg23715749, cg05582046,cg12698 784, cg19943783, cg12217308, cg10133464, cg18222582, cg20914900, cg25769013, egO 0901946, eg01256665, cg07962785, eg 12147485, eg 16859324, eg 17355241 , cg00020967 ,cg03689582,cg10995281, cg14135079, cg17133224, cg27541630,cg08486929,cg0941 1884,cg13972591,cg14138133,cg24055792,cg25618259,cg26161709,cg00374136,cg 17636033, cg00533340,cg00614420,cg27593341,cg00253182, cg05998740,cg0886913 7, cg12540729, cg20256820,cg18895088, cg03734035,cg06135899, cg09224753,cg169 33762, cg05811362, cg23798668,cg03915940, cg09283223,cg10411625, cg01040169, c g14159007,cg25430696,cg00375637,cg02477877,cg03282295,cg12325285,cg050454 27, cg09155591 , cg25472693, cg26580761 , eg 11213248, cg23132327, cg02735500, cg03 247944, eg 10596451 , eg 14571888, cg21594924, cg25812309, eg 18215716, cg26708724, cg02658427,cg07592198,cg11876492, cg15675123,cg21108929, eg 10842403, eg 14541 653, cg07856758,cg24098404, cg12467098, cg15032604, cg22895379,cg27403669,cg2 4495475, cg03963219, eg 17158205, eg 19320263, eg01530213, eg01964552, cg07718382 , eg 10360552 ,cg22999786, cg04099673, cg08170375, cg05296676,cg06821993, cg0923 3851 , eg 17445690, eg 12532791 , cg21233515, cg21982700, cg23810710, eg 10044431 , eg 11065139, cg01036731,cg01311955, cg03479278,cg13913654, cg20823145,cg0208908 6, cg18312587, cg01387036, cg07503658,cg06162751, cg07831322, cg19721802, cg015 65291, cg08849191 ,cg00458652,cg06431586, cg09246833,cg01337940, cg01337968, c g16717162,cg00935993,cg20079997,cg11255523, cg17931041, cg00571067, cg147738 17,cg20239358,cg00351554,cg14155027,cg24102158,cg26234266,cg08999352,cg13 779243, cg14641582, cg03835378,cg15219347, cg15352568, cg26819916, cg01578726, cg15155285, cg24714022, cg07967531, cg14645926, cg17490428, cg06324419, cg11370 011 ,cg05700726,cg08806986,cg08846467,cg04287966,cg09981112,cg04394655,cg0 6912601,cg09002357,cg 10130162, eg 17109850, cg25356940, eg 14037187,cg22855767 , cg24757752,cg26001285, cg03500317, cg11521542, cg14371153, cg16517195, cg2334 1202, eg 14275159, cg24517995, eg 11540815, cg17625407, cg23697027,cg05151280, eg 09380648, cg14171448, cg19422969, cg20787665, eg 14559455, cg00095772,cg0311203 3, cg13436782, cg14693112, cg21815807, cg10214858, cg12074585, cg01288598, cg065 44464, eg 12250993, cg24234169, cg21268658, cg01020356, cg04484826,cg12679790, c g13315728, cg03900021 , cg14379908, cg14930067, cg20645177, cg18729148, cg049845 95, cg24466280,cg05588658, eg 11734988, eg 12419843, eg 15460093, cg19024838, cg22 120825, cg02661437, cg05300400,cg23404101, cg10237142, cg11052339, cg11754974, cg25605174, cg03733940, cg04848904, cg09541348, cg21764050, eg 11709870, eg 12238 440, cg10600983, cg13185963, cg13603967, cg16699818, cg17902290, cg02896705,cg0 8789486, eg 10702457, cg03403440,cg15779785, cg00508772,cg22867837,cg02024466 , eg 11606607, cg23723410, cg24431515, cg27316361 , cg05527500, cg03979622, cg0441 1315, cg09785904, eg 16046143, cg20725256, eg 14753161, cg06962642, cg21136715, eg 26040278, cg08733774, eg 14780747, eg01900557, eg 10492030, eg 16144294, eg 1722268 5, cg23028467,cg27070950,cg08560717, cg15508641 ,cg25803693,cg00810914, cg011 42302, cg03761979, cg21339819, cg00425944,cg00840320,cg03770410,cg14515779, c g01152303, cg22847846,cg25515163, cg25622922,cg06008844,cg14543641, cg184792 49, cg26103788, cg09840599,cg13648417, cg18292763, cg08544192, cg17786378, cg21 288861 ,cg23693705,cg24097253,cg20027419,cg01386581 ,cg09510464, cg18719170, cg03979024, cg13056013, cg10298988, cg15387943, cg15810996, cg02322229,cg15504 958,cg16328016,cg22736850,cg10190839,cg11640973, eg 18467542, cg01133348, egO 5638563, eg 19228334, cg08301628, eg 14030987, eg 14377687, cg04634639, eg 14262490 ,cg11713549, cg12171339,cg02585622,cg24922129,cg14271013,cg23509486,cg2040 3038 , cg08713722 , cg04410987, cg06569562 , eg 14303972 , eg 16925454, cg00633323, eg 00872695, cg06847188,cg12851039, cg04311466, cg14230692,cg21058973, cg2596019 6, cg02676881 , cg19517232, cg23037471 , cg12813402, cg15439546, cg18701296, cg219 11601, cg02577049,cg08166063, cg13957124, cg19709585, cg21728792, cg22677260,c g01146501 ,cg01710791 ,cg24027061 ,cg25344734,cg22235846,cg23649784,cg257267 56, cg26677075, cg03222387, eg 18319262, cg21395012, cg03464765, cg05965330, eg 13 832372, cg25334834,cg05431723, cg07010190, cg13518988, cg21071391 ,cg06052921 , eg 10766588, eg 19484757, cg25887789,cg02852657,cg06619807, eg 14375387, cg26740 452, eg 10977352, cg26023228,cg27281765, cg01162378, cg01209723, cg09127801 ,cgO 5563385, cg24389182 , eg01655671 , cg05549611 , cg09558036, eg 12074667, eg 14116139 , eg 15435830, cg07574683, eg 12292121 , eg 19926531 , cg08626830, eg 13510759, eg 1667 1669, eg 17673691 , eg 13911398, eg 17826107, cg21612207, cg21949625, cg05469926, eg 18328891, cg03714127,cg04924300,cg27603711,cg01170064, cg06050191 ,cg1131770 5, cg17688733, cg18082332, cg12606891 ,cg21136358, cg07970422,cg08232716,cg120 88497, cg23562858,cg06364604, eg 12823072, cg06685283, eg 10969470, cg16166047, c g01341176,cg12753303,cg25719848, cg22039879,cg08714754, cg10102375, cg240653 12, cg25536676,cg00626749,cg18202167, cg18633672, cg06612890,cg21502869, cg23 204810,cg03715130,cg22138564,cg06089512,cg 18691000, cg26119123, cg05096809, cg23099319,cg24512685,cg00015189,cg03727359,cg05689103,cg22563704,cg22729 681, cg03386765,cg10853637, cg10314752, cg12277288, cg19159488, cg24922059,cg1 3155387, cg08647476, eg 12150022, eg 14059132, eg 16756906, eg 16764635, eg 17686661 , cg22626578, eg 13363124, eg 14744870, eg 19357976, cg07390072, eg 14557853, cg2615 3911,cg15428679, cg20574381 ,cg25907190, cg12421565, cg16222733,cg09548897, eg 22542859,cg26510980,cg24717158,cg25505044,cg18278298, cg08018024, cg2269309 5, cg18646138, cg19763742, cg02345255,cg03183832, cg04715975, cg19035815, cg103 85590, eg 15944497, cg27340584,cg00219321 ,cg05962916,cg09230732,cg11419186,c g08822494,cg11967110, cg24605288,cg27461200,cg11100450, cg21908628, cg270261 92 , cg00168783, eg 10920769, eg 16328772, cg24175748, cg24517863, cg05510702, cg23 706187, cg05593759,cg06916729,cg11904960, cg17822427, cg21106695, cg00561673, cg26293830,cg13226797, cg02353570,cg10626682, cg23971995, cg00816135, cg08094 135, cg10298812, cg15713801 ,cg26496722,cg05847835,cg23703264,cg16161409,cg0 2515839, eg 13408940, cg23016723, cg24219671, cg24823970, eg 11963614, cg03389982 ,cg11171549, cg15981619,cg25002070,cg20672930,cg23483799,cg26550938,cg0730 6108, cg09489323, cg00916220, eg 14369015, eg 19214324, cg00773370, eg 10850119, eg 11506090, cg23581811,cg01957034, cg17340837, cg05000080,cg17831137, cg0369602 8,cg05610977,cg11291765, cg23135352, cg23702486,cg01141580, cg06374834,cg073 91367, cg08592917, cg01938018, cg03273057,cg18945467, cg25971351, cg07467095,c g08093278,cg09692173, cg15219664, cg20583679,cg01716527,cg17701208, cg100896 56, cg00555538, cg01795784, cg05497107, cg08024813, eg 15908102, cg26260728, cg02 321064, cg23576477, cg20368972, eg 11507895, eg 19008266, cg22920604, cg03577347, cg08999290,cg27224069,cg01340314, cg16399751, cg18337820, cg10821358, cg00437 794, cg02732358, cg12467852, cg06669598,cg10226143, cg01890321 , cg05867368,cg2 0674142, cg00356204, cg02201827,cg09884480,cg11029504, cg15288310,cg18139862 ,cg25589803,cg01297700, cg02759193, cg01607277, cg05208325,cg25530583,cg0241 5992 , eg 14399424, cg03593336, cg06772580, eg 11127156, cg20995142, eg01977110, eg 03077069, eg 10652833, cg20068528, cg00990690, eg 14285012 ,cg21718868,cg0742086

7,cg11215154,cg13477849, cg02428931 ,cg04186484, cg16158220, eg 10956147, cg038 46808, eg 13013306 , eg 14076860 , cg08055131 , eg 18679544 , cg02113096 , eg 15794372 , c g00008488,cg00083685,cg22349931 ,cg05838101 ,cg26119441 ,cg17100200, cg240006 79, eg01535449, cg06419258, eg 12936671 , cg03214715, cg06504337, cg09514191 , eg 10 472395, cg05703842,cg06834427,cg05853722,cg10406289, cg00169164, cg02542440, cg03498145, eg 11372669, eg 15523550, cg04607951 , eg 10701568 , cg23779692 , cg27234 239, cg05201573, cg18540455, cg25552317, cg27269561 , cg13424402, cg04581571 , egO 6537801,cg07543054,cg04673478,cg06064098, eg 10795789, eg 16431965, eg 18458017 , cg22145916, cg03096347, cg09278656, cg21467426, cg23939000, cg09239582, cg0384 5585 , cg05494579, cg20707892 , eg 16931825, eg 19948457, cg26210602, cg27480629, eg 04687750, cg09467485,cg26892353,cg07811262, cg06603239,cg23583433,cg0724136

8,cg13134399,cg22553965,cg09651708,cg19283354,cg01998146,cg12683613,cg198 30260, eg 10458967, eg 11459744, cg04901269, eg 16670852, cg05941631 ,cg17595688, c g01251971 , cg07087673,cg13685095, cg15100728, cg07900886,cg08701208, cg123630 11,cg02751824, cg18165540, cg07153441, cg18621123, cg02719415, cg12307132, cg03 743675, cg04004205,cg23969922,cg07209709,cg02338142, eg 16790986, cg20548175, cg16822143, cg09156426, cg19107647, cg26922188, cg03419232, cg04454585,cg02639 353, cg07233394,cg18241469, cg19941758, cg00922073,cg01992540, cg09346737,cg0 5436462 , eg 18499396 , cg23848614 , cg00909424, eg 18287616 , eg 11666857 , eg 13964184 ,cg15422382, cg17029975, cg19137649, cg23605722,cg23770524,cg01570662, cg0277 0728, cg03378318, cg05297079, cg06304806, eg 12226524, eg 14057277, eg 19850163, eg 23894980, cg25266005, cg07469143, eg01264826, cg05023437, cg07650936, cg0470555 3,cg14784415,cg21503237,cg25219515,cg25747839,cg13121728,cg22061651 ,cg084 18508, cg11236966, cg13430425, cg24465706,cg20506807,cg00813745, cg02057113, c g06673559,cg02560300,cg09096001 ,cg07148467,cg23746600,cg17741707, cg206423 00, eg 15875166, cg04147642 , eg 14518555, eg 10123945, eg 13453411 , cg00309970, cg06 550882, cg08101300, cg18577232, cg07555724,cg09946448, eg 18297349, cg20900764, cg19051504,cg23433118, cg05779950,cg10282410,cg13275152,cg21750179,cg26198 700, cg13240804, cg26340411 ,cg05067963,cg04048740,cg11123381 , eg 12256003, eg 1 2411374, cg16311827, cg17746316, cg23564535,cg12471572, cg10835711 ,cg03905224 , cg06880836, eg 10503840, eg 16994790, cg07409511 , cg25232769, cg08362449, cg2385 8591 , cg00226831 , eg 13464018, eg 16511920, eg 19710449, cg24711914, cg26215571, eg 04751029, cg09315767, cg27236320, eg01896085, cg02124081 , cg05725080, eg 1248691 3, cg17145397, cg19443719, cg20311092, cg04225347,cg12187305, cg00849943,cg146 66411,cg11391618, cg02651542, cg02950886, eg 17420218,cg07914107,cg18404600,c g22563312,cg00908004,cg04351979,cg05252958,cg14192813,cg03983597,cg156785 13, eg 18740057, cg25957451 , cg00610260, cg04432215, cg20932516, cg23657601 , cg05 252418, cg10279395, cg16922900, cg13407446, eg 14000393, eg 11594290, eg 14321373, cg20535290,cg14602849, cg08328431,cg08093323,cg21066622, cg01519599, cg17237 881 ,cg25386845,cg06561990, eg 18568531 ,cg07643321 ,cg15186616,cg02384859,cg0 3209496, eg 16487794, cg23531873, cg08235522, cg08715684, cg21057467, cg06817691 , cg07917546, cg20927728, eg 12080709, eg 13471586, eg 15704304, cg26143350, cg0429 8184, cg14488661, cg01413698, cg05087600,cg07701004, cg14106085, cg16194968, eg 18214045,cg22122925,cg00534136,cg01412777,cg06668506,cg00682487,cg 1550440 8, cg22651787, cg20487043,cg06278619, eg 11535059, eg 12942052, cg21374153, cg220 06210,cg04437413, cg04880138, eg 10940969, eg 15638646, cg05534175, cg05745656,c g12367036,cg13210187,cg24118950, cg05579478,cg07454847,cg08697689,cg260157 12 , cg27323711 , cg27381557, cg05214947, cg06910114, cg07462670, eg 10281394, cg26 067319,cg27054943,cg07950307,cg12254430,cg02628826,cg 13175191 ,cg20972167, cg27492860,cg12818354, cg08156662, cg18023343, cg20130062, cg03927729,cg05033 749,cg21600965,cg24008219,cg26695659,cg24267038,cg16283496,cg23849965,cg1 9618152, cg26849457, cg07795168, eg01259329, cg07631013, eg 11308335, eg 19485748 ,cg22720139,cg25901841 ,cg26347632,cg00595212,cg01152727, eg 13342435, eg 1592 6477, cg20536432,cg26376411 ,cg16230625,cg13098671, cg19239270, cg22629196, eg 23704412, cg08215302, cg09518009, cg23913222, cg08835443,cg01545964, cg0651861 8, cg13934606, cg01086895, cg05785919, cg10686439, cg12036105, cg20083107, cg272 36648, eg 13984803, cg23484980,cg26377963,cg05992372,cg01690037, cg18816399, c g23227881 ,cg04757390,cg06206801 ,cg16231809,cg27005118,cg17766828,cg055792 32 , eg 13735219, eg 10614159, eg 14350158, cg24995915, cg05215420, cg24959965, eg 12 115397, cg16929960,cg17048267,cg25441879,cg11208967, cg07393014,cg19598692, cg10557352, cg20414709, cg03616122, cg06449334,cg15905623, cg09858749,cg09292 306, eg 19610932, eg 10474158, eg 11673867, cg27082881 ,cg02867448,cg 16268233, eg 1 8912897, eg 12481537, cg06301581 , cg07704578, eg 11816191 , eg01726939, eg 18903583 , cg23624401 , cg05241956, eg 17613498, cg03375366, cg05948962, cg09653271 , cg0049 2341, cg04099189, cg06623274,cg10695848, cg14317321, cg14945834, cg17278207, eg 04409427, cg04692760,cg10322118, cg24369891,cg16577081 ,cg23858197, cg2691969 5, cg09550257,cg10191529, cg06569954,cg07056626,cg01543670, cg15979932, cg073 04943, cg12213302, cg14526579,cg25371017, cg24347611,cg18674267, cg04941087, c g16017696,cg13135456,cg26645655,cg19757586,cg19272483,cg06650235,cg274102 55, cg18755094, cg26433780,cg09766263,cg09901892, cg26848446,cg13459035, cg06 082664, cg15288350, cg24997585,cg14080063, cg02373104, cg05917797, cg05125615, cg00549669,cg13359054, cg12112007, cg04265261 ,cg23798183, cg07300559,cg02648 738, cg24736935,cg07106379, cg04290835,cg09301293,cg20190133, cg18238718, cg2 3572741 , cg22538861 , cg02843821 , eg 13625497, cg24474844, cg07416876, eg 10290814 , eg 13655385, eg 19885684, eg 12935965, eg 17568934, cg04675475, eg 11909640, cg2418 6440, cg13916895, cg01759672, cg02925229,cg27452156, cg08198512, cg06585913, eg 20018086,cg20780850,cg14162912,cg07943346,cg27241753,cg00192701 ,cg 1733408 0,cg08940009,cg25081347, cg05094706,cg06007464,cg10948642, cg07594472,cg053 71417 , cg03694391 , cg08994482 , cg22307153, eg 15403758, eg 16317961 , cg03846063, c g03998493,cg22195036, cg07246050,cg24652706,cg00499564,cg13602065, cg239069 17, eg01174441 , cg05484231 , eg 18549036, cg23828170, eg 14671764, cg05540767, cg27 330757, cg00423048,cg10071595, cg13769139, cg12172659, cg26742247,cg06197751 , cg08398556, eg 15872094, eg 13345137, cg03364201 , cg22207171 ,cg 14141238,cg 13785 200, cg05184978, cg13330919, cg17004392, cg26237426,cg00347721 ,cg08855861 ,cg1 7658113, cg06504205, eg 13416895, cg01223299, cg05605029,cg20592123, cg21105343 , cg09293161 , eg 18173531 , eg 16801686, cg20515400, cg24008892, cg00118233, cg0408 8012, cg05803606, cg00234613,cg04352571 ,cg23692401 ,cg26001950, cg10031493, eg 13891068, cg00396263,cg16576213, cg00331548, eg 14522181 ,cg 14190534, cg0889047 7, eg 18496781 , cg23682945, cg02467602 , eg 11929489 , eg01742177 , cg05257315 , cg272 38903,cg06560102, cg01772842, eg 19666514, cg05181597,cg09661721 ,cg14852364, c g15613014, cg05883794,cg04357722,cg14989644,cg07993897,cg05206599,cg212399 97, eg 11942086, cg04002950, cg02335909, eg 12731799, eg 11575234, eg01573162, cg03 074357, cg18337324, cg04875420,cg07851766, eg 14653685, eg 18258412, eg 11879548, cg27262174,cg21232331,cg01960300,cg02030652,cg10794962,cg00589708,cg11878 452, cg25307074,cg10909581 ,cg20589883,cg19092999, cg00942432,cg17589284, cg2 6151000, eg 10712837, cg21323441 ,cg07264777,cg02443173, cg22488883,cg21553843 , cg04766371 , cg06318062, eg01710780, eg 16353350, cg25660490, eg 14521373, eg 1866 3839, cg27500983, cg04619585, cg23170174, cg03105083, eg 10741323, cg04809195, eg 00069401,cg18939117, cg02537078,cg23010352, eg 13476739, cg22967140, cg0863892 9, cg02741329,cg03885264,cg03365629,cg03601938,cg08901057,cg11751569, cg180 90428,cg 18143967, cg06580966,cg22399646,cg24759237,cg07383968,cg20789595,c g07602072, cg15722376, cg17321814, cg22622254,cg09866598,cg00825491,cg016662 35,cg24722354,cg05270119,cg09562563,cg22800555,cg04725405,cg06214728,cg14 106310, cg23423933, cg26133126, cg13122641, cg15143010,cg26445041 ,cg12463110, cg06398743, cg22787530, eg 19909996, cg06363014, eg 12064373, cg07187902 ,cg03601 886, cg18596616, cg20870394,cg22057888,cg09966880,cg19776757, cg04539172, cg1 2105679, cg17984198, cg24390932,cg09726239,cg23583580,cg22668169, cg08623636 , cg24555980, cg24398923, eg01075539, cg05455876, eg 13984173, eg 13799853, eg 1464 0281 , eg 13602484, eg 12105077, cg04891490, eg 18463149, cg09289202, cg09807033, eg 04167764, cg11224423, cg12421602, cg16851140, cg23797100,cg18417449, cg0233671 8,cg00670456,cg15150652,cg06799180,cg16852369,cg09229183,cg15883606,cg156 45372, cg16520701 ,cg22784060,cg05433657,cg12045494,cg11775528, cg06077723,c g00848608,cg26703153,cg21857190,cg14311559, cg01167337, cg21647361, eg 193601 12, eg 13545909, eg 13890969, cg27512176, eg 15381366, cg07199500, eg 17978425, cg23 077515, cg17253108, cg13792757, cg13826499, cg06604103,cg18252968, cg05991092, cg16112359, cg04790032,cg25226400,cg06232845,cg20249877, cg13395035, cg15962 313, cg05350386, cg20823049, cg08869547, cg02541031 , eg 12813734, eg 14979433, eg 1 8559596, cg06613765, cg25067686, cg04114788, cg09808626, cg22940104, cg03765980 , cg21293562, cg20429027,cg12492481, cg20275925,cg10846857, cg07086295,cg1804 7961 , eg 11892349, eg01864015, egOO019877, cg07948045, cg00306305, eg 18095187, eg 08151337, cg13350140,cg14222861 ,cg10147666,cg03871352,cg23037411 ,cg1321546 7,cg10828159,cg06741849,cg19713911 ,cg18532131 ,cg22417420,cg03434660,cg101 03000, eg 14458361 ,cg02883146,cg05990805,cg07930167,cg21445157,cg02151068,c g13390092, cg25718696, cg01705575, cg12269858,cg23476638,cg04696491,cg232336 46, cg04060728, cg04342821 , cg20739504, eg 12383675, cg25793592, eg 14410589, eg 19 434320, eg 17700558, eg 18207721,cg22912044, cg21661138, cg11341086, cg15766982, cg10663144, cg25961292, cg02697402, cg15244830, cg16729327, cg19926245, cg24838 240, cg19510180, cg03230970,cg13470069, cg10040976, cg08963013, cg24655022,cg2 4774960, cg02648941 , eg 14042504, eg 19235974, eg 13410558, eg 12081303, cg06127426 ,cg08982919,cg27188026, cg07324432,cg26311699,cg05575921 ,cg13317817,cg2040 1551, cg23488395, cg05395061 , cg02255511 ,cg05459097, cg02824817, cg05503590, eg 21599943, eg 12504163, eg 19442702, cg21974239, cg09102665, cg00748911 ,cg0827628 0, cg09219302, cg09411953, cg02393447,cg06893970,cg02377452, cg13615994, cg226 52934, cg01687217, cg25102652, eg 15956845, cg00493179, cg22598233,cg19255656, c g08069370,cg00738841 ,cg11258076, cg11419029, cg19162556,cg17949643,cg181299 61 , cg06771923, cg24715467, cg27427999,cg25140869, cg27443093,cg14614314, egOO 655804, cg25880804, cg25850828, cg03827471 , eg 10452060, cg07789792 ,cg08104402 , cg15438476, cg03673094,cg01990964, cg04835180, cg00859465,cg08301035, cg09854 717, cg13001127, cg11744006, cg00719373,cg22262895,cg00112251 ,cg02098159,cg1 4448830, eg 18300285, eg 17485135, eg 12663083, cg04883135, eg 19674518, cg07443246 ,cg06594012,cg03297221 ,cg08401557,cg06717492,cg03102015, eg 14524897, eg 1828 3554, eg 15897145, cg24232594, cg05040219, cg04104871 ,cg02102278, cg25328784, eg 20860638, cg09370104, cg25045630, eg01132053, eg 11579636, eg 15118801 , eg 1890965

8,cg21566642, eg 11523681 , eg 12423278, eg 16523653, eg 17375248, eg 10080598, eg 166 20857, cg06846862, eg 19578175, cg21896800, cg04419610, cg16896659, cg22510476, c g24705163,cg20367589,cg20324165,cg08803553,cg06348490,cg05657091,cg085360 48, eg 10386443, cg21836275, cg21031702, eg 11509169, eg 13042138, cg23780216, cg26 416323,cg10354813, eg 17225824, eg 14411823,cg27063741 ,cg06525193,cg15958777, cg24716369,cg21165852, cg09107449, cg24154257, cg11815425, cg10768565, cg24394 990, cg13927504, cg06581980, cg20246820,cg17059405, cg23373396,cg24639998,cg1 6219583, cg24879592, cg00415263, cg06681129, eg 15580167, eg 14396758, cg26443106 ,cg00091513, cg25405984,cg12330330, cg15157901 , cg19123891, cg02689667,cg2536 0535, cg09297236,cg13793438, cg24372849,cg23061795, cg18253356, cg19720914, eg 27416513,cg18793631,cg06855286,cg20227886,cg01677248,cg09558105, eg 1985957

9, cg12852294, cg22900035,cg08601357, cg17481122, cg00341742, cg19209269, cg063 94209, cg09069730,cg08495968,cg04327617, cg09242880, cg07568616, cg24445870, c g24807448,cg16001150,cg02914011 ,cg09191750,cg09834465,cg25971170,cg259972 03, cg24845380,cg15009043, cg07701514,cg23855413,cg13401330,cg01239268,cg17 974142, cg26284874,cg11908057, cg27311153, cg09612195,cg09985282,cg20569034, cg17292252, cg01107130, cg22927076,cg20949608,cg02563530,cg23542399,cg24819 354, cg05475352,cg13280536, cg06173663, cg24759599,cg19648647, cg06721232,cg1 7505852, cg23229205,cg10677078, cg24145739, cg23187744, cg18995340, cg04618613 , cg00549064,cg 12216469, cg24433766, cg26730830, eg 10323188, cg00816037, cg0288 7048, cg05709402,cg17092340, cg06531612, cg23034100, cg23913077, cg02164556, eg 13636986, cg11441074, cg23890059,cg06316133,cg26590660,cg02008691 ,cg0530417 7, cg06940451 ,cg09381706, cg14610269, cg26764345,cg17355622, cg10246141 , cg227 06186,cg16318598,cg25178749,cg06100442,cg08806184, eg 15245581 ,cg23317604,c g26116742, cg03870123, cg19437278, cg05043032,cg19650253, cg01444058,cg070053 63, cg26594697, cg03052074, cg03630413, cg08089671 , cg22683243, eg 11827131, cg26 436158, cg13806103,cg13937986,cg08981817,cg07779693,cg01782066,cg05032607, cg21314813, cg22690294,cg21578000, cg06852037,cg04423696,cg07159849, cg19242 173,cg26802731 ,cg01015647, eg 17867417, eg 19219560, eg 13917863,cg26279261 ,cg2 2583415, cg08805400,cg08526024, eg 19577080, cg09506336, eg 19028369, eg 11095247 , eg 11116035, cg06922731 , eg 12410824, eg 11837267, eg 17408087, cg20449188, cg2306 5174,cg25848652,cg07925687,cg22737945,cg24786498,cg00572533,cg19803219, eg 14727634,cg12095612, cg22603111,cg23023797,cg03411401 ,cg26253639,cg 1207037 9, cg23449165, cg25706552,cg10236631 , cg26109093, cg15500084, cg00903088,cg273 98640, eg 11484783, cg07654629, eg 13068706, cg04802221 ,cg09241763,cg27598629,c g24984532,cg02583271 ,cg26994192,cg12906108,cg08421532,cg08805459,cg104912 53,cg08760643,cg06785864,cg09547502,cg17862993,cg16492986,cg20181492,cg16 735465, cg25906741,cg05452558,cg00172297, cg09206496, eg 16792445, eg 15404586, cg23399959, cg02476348,cg04427437,cg01316056, cg18210294, cg11751344, cg18909 932, cg00921219, cg08785214,cg24206669,cg11718206, cg19028672, cg23758687,cg0 5185311 ,cg02389317,cg25365774,cg26056477,cg04513846,cg22568590,cg00379377 , cg09037196, eg 12252202, eg 16016960, cg00218939, cg09769090, eg 17574785, cg0972 9624,cg23551859, cg23042404,cg02422847, eg 10823785, cg02875280, eg 10839583, eg 15779701 , cg02585142 , eg01680550, eg 12638728, eg 14273822 , cg06557491 , cg2448015 2, cg04657461 , cg15656971 , cg16504346, cg15872714, cg20533970,cg13931996, cg123 06228, cg07886153, cg22088017, cg02398482,cg08053843, eg 14704597, cg13714322, c g20610581 , cg10879653, cg10264354, cg14202099, cg14160433, cg04885068,cg156439 21 , cg08799727,cg 18122217, eg 16212453, cg07828394, cg05096948, eg 13521254, cg04 872399, cg15864733, cg21433059, cg05941610, eg 12605277, cg20984107, eg 11919153, cg04213089, cg26711732, cg14944686, cg14414819, cg01590359, cg23741509, cg07017 597, eg 10092691 , cg26691449, eg 16943920, eg 12947596, cg21428874, cg05520472 , egO 5988523, eg 10203076, eg 17697157, cg24743853, cg24322628, eg 12192217, eg01940273 , eg 13234062 , cg04784898, cg24704344, cg07471572,cg08921063,cg00659931 ,cg1987 9960, cg23871994, cg00594335, cg09524078, eg 18063120, cg03266158, cg00198926, eg 05026033, cg12979120, eg 18824043, cg05462406,cg01483219, cg27301674, cg1325725 0,cg04475953,cg00821270,cg22076123,cg19256906,cg11616100, cg16782494,cg136 21827, cg02268935,cg26079183, eg 15066676, cg00332745, eg 10939418, cg05851533, c g17304885, cg18397657, cg02314514, cg19644994, cg16998656,cg22493361,cg239638 58,cg22701672,cg20287671,cg20937611,cg07893176,cg11819702,cg06041223,cg12 664706, cg03970643,cg16090433, cg26255388, eg 13910625, eg 19387137, cg06943549, cg19024588, cg01910445, cg08445278,cg22800884,cg04338281 ,cg01694519, cg14480 426,cg12984320,cg15148064,cg26342141 ,cg15451413,cg23701676,cg06530319,cg1 9532402, cg05720154, eg 13463909, cg09226031 , eg 15089794, eg 13944084, cg25801428 , cg26340538, cg05842175, cg22000552, cg02392724, eg 13647459, cg03618811 , eg0190 1893, cg20268526,cg22546859,cg11946001, eg 14653849, cg20985193, cg20707670, eg 19860586, cg16995838,cg13515142,cg23613409,cg27576584,cg06945179,cg2636983 3,cg16327489,cg17696434,cg14504418,cg21972318,cg04263685,cg12126482,cg030 03978,cg15719025,cg16187975,cg18573752, cg02276825,cg22477428,cg10167229,c g13131270, cg18924677, cg13534190, cg10850197, cg08920792,cg14105997, cg060302 58, cg04510586, cg02976009, cg21514857, eg 16764564, cg02025944, cg08498262, cg07 979962, cg11628487, cg12944681, cg13158571, cg26878169, cg06903103, eg 17509279, cg22550445,cg01120434, cg08959677,cg17624315, cg25248445,cg21369592, cg24733 080,cg23861263, eg 19119369, cg00473386, eg 10528835, cg00360176, cg07397167, eg 1 1646078, eg 13996453, eg 13616190, cg02465086, cg00639121 , eg 13521124 cg08013199, cg14237981, cg14343986, cg00676085,cg08613468, cg21428348, cg24131 844, cg07741182, cg15836850, cg02395684,cg18544888, cg02361810,cg21605988,cg0 4796828, cg06261400, cg00835464, cg23222169, eg 12431105, cg20284891 , cg06790594 , eg 12505757, cg06240209, cg00068391 , cg04522310, cg07791014, eg 13818588, eg0118 5578, cg22082243,cg23517469, cg14514454, cg13188998, cg08736052,cg06421794, eg 02204148, cg06706159, cg05219816, cg10240906, cg04759187, cg06964478,cg0365754 3,cg13558115, cg01226417, cg13552468, cg18123613, cg11297526, cg16686805,cg019 14045, eg 15416972, cg08903528, eg 11860777, cg02557906,cg07172256, cg16867034, c g03984537,cg12457270,cg00010992,cg02579332,cg02490253,cg06645166,cg236530 51 , eg 14905429, cg27102469, cg25736198, cg02928935, cg20821424, cg04855961 , cg06 786349, cg06174908, cg22520834,cg03134230, eg 13703619, eg 13975062, eg 18948380, cg14629220, cg15493742, cg20556988,cg13314718, cg14815325, cg24699433,cg08870 322, cg05433069,cg07406197, cg22844232,cg02249904,cg06439809,cg15875292, cg2 6917253, cg27130364, eg 16245761 , cg09120267, cg05241201 , cg05215056, cg23346716 , eg 14072889, cg04260557, cg07317843, eg 11820840, cg08351914, eg 11952501 , cg0056 8027, cg09289622,cg16196640, cg04552920,cg10148755, cg07222434,cg17151560, eg 25073725,cg26431824,cg00291981,cg01612366,cg20566904,cg05906056, eg 1025850 5, cg12736406, cg10929628, cg25660811 , cg13617280, cg09841898, cg25497959,cg247 65188,cg09486367,cg25349981 ,cg23596826, eg 19314660, cg09215353, cg02579336,c g 13150358, cg00673794, cg26294406, cg26594532, cg21629653, cg04949537, cg076680 08, cg06009834, cg23059670, eg 18943812, cg23209588, eg 17033598, eg 11772995, eg 13 344434, cg22609114, cg21431387, cg02296029, eg 18815657, cg03858144, cg25725605, cg14176737, cg22996083,cg07977900,cg24510700, cg10643750, cg25185710,cg07658 646, cg09833249,cg17647540, cg05081388, cg03312587, cg14347471 , cg02427831 ,cg2 1205320, cg17657214, cg19837806, cg00154107,cg22996308,cg11189022, cg04571973 , cg04031534, eg 16664338, cg07141356, cg02799945, eg 13609353, eg 12300939, cg0881 4268, cg22796025, cg26261291 , cg08347473, cg20432667, eg 12873059, eg01370416, eg 00092151, cg16009614, cg04446790,cg06765292,cg01027010, eg 19227053, cg2169691 3, eg 10700232 , cg22902669 , eg 17394462 , eg 15693937 , eg 16276452 , eg 16133240 , cg242 75885, eg 14296039, cg06747919, eg 19665213, cg15965233, cg20663588,cg08054040,c g21261467, cg12876333, cg01925521 , cg20605947,cg11517071, cg04840076,cg114271 77, cg23198935, cg09272724, cg07520074, cg20785459, cg25010149, cg22107412, egOO 685969, cg07046120, cg10274863, cg03919425, cg02279936, eg 16029975, eg 17717238, cg26532638,cg04269057,cg04482879,cg02635662,cg12343123,cg07444054,cg19011 868, cg21994174, cg06840680,cg09857070,cg18066856, cg24717898, cg26082742,cg0 8003789, cg23964606, eg 13615341, cg07692997, eg 18872946, cg00940867, cg03901784 ,cg26735637,cg04963207,cg11130322, cg16024677, cg24579604,cg13527652, cg0640 0065, eg 11227777, eg 17636077, cg00391399, cg00081238, eg01868071 , cg26225847, eg 01465596, cg25094735,cg02645295,cg03701425,cg13166875,cg26445457,cg2212244 9, cg21730797, cg00324592, eg 17298437, eg 19644978, cg07467618, eg 11363886, cg268 82409, cg21324045, cg03877568,cg23029573, eg 11361983, cg21420536, cg03938359,c g16085190,cg10760339,cg00936911 ,cg25482411 ,cg02592473,cg18504358,cg196882 49, cg00284511 , eg 13925364, eg01290149, eg 12695061 , cg09570974, eg 11084602, eg 11 128704, cg15304464, cg03675886,cg09979899,cg22004053,cg00971508, cg21633698, cg22303827,cg03897954,cg08638785, cg14463669, cg27618090, cg15502611 ,cg06708 731, cg24710752 cg01905478, cg01150480, cg04116821, cg26127201,cg15907897,cg20033771 ,cg22657 015, cg27191457, cg17635140, cg02814485, cg25574227,cg23437166,cg13872278, cg1 0448915, cg25598052, eg 15705086, eg 16745549, eg 17709086, eg 11504739, cg03125531 , cg09444206,cg27139067, cg00716787, cg22966348, cg23446939, cg04367033, cg2289 2549, cg22785562,cg27517308, cg15612077, cg17772212, cg15899666, cg24167611, eg 20275129,cg04141477,cg00381511,cg08501430, eg 12304447, cg05519121 ,cg0189277 2 , eg 14695609 , eg01105183 , cg03919942 , eg 14258341 , cg25398566 , cg05400252 , eg 180 80655, cg04644869,cg05251646, eg 10800023 cg09892781, cg16288354, cg03197032, cg00545886,cg13576095, cg16744238,cg11345 955, cg07945323,cg13901000, cg20917637, cg19540371 ,cg01082980, cg14170835, egO 4056774, cg05055128, cg03125594, eg 17933407, cg02870820, cg25917510, cg25410746 , eg 14285025, cg02757561 , cg21592241 , cg08172581, cg06053634, cg24368865, cg0014 4814, eg01941680, cg00905286, eg 16608731 , eg 17216807, eg 19646503, cg07192240, eg 22956483, cg20060226, eg 17507529, eg01164094, eg 13974400, cg26031952 ,cg0072365

6, cg10539002, cg26494337,cg15991427, cg14821327, cg18953280, cg01553707, cg067 71060,cg05949502,cg 17851242, eg 15395837 cg12785472, cg02597665,cg06875305,cg02275004,cg07148458, cg15597136, cg03985 360, eg 11689786, cg09926562, eg 19582128, eg 17443976, cg01044637, cg05433152, eg 1 2685187, cg08635064, eg 16676595, cg06044767, cg05265076, eg01905058, cg23977911 ,cg07258372,cg27056681 , cg05706698, eg 18722504, cg07465556, eg 13456408, eg 1725 7024, cg02372113, cg10394903, cg00171704, cg12728791 ,cg19128351, cg15009540, eg 05268155,cg22844368,cg16877242,cg20330217,cg07502500,cg 10151953, cg0300607

7,cg04328575,cg02231325,cg14943392,cg08648041 ,cg05926364,cg06644428,cg098 83671 , cg08370347, eg 14316800, cg20736404 cg05221875, cg04554217 , eg 17753162 , cg21280061 , cg05771184, eg 13560136, cg24574 592,cg27248333,cg04770813,cg02955114,cg04842116,cg10880082,cg07677531 ,cg2 7208725, eg01815259, eg 19306866, eg 19319069, cg05361134, cg09264088, cg22963164 , cg03428156, cg02589483, eg 16075933, cg27110790,cg26802548,cg04749156, eg 1393 0177 , cg06630988, eg 11901510,cg11593346, cg06171619, eg 18955165, eg 19229209, eg 12370917, cg05466464,cg03450593,cg09296212, eg 19454017, eg 18284252, cg0578453 2 , cg07382101 , cg26685998 , cg22650146 , cg08278002 , cg06029363 , eg 18304001 , eg 110 69125,cg07955677,cg01545140,cg26754826 cg03212480, cg22744180, cg26766900, eg 19950548, eg 10215678, cg25880320 , eg 15659 409,cg24168276, eg 11028188, cg20579564,cg00214268, eg 16574052, eg 10841913, egO 2588591,cg12981270,cg16116845, cg13319417, cg27415969, cg19026125, cg15302078 ,cg04929526,cg10841831,cg14965708,cg03206460,cg13118714, cg04873792,cg1205 2260 , cg22070880, cg09640682 , eg01085216, eg 18817607, cg24107351 , cg24826610, eg 10061117, cg19346476, cg16016281, cg09374673,cg08560531 ,cg06638979,cg 1202569 0, cg11577329, cg15276175, cg15284457, cg05008539,cg23064609,cg04841293, cg128 33670, cg25629615, cg03882355, cg02899584 cg23221867, cg15144058, cg13609053, cg11321928, cg08261158, cg00776208,cg15662 224,cg05540397,cg11126205, cg19426248,cg26427099,cg16240962,cg18756771 ,cg0 4111064, cg06093878, eg 16531679, cg09869474, eg 13215579, cg24438354,cg03098388 , cg08499559, cg20588106, eg 13738167, cg23848131, cg04548519, eg 10900643, cg0694 3627, cg13622587, cg09445162,cg19182918,cg24401026, cg06758664, eg 12760525, eg 00877703, eg 15235057, cg00443971 , cg27523974, eg 15650298, cg07891507, eg 1335078 3,cg16645720,cg05649906,cg16787065,cg16504661,cg05043074,cg02728611 ,cg100 83465, eg 10684792, cg24535475, cg22325606 cg13469286,cg08835755,cg05012578,cg22582113,cg17148467,cg20811145,cg14534 000,cg22863209,cg24928687,cg08208917,cg22442901 ,cg08229950,cg09045933,cg1 5883033, eg 18656581 ,cg22055932, eg 17091020, eg 19057227, eg 15285494, eg 19387359 , cg03061485, eg01989908, eg 13066846, eg 14005049, eg 12485972, cg02108802, cg0595 1275, cg02119220, cg00802855, cg02693125, cg24075549, cg04748673, cg22051399, eg 08308286, eg 15872651 , cg27302137, cg02058918, cg08553360, eg 13797580, cg0863898 9, cg12001774, cg17741106, cg06565131 ,cg20866308,cg17399352, cg02774302,cg002 57103, eg 14028577, cg08235183, cg00256873 cg27471904, cg25581063, cg10930293, cg20109855, cg25751453, cg19833317, cg08336 727,cg14620352,cg09905199,cg17612071 ,cg00203620,cg16736054,cg20396509,cg1 4270562, cg06752313, cg10226744, cg04155086, cg17918185,cg22556898,cg04174538 , cg09512004, eg 13925686, cg24486784, cg03957043, cg21384691 , cg07154840, eg 1362 1836 , cg06905506, cg05240210, cg22887246, cg08263571 , cg09428766, eg 13320478, eg 09990539, cg15487646, cg00710249, cg00613551, eg 16977799, cg05013909, cg0004883 2, cg25575732,cg27387682,cg01621576,cg08569460,cg21142904, cg21268422, eg 162 68937, cg09359616, eg 16089929, eg 15096815 eg 10039041 , cg04873130, cg07121693, cg24607328, eg 12587133,cg02118245,cg22892 110,cg27500519, cg20834927, cg20962960, eg 14047836, cg07853758, cg02892898, cg2 0310230,cg00481421,cg11566267, cg23041973, cg10528455, cg20181600, cg27106356 , eg 12594749, cg23999956,cg08035942,cg05072537, eg 18224611 , cg04320510, eg 1788 5794, eg 13099959, cg04504441 , eg 15446373, cg00586058,cg25425721 , eg 16284524, eg 13039021,cg27645204, cg17691263, cg01752326, cg22520453,cg00032643, eg 1224804 0, eg 16036672 , eg 19066520 , cg06034255 , eg 17131560 , eg 14690916 , eg 14934821 , cg074 34433, cg05657792, cg21181453, eg 15268992 cg06663617,cg02807040,cg02652405,cg24069768,cg18139806, cg00256155,cg21919 556, cg17281217, cg12703652, cg15934058, cg22040301 ,cg09356141 ,cg24982532,cg0 6112554, cg14688299, cg20576825,cg12080113, cg25073137, cg01703510,cg26945329 , cg27342910,cg13138552, cg16936906, cg05934755,cg14965366, cg16395712, cg2156 4128, cg07629549, eg 14654822, eg 17584035, cg16261581, cg14908766, cg24114899, eg 20471982, cg26420724, cg15502416, cg17873815, cg26081466, cg02565650, eg 1632783 9, cg07111425, cg03124710,cg18007899, cg22907892,cg27413508, cg16538000,cg056 60803, eg 11090079, cg20248442 , eg 18354714 cg24010210, cg14538785,cg21103383, cg20387329,cg24458712,cg07183411 ,cg13072 500,cg14550437,cg20933515,cg21952813,cg07601592,cg09472084,cg26760927,cg1 0877199, cg18161670, cg09049927,cg12384236, cg08851880, cg22993715, cg24373253 ,cg00109131, cg21593900, cg23911285, cg05138468, cg06774674, cg11604604, cg0329 1085, eg 16273152, cg25211200, cg05526036, cg09831620, cg00045910, cg06460190, eg 03511735, cg21328081, cg18949044, cg03058602,cg09567344, eg 11543615, cg0675327 3, cg16518765, cg26784929,cg20070055,cg20479557,cg13768679, cg06076690,cg078 69814, cg25457744, eg 13204992, cg26531478 cg22647566,cg21095673, cg20518066, cg01996496, cg22458779,cg21722691 ,cg05826 626, eg 18475568 , eg 16844105 , eg 16486653 , cg26360664 , eg 16382935 , cg25234080 , eg 1 5638540, cg08573869, cg04840761 , cg26116741, eg01266375, cg04557677, eg 18775018 ,cg16698279, cg15692227, cg06695626, cg14909198, cg00262225,cg12926645,cg0057 7786, cg08818893, cg08668676, cg22412747, cg24834868, cg21501179, eg 19611374, eg 17714110,cg16965576, cg18821316, cg15136597, cg18305031 ,cg03531878,cg1289219 8, cg26412995, cg05749628,cg13439181, cg26832528,cg17300870, cg12862611 ,cg237 00778, cg27440574, eg 16947168, cg26430393 cg25968206,cg01794862, cg08886779,cg22519738, cg04988974,cg04999785,cg24302 127,cg00651020,cg12860194,cg16244362,cg09738884,cg03575231 ,cg22253596,cg2 1426547, cg09831641 ,cg04804604,cg05227215, eg 16502933, cg23066837, eg 14586941 , eg 13666594, cg23736024,cg20597382,cg00210002, cg03156112, cg23358544, cg2640 2799, cg07645993, cg03312565, eg 19579176, eg 11824401 , cg26220773, eg 18181654, eg 15409399, cg06798115, eg01297269, cg07313499, eg 16999626, cg22330749, eg 1940504 0,cg27582081 ,cg25784617,cg19501889,cg24767315,cg25790695,cg08723126,cg151 53815, eg 10307152, cg27544190, cg08128105 cg02933002,cg00344929,cg13305976,cg05680417,cg25881591 ,cg00659919,cg26910 651 , eg 18257574, cg05327509, eg 19586143,cg23754710,cg 19548470, cg03523685,cg0 2695267, cg20742865,cg17706662, cg25798600,cg24015119, cg05226322,cg08753706 , cg25936635, cg03544657, cg02150582 , cg09695592 , cg04185542, cg22134764, cg0690 4008, cg04141574, eg 13292900, cg26129650, cg26489368, cg08947191 , eg 12390524, eg 12201766,cg12145552,cg16225753, cg24949344,cg21441575, cg15121157, cg1694524 9, cg06293449,cg07325763,cg05856677, cg16697062, cg13047954, cg03770437,cg130 19306, eg 14466661 , cg06300969, eg 16958337 cg01962644, cg05108346, cg25405123, cg10165378, cg12612854, cg16941662,cg01950 524, eg 15672656, eg 15603812, cg08967516, cg24026388,cg11499262, cg09291268, egO 7781332, eg01274028, cg21937244, cg05257821 , eg01936915, cg22685867, cg25840822 , cg27387232, cg04973839, cg02794695, eg 18247897, cg24853266, eg 10445315,cg2762 3937, cg19180710, cg02257635, eg 15482623, cg01886809, cg06556827,cg23911330, eg 22087352, cg06641938, eg 18482960, eg 16492392, cg04335779, eg 16293983, eg 1375881 4, cg06315177, eg 17297937, eg 11323650, eg 13852948, cg27589988,cg08875048, eg 163 84355, cg00714464, cg02334668,cg23717719 cg08008299, cg16591579, cg20080082,cg08846333, cg13434714, cg21855154, cg15775 200, cg04422300, cg24325030, cg03060036, eg 10493185, cg22253168, cg07011512 , eg 1 2473257, cg04660686, eg 13878136, eg 10395603, cg08939974, cg22714000, cg03085224 , cg22372104, cg05523370, cg06168363, cg21051423, eg 12313954, eg 17321476, eg 1903 8278, cg02912828, cg23814223, cg22862208, cg21005072, cg08133062, cg06099304, eg 09387867, cg27303185, cg07207669, cg22574288, eg 18751203,cg00846297,cg2477468 2, cg04388076,cg23716309, cg13895393, cg07718324, cg16657103, cg20576896,cg160 27622, eg 14976658, cg03447546, eg 13187238 cg01282725, cg02725398,cg15835808, cg16564146, cg23545828,cg09293890,cg02799 298, cg26470737,cg06174360, cg06588802,cg27168133, cg10015665, cg13604909, cg2 3539633, eg 14419740, cg05984845, cg07826936, cg21817842, eg 17478534, cg06775068 , cg07346177, cg21963179, cg06033721 , eg 13752138, cg09728659, eg 16431802, cg0406 1284,cg00132863,cg20529866,cg26997176,cg25527254,cg16920991,cg27473972,cg 07101208, cg26242064, cg07606171, cg18546846, cg06496470, eg 12055395, cg0252206 1,cg01040097, cg03560743,cg20566286, cg13172554, cg22196878, cg16306959,cg045 09755, cg07545786, cg24181875, eg 16071105 cg07810770, cg06335515, cg09536368,cg00755470, cg15919772, cg13995651 ,cg22832 883, cg23288298,cg00930246,cg02115416, cg25386729,cg05270688,cg26269733,cg2 1850510, cg22761308, eg 14625095, eg 14876551 , eg 11973052, eg 18745274, cg09046056 , cg07321494, cg05383958, cg06258294,cg09131893, cg22528172, cg24866936, cg0099 9267 , cg23007040, cg26943082 , cg21897825, cg08264266, cg24293344, cg02661879, eg 21820890, cg09313053, cg07980995,cg12557418, eg 10821964, eg 11519623, cg2297894 0,cg02139671 , cg08704621 ,cg01083434, cg26224574,cg25258212,cg05886453,cg051 31533, cg12299478, eg 13683227, eg 18572353 cg12111351, cg14237069, cg09533820, cg16540134, cg22003283,cg01855245, cg18049 300, cg09733312,cg19365810,cg05353977,cg00096065,cg18611281 ,cg22120395, eg 1 3449418, cg27119004, cg23173307, cg07511259, cg22036813, cg07982740, cg23026930 , cg05329099, eg 10413169, eg 18482250, eg 12243763, cg08633209, cg07635106, eg 1349 1045, cg27451610,cg10759590, cg12413232, cg07972805,cg01850202, cg19513486, eg 26265457, cg07723345,cg05935576,cg22573917, cg00493139, cg21526357, eg 1760426 4, cg22402467,cg15281294,cg02026013,cg01169259, cg05710165,cg08884280,cg197 02047, cg06643080, eg 11229334, cg07092448 cg22775544, cg17850880, cg03847279,cg27492744,cg25130357, cg10146623, cg01103 911,cg07238434, cg09761288, cg23117647, eg 15764364, cg27358936,cg09377736,cg0 7807957, eg 17601785,cg03790189,cg02592999,cg 16462297, eg 10154677, cg24473832 , cg25440538, cg27387307, eg 18555787, eg 19471424, eg 13876960, eg 12069641 , eg 1010 7338, cg07514654, eg 17150306, cg27636961 , eg 19811148, eg 14067559, eg 10061721, eg 23335980, cg13180110, cg21747360,cg20049702,cg25903220,cg11217744, cg1145689 6, cg26975470, eg 17788342, cg21148642,cg10996258,cg 10197881 ,cg08831354,cg012 88645, eg 19469189, eg 13966699, eg 14784373 cg02040705,cg26064959,cg01163362, cg15854548, cg18947120, cg14321743, cg05919 314, eg 18369659 , eg 11348599 , cg27073349 , cg26388707 , cg04496665 , eg 13214149, cg2 0054085, cg02755635, cg06292396, eg 14900160, eg 12633911 , cg20698170, cg04843855 , cg07825023, eg 18935516, cg27243405, cg06462841 , cg26086339, cg25111337, cg2447 9859,cg20057935,cg11647719, cg13506281 ,cg17940495, cg08361278, cg19265304, eg 19725340, cg13526520, cg18023640, cg06319359,cg23352747,cg20930202,cg0429547 3,cg18624049,cg19415162,cg23997083,cg00519537,cg07567777,cg05183173,cg273 10761, eg 18321037, eg 18805343, cg01618923 cg11163337, cg13323364, cg03955932,cg06508056,cg01773293, cg14471943, cg06419 748, cg05221370,cg11921260, cg23813411,cg08018188, cg18641655, cg13004832, egO 6965775, cg20337871 , cg04595983, cg02940362, eg 10629806, cg00829594, cg21802208 , cg05717473, cg27237085, cg20930082, cg00763945, eg 15764264, cg05448440, cg2552 7554 , eg 11869183, cg23731331 , eg 10643493, eg 12874092, cg21600850, cg24433341 , eg 17333747, cg07460524, cg05304553, eg 18375974, cg20449816,cg09776434,cg 1632789 1, cg00983740, cg14446951 ,cg23894533,cg02681040, cg07122824, cg18195560, cg050 90785, eg 17341892, egO0183590, eg 17487029 cg23247476, cg00927256, cg12686273, cg16419457, cg01023808, cg23163081, cg13698 542, cg27002866,cg20316715, cg09274614,cg05194498, cg15673913, cg07226523,cg0 2550423, eg 12107908, eg 16266918, cg09732913, eg 17465410, eg 12081643, cg06907479 , cg07123550, cg00722394,cg03315346, eg 15858052, eg 14235273, eg 18790787, cg0423 2458, eg 19243398, eg 11823128,cg22344413,cg27269790,cg06596521 ,cg13377560, eg 15997719, cg00858439,cg09148147, cg24528350,cg23452414, eg 18627442, cg2385670 7,cg09370413,cg21221557,cg00440538,cg02457789,cg15799397,cg20872422,cg210 51473, cg06568438, eg 17700374, eg 18438647 cg26723928, cg14445311,cg23133513, cg01068931 , cg18567882, cg07984754,cg08743 032,cg06555521 ,cg21711958, eg 10636403, eg 19256532, cg21132577, cg07206053,cg0 6933163, eg 13916266, cg23166770, eg 14853565, cg23631669, cg06575692, cg25423755 ,cg17187835, cg04921244, cg07663260,cg09037514,cg09312809, cg10855874, cg1265 1540, cg07015203, eg 15077994, eg01238590, cg02282594, eg 13743913, eg 16648036, eg 10348904, eg 12085846, eg 15068520, cg27025384, eg 19138478, cg20487212 ,cg0305723 6,cg02315899,cg16673296,cg05924780,cg00087355,cg12488207,cg01742138,cg199 10890, cg25431432,cg07202598,cg04731618 cg07761524, cg07830794, eg 14353539, cg23371050, eg 11331215,cg08687052 ,cg26055 435, cg05579575,cg08482935,cg08320031 ,cg14237154,cg18664712,cg11105934, egO 1545186, eg 18178505, cg06250549, cg02336163, cg22478500, cg04834534, cg00007898 , cg08107701 , cg21222178, cg00885397,cg 14285638, cg00300637, cg07092880, eg 1384 5351 , cg24282488,cg05150664, cg27640114, cg07785556, eg 13805761 , cg26037727, eg 25546488, cg15719148, cg13882712, cg08901754,cg22545592,cg03669896,cg0135394 6, eg 19566417, eg 13016851 ,cg05331755,cg07262264,cg02669544,cg 10521128,cg089 98166, eg 15032393, cg23557597,cg04742556 cg20224084,cg06086073, cg18153326, cg25945732,cg15059513, cg04012600, cg20744 546, cg00086266,cg10985634, cg07228860,cg03252902, cg17799757, cg10832941 ,cgO 2580987, eg 15280876, cg00277388,cg21648686, eg 15444626, cg05562794,cg25440278 ,cg15179060, cg02537664,cg17907200, cg25735890,cg26694615,cg09363526,cg0117 2073, cg26961622, eg 13679466, eg 19580156, cg08520005, cg20974856, eg 14522632, eg 04861230, cg06058668,cg15231687, cg06861301, cg05203206,cg27301596, cg2274844 3,cg08366126,cg22264625,cg06237092,cg13163124,cg01414010,cg05861635,cg204 12255, eg 14332439, cg00007127, cg23005186 eg 15488427, cg06725884, cg06785147, cg08474748, cg23181968,cg09662430,cg 19607 165, cg16626623, cg14276006, cg27268120, cg14984570, cg09874271 , cg11453898, cg1 4829378, eg 10962336, cg00483256,cg26362613, eg 13258831 ,cg02706575,cg 17347593 , eg 15608645, eg 10096955, cg24260662, eg 16311044, eg 16879608, cg07340894, cg2144 1657, cg26105227, cg25900902,cg26893314, cg04186726, cg03495237,cg06983900, eg 21848117, cg27374423, eg 13864354, eg 10019844, cg04037044,cg 15636859, cg2366121 4,cg21012050,cg00584815,cg20133164,cg18479329,cg00853264,cg24659638,cg226 86400, cg07048951 , eg 12052144, eg 11813473 cg20825834, cg08880858, cg24099592 , cg25653449, cg21106508 , eg 15465121 ,cg22911 410,cg21097180,cg04520418, cg20817245, cg23270924,cg10949822, cg19593949, egO 1038167, cg17996099, cg01261503, cg27030612, cg25148528, cg00334424,cg07048017 , eg 10810769, cg00688819, eg 12680106, cg22202191, cg23765843, cg06478995, eg 1524 2175,cg04155450, cg23711036, eg 18027291 ,cg06617676,cg22421766,cg23849564,cg 10857750, cg24689177, cg03095548, cg24630141 , cg26217588 , cg02298771 , cg2109029

8,cg23766996,cg 11178684, cg24905864,cg23812848, eg 19300124, cg01084722, cg236 41283, cg11031708, cg21180080, cg18525873 cg08973419, cg10961323, cg05837855, cg12711018, cg15575339, cg24437221 ,cg09537 606, cg23899092,cg02958167, cg23588893,cg14835545, cg00562731,cg08743596,cg1 0336406, eg 12970914, cg00171700, cg08985767, cg26438819, cg02258066, eg 11963398 ,cg24156393, cg13254969, cg14837544, cg11971662, cg25332295,cg11180245, cg2317 1636, cg04513214, cg08167808, cg06430231 , cg20384702, cg27022853, cg22144937, eg 25276668,cg18255504,cg16550010,cg25948591,cg 14147055, cg08610041 ,cg0242525 7, cg08211538, cg11870309, cg18330571 ,cg21171772, cg21546532, cg26047440,cg045 12899, eg 13324826, cg21322436, cg20300315 cg04363092,cg24106734, cg02417523, cg13634602, cg17276794, cg22333163, cg00558 219,cg03452609,cg15754248,cg17100770,cg07895913,cg09568274,cg03520103,cg1 3320114, eg 13859533, cg06432061 , eg 19394857, cg08326019, cg04388898, eg01315201 , cg25876087, cg05402062, cg24120162, cg27460122, cg27578977, cg23049298, cg0999 8189, cg08717751, cg00819048, eg 17275624, eg 15199735, cg07897699, eg01321034, eg 11442616, cg26114457, cg08665704,cg27111925, cg00733375,cg02413974,cg2567089

9, cg15768810,cg02439778,cg25134283, cg02001916, cg12596527,cg07588014,cg140 11327,cg05388262,cg05469285,cg02770028 cg25349276,cg19168631, cg27447753,cg03846216,cg02034937,cg26374481 ,cg05860 079, cg15931507, cg00174447, cg13970216, cg27652974,cg13295050, cg20254419, egO 3189545, eg 19669978, cg07105947, cg06229674, cg05879734, cg00262061 , eg 12669014 , cg10407096, cg16905092, cg18778755, cg01177737, cg25072880,cg11732952, cg0317 3783,cg24107619, cg06375652,cg05098023,cg13508543, cg19135416, cg01769070, eg 23309303, cg18955698, cg13427473, cg24944979,cg01032946, cg20530585,cg0227902 3, cg18865631 ,cg08951101 ,cg24411043,cg21693060,cg17610181 ,cg10890501 ,cg216 18017, cg17860026,cg09871101, cg20610155 cg03582491, cg13770684, cg21106962, cg16353345,cg24354664,cg08926977,cg21028 994, cg23265294,cg19053250, cg21322149, cg15392109, cg00541100, cg14121014, cgO 1909777, eg 16277777, eg 12076770, cg23172884, eg 18656873, cg09805692, cg04481062 ,cg27400208,cg17873829, cg26157534, cg11784537, cg26526047,cg12706256,cg2245 3818, cg11283829, cg05011414, cg22373112, cg15756420, cg03381546, cg26932830, eg 17015173,cg13471735,cg26999041,cg11103273,cg23341126,cg06757810,cg2410179 0,cg08084154,cg07385743,cg09955304,cg04169881 ,cg21323106,cg00848245,cg182 47396, cg04032181, cg26001655, cg00415119 cg21646032,cg01832997,cg24206161,cg00748092,cg22112340, cg01777397, cg04799 838, cg10010036, cg16578864, cg17331567, cg20857207,cg19150929, cg26910936, cgO 2285673, eg 14050954, cg00902140, cg21915811 , cg26873392, cg06790661 , eg 12289801 ,cg25818299, cg19571598, cg18753664, cg02977388,cg10185890, cg06482925,cg2275 2345, cg08697709, eg 18986451 , cg00041980, eg 14624806, cg01610639, eg 18427036, eg 20595477, cg08159269, cg24321297, cg05749126, cg06193561 , cg11895615, cg1395690 7, cg16867680, cg07592724,cg15052447, cg18393511 ,cg07177011 ,cg00454044,cg261 62160, eg 14732547, cg06636356, eg 16904446 cg25554596, cg05142617, cg09235900,cg13822158, cg19253120, cg18278528, cg11143 475,cg05490069,cg04034095,cg24966902,cg23032364,cg07485457,cg22870710,cg1 7858283, cg01845277, cg22943580,cg03601211,cg21699602, eg 17580020, eg 10007075 , cg23811057, cg01235305, cg06300884, cg06623333, cg22613601, cg03306946, cg0726 4223, eg 13464717, cg04589904, cg25586244, cg27236242, cg01255337, cg00719568, eg 10320759, eg 12039910, cg08206820, eg 13029758, eg 19647865, cg22092397, eg 1160294 4,cg10414074,cg12301584,cg04599946,cg09001356,cg03408497,cg12358061 ,cg078 19892 , eg 18245269, eg 17372581 , cg23668160 cg26486640, cg22150750, cg03424174, eg 13180038, cg23041045,cg25557260,cg 14279 997, eg 15351741 , eg 17981236 , cg09103423 , eg 13593617 , cg24770845 , cg06465330, cg2 0480427, cg24022206, cg22130216, eg 19626403, eg 12045634, cg25961123, cg23137184 , eg 14240393, cg04421891 , eg 15454895, eg 18904993, eg 16789849, eg 18403673, cg0318 6425, eg 14691388, cg03078097, cg09703142, cg06545213, eg 15225188, cg20077773, eg 11781319, cg01950058,cg04031411,cg15554338,cg24664798,cg12152315,cg1818776 2, cg13342590, cg18676070, cg05913141 ,cg03048488,cg21617031 , cg16222612,cg146 31910, eg 16387654, cg06392331 , eg 10606512 cg07082484,cg01528340, cg16570738, cg09965165, cg03218073, cg05114733, cg06527 124, cg12083083, cg16942579, cg25499033,cg18586479, cg14970186, cg01263474, cg2 4492744, cg25051970, cg23550034, cg23149986, eg 10012533, cg27514653, eg 11443017 , cg26286198, cg25382338, cg07514693, cg02837162, eg 12549554, cg00038020, cg0746 6531 , cg14597848, cg11044823, cg01171264, cg01446731 ,cg16128122,cg14817226, eg 00984009, cg07338058, cg21377881 , eg 12886293, eg 14446033, cg09738259, eg 1730443 3, cg13153710, cg12417815, cg03583643,cg15456502, cg00426425,cg12793510,cg081 60172 , eg 10206882 , cg20306022 , cg02505827 cg14905039, cg07251280,cg11052190, cg23787564,cg22510961 ,cg13981380, cg17713 399, eg 18603679, cg07933493,cg04717045,cg08765638,cg00080989,cg24719366, cg2 5301142, cg08944986, eg 16168723, eg 12821058, eg 15851309, cg02330548, cg25863895 , cg03749016, cg05508408, cg05094594, cg26652562, cg02617551 , eg 16582792, cg0592 5767,cg09034874,cg08587406,cg07054788,cg08459746,cg03500452,cg06979412,cg 25017250, cg01131790, cg11057199, eg 16024892, eg 11294750, cg04817148,cg2390223

2, cg14954998, cg18169510, cg14338830, cg08318336, cg10999045, cg07012128, cg229 71600,cg05815818,cg04320404,cg25823332 cg22233425,cg23988529,cg23718283, cg12300074, cg06803436,cg10135571 , cg23435 082 , cg00846988 , cg25248124 , cg00600933 , cg05863116 , cg07876823 , eg 17810066 , eg 1 5292949, cg24411488, cg27608742, cg02046340, cg08940637, cg04214103, cg08190441 , eg 16807089, eg 12788320, eg01217745, cg21296402, eg 11954763, cg06531205, eg 1344 1784, cg20380755,cg01773584, cg18637232, cg04679515, cg17270519,cg25481844, eg 25874150, cg27056418, cg00731003, cg14258745, eg 17020782, eg 14569250, cg0955409

3, cg10923746, cg00110724, cg03740864,cg00273543, cg14082658, cg09372617, cg044 56892 ,cg02163039, cg27485530,cg21445676, eg 10917156, cg27337217, cg26280758, c g26702236, cg18342814, cg25961805, cg22395422,cg03031352, cg13808011,cg122203 53,cg23535917, cg22562590,cg20998469,cg10976745, cg15221554, cg00131115,cg01 530024, cg19076895,cg08017248,cg04817613,cg17779296,cg03697708,cg20497212, cg19135382, cg05365887,cg00385063,cg11451230, cg21035483, eg 15080866, eg 10061 107, cg00597666,cg15275636, cg15636860, cg10959440, cg20781713, cg16819395, cg1 3955487, eg 11342678, cg02377509, eg 14079018, eg 15377152, cg00602245, cg21504064 ,cg05295841,cg20835656,cg09459339,cg05654290,cg03096954,cg20371891,cg0442 1553 cg17218814,cg03841136,cg26218380,cg12351039,cg09534501 ,cg06536378,cg04481 722, cg08170141 , cg13340442, cg01135834, cg02339197, cg27440659,cg14977879,cg0 5805997, cg00643829, cg23486580, cg23042847, cg24332435, cg06359096, cg22608179 , cg25833989, cg09714851, cg24249450,cg 15374777, cg07798774, eg 17415239, cg0404 7293, cg21430814, cg03436878,cg05143092, cg18789918, cg16579190, cg26733352, eg 06891164, cg23208430,cg01018360, cg24198611,cg00537351 ,cg08110692, cg1167167 0, cg08795589, cg15253204, cg16743005, cg01823079, cg19943781 ,cg06528862,cg197 83404, cg26074535,cg05588169, cg23765633 eg 12494446, eg 12419239, cg00781833, cg00557854, eg 17632590, cg06845722 ,cg02939 105, eg 16296438 , eg 16106062 , cg05329480 , cg24662653 , eg 15729809 , eg 16071359 , eg 1 9263448, cg07850896,cg04394496, eg 11233586, cg21051668, eg 12639498, cg05899471 , eg 12563872, cg24890103, cg03669033, cg21631854, cg23900696, eg 10920339, eg 1506 9315, cg00623655, cg08247347, cg23715214, cg25383615, cg24407312, eg 11165960, eg 13988645, eg 19633446, cg01938249, eg 10847113,cg22341471 ,cg10609370, cg2683465 0, cg22062450,cg04742515, cg01740768, cg01192051, cg25607025,cg02654358,cg236 27353, eg 19545098, eg 13811911, cg22840441 cg05921260,cg12193817,cg08131401,cg06338928,cg14242727,cg09427273,cg01514 449, cg14576128, cg01974869, cg19078846, cg26062979, cg16904399, cg13024382, cg1 3995193, eg 15581201 ,cg25848630, eg 17179923, cg20345589,cg01535380, cg22857328 , cg06835786, cg05350879, cg05952543, cg06443562, cg25665909, cg24510074, cg0826 7789, eg01661211 , eg01449724, cg21653489, cg05846798, cg21044797, cg00209431 , eg 09835575, cg06293629,cg20426698,cg12313832, cg26230851 ,cg21849844, cg2029790 7,cg04079617,cg08801953,cg06635764,cg20899151 ,cg22124859,cg15863128,cg212 32671 , cg06623385, eg 12118979, cg03587511 eg 10579128, eg 13997469, eg 17086748, cg07525221 ,cg01023967, cg04470754,cg09917 566, eg 17007658, cg06046714, cg00159214, cg02248320, eg 17423458, eg 14955615, egO 2405016, cg12741142,cg02249322,cg09994445,cg06108459, cg22330924,cg18994205 ,cg24135606, cg08755517,cg00203736,cg07376696,cg19129887, cg00711959,cg2181 3376, cg21302289, cg05630272, cg23815915, eg 19510247, cg09798688, cg24754223, eg 12585732, cg21924617, cg27270565, eg 14354272 , cg09385285, eg 19400076, eg0112225 1,cg01662301 ,cg02050376,cg02222722,cg13543833, cg20237890,cg23265500,cg075 12645, cg02175741, cg09244200, eg 17623197 cg20145897,cg01245223,cg04539418,cg20699573,cg07111861 ,cg17744019,cg06541 894, cg06652146, cg20102019, cg02239021,cg22821554, cg05155450, cg01021488, egO 6749502, eg 11062956, cg24959365, cg02335141 , eg 14430679, cg02730364, cg24674138 , eg 14490515, cg06335843, cg25632561 , cg08053414, cg03707061 , cg08804096, eg 1130 3204, cg26187962, cg04070324,cg12076953, cg22861891, cg11129769, cg22809952, eg 05959265,cg15371835,cg09959585,cg17455297,cg19447630,cg 14132013, cg0619751 7,cg04796091 ,cg07586819,cg20132173,cg01532946,cg03842617,cg10824491 ,cg109 43931 , cg03838714,cg09564132, cg00699934 cg02347881,cg20691469, cg01981252, cg18621433, cg26558951 ,cg22981961 , cg25939 869,cg01810719,cg24652271 ,cg20796968,cg09610767,cg24676612,cg16381207,cg1 0589462, cg05401364, cg05545454, cg21294945, cg22424056,cg18165707, cg10030417 , cg02969343, cg05460226, eg 17085250, eg 19408145, cg09416959, eg 10377629, eg 1321 3987, cg07877852, eg 14499653, cg03381863, cg04285257, cg21864323, cg09993189, eg 12160330, cg14375754, cg21310911,cg26584152, cg12054080, cg01206171 , cg0212491

8, cg02668177, cg01856558, cg22447778, cg12871964, cg13606592, cg10490370, cg013 75124, cg11818449, cg09430020, eg 13691428 cg24756642,cg19035181, cg07569575,cg19701084, cg22246906,cg01282402, cg11594 892,cg26993213,cg16775678,cg08658111 ,cg26931115,cg25448999,cg06573741 ,cgO 6243638, eg 10545536, cg24361079, eg 14768311 , eg 10029105, cg03598494, cg06830704 , cg04747863,cg26449328,cg26109401, cg10658349, cg15052791 ,cg03982355,cg0885 2641 , cg09322023,cg24994736,cg04264103, eg 13780315, cg20528127, cg24024426, eg 06325249, eg 19014186, eg 17298925, cg22279585, eg 12132969, cg07500432 ,cg2319302

9, cg15879630, cg02717655, cg27503398, cg14666310,cg27583171 , cg12025732,cg181 98301 ,cg22780193,cg05750047,cg00826313 cg08669738,cg23680049,cg21163200, eg 13655566, cg23072711 ,cg18310007,cg14117 481, cg27170178, cg06558623,cg04212568, cg14817923, cg05551748, cg22567305,cg0 3652715, cg04747996, cg26826793, cg21368091 , eg01138422, cg24678581 , cg02823783 ,cg22018742, cg27300887,cg23927769, cg18260416, cg00997699,cg20339840,cg2188 8154,cg15081722,cg24585833,cg08188436, cg04761414,cg00103075, eg 17600948, eg 27521838,cg00013301,cg04811316, cg21497990, eg 16317440, cg06404526,cg0563718 8,cg06653176, eg 17860117,cg08017249, eg 16718710,cg25671376,cg04641380,cg166 94182, eg 18425570, cg05600044, cg21954138 cg25091573, cg03387842,cg05147677, cg20994225,cg05639937,cg08287285,cg27475 349, cg10744318, cg27598761 ,cg02304909, cg11354908, cg18409646, cg04468493,cg1 7095810, eg 19015303, cg26734421 , cg09039252, eg 14493103, cg21772168, cg06836877 , cg25198545, cg09967308, eg 10968036, cg00324719, eg 11090352, cg21223075, eg 1116 5254, cg04721023, cg03636183, cg11575359, cg22436527,cg24149324, cg21458041, eg 15781363, cg08351163, cg02987249,cg05263382,cg00780810,cg24100017,cg2428602 1 ,cg05768272,cg15453315, cg08642081 ,cg18104148, cg17525879, cg02493842,cg201 41751 , cg21281379, eg 18589526, cg08254831 cg19942977, cg13735819, cg03340174, cg05200606,cg26578408,cg02148024,cg02399 454, cg05350199, cg21581821 , cg22741823, cg18062860, cg18801825, cg01781567, egO 1939220, cg02917596,cg11985116, cg16529477,cg04944931 ,cg14156381 ,cg12896940 , eg 15583263, cg22268340, eg01475980, cg25005611 , cg20823977, eg01207437, eg 1007 5436, cg21839338, cg02644610, eg 12692440, eg 18128182, cg26927939, cg00908553, eg 10660367, cg05670650,cg20331102, cg23652146, cg21593690, cg02350425,cg1468533 9,cg23716866,cg24691329,cg20047677,cg 19529599, cg02508008, eg 19677893, cg013 01805, cg13126844,cg09801687,cg13591427 cg08245420,cg18750049, cg22700027,cg06055845,cg07030052,cg09328049,cg05925 971, cg06399881 , cg14144229, cg05000431 , cg17921863, cg17942553, cg03123104, egO 2451508, cg04217306, cg07965110,cg17625781 ,cg09451572,cg05976652,cg23069718 , cg20972416, eg 11035319, eg 15254632, eg 14596247, eg 18964076, eg 10975798, eg 1695 8668, eg 11201229, eg 15442746, cg22431466, cg06735601 , eg 12672548, cg24789907, eg 16316042, cg15183457,cg05629898,cg19794013,cg16346827,cg12239378,cg0513181 5, eg 11380580, cg24467794, eg 17938553, cg22180994, cg27340703,cg20792010,cg085 08567, cg00717022,cg23971160, cg16595750 cg09221478, eg 10219164, cg09746063, eg 18793799, eg 15541287, eg 13686331 ,cg00046 819, cg21568585, cg13968679, cg12048508, cg16259362, cg13453424, cg12588957,cg0 3668475, cg00075608, cg24226148, cg23014176, cg25975873, eg01401037, eg 15255653 , eg 13377965, eg 19915997, cg26927231 , eg 13251484, cg04939302, eg 16925733, eg 1110 0993, cg11943190, cg27282550,cg09016162,cg23261372,cg11791726, cg07416885, eg 27246938, cg00960781 , eg 14836905, eg 15711288, cg02379339,cg 12862567, cg0863544 9, cg18762944, cg12296326, cg18499001 , cg14259179, cg19464231 ,cg09932216,cg154 98228, cg03891993,cg03526325,cg08339915 cg00124685, cg05465134, cg19773477, cg21886959, cg10461076, cg11845159, cg03801 680, cg26808687,cg10455200, cg04498198, cg12185828, cg05840756,cg09820557,cg1 4556646, eg 18999998, eg 18813545, cg03652564, eg 11018363, cg09613745, eg 17345703 ,cg08040094,cg10238302, cg10046212, cg19680485, cg25810695, cg02230854,cg1715 9137,cg02644711,cg04634061 ,cg16667232,cg09330979,cg15676837,cg06798642,cg 23070599, cg01835232, cg26055446,cg00516272, cg25680008,cg25920792,cg2242282 5, cg20285274,cg00458261 ,cg03367643,cg05873359,cg15897287, cg24339370,cg166 93881 , cg24375465, eg 15369063, eg 16936953 cg11238028, cg26127231,cg19410645, cg17978331 ,cg26877380,cg19928294, cg05798 633, cg04925599 , eg 12806067 , eg 11238129, eg 16447704 , eg 12108849 , eg 14914924 , cg2 1045828, eg 14387335, cg08458637, cg08962888, cg24004055, cg04476531 , cg06411137 , cg22339647, cg24793300, cg22310079, eg 17211779, cg03958841 , cg06335209,cg 1042 1587, cg09913382, cg03678566, cg24810404, eg 17330047, cg02089721 , cg23311967, eg 09428487, cg19586851, cg06729284,cg09190907, eg 14635132, cg06535121 ,cg1115764 0, cg18962557, cg22758721 ,cg01315151 ,cg05726910,cg00003622, cg18030133, cg176 03321 , cg01442529, cg23670563,cg02410828 cg25597434,cg19527946,cg17929068,cg03644629,cg01092811 ,cg06681240,cg09511 896, eg 13292263, cg21128127, eg 16347403, cg08849079,cg01982045, cg07066019, cg2 0440041 , cg04018164, cg04179482, eg 15609002, cg09600096, cg24539536, cg27122888 ,cg15818631 ,cg19452060, cg08697285,cg26504229,cg27180298, cg05061370,cg0783 5844 , cg24868790, eg 11455895, cg03348631 , cg04832619, eg 10336072 , eg 16961397, eg 17491947, cg09290242,cg14857024, cg16885876, cg00842158, cg06009031 ,cg2499040 0,cg27183456, cg21866931 ,cg 13692196, cg02560408,cg02857166, eg 11885976, eg 190 84075 , cg03635968 , cg23960736 , cg05662892 eg 12910977, cg00998782, cg02473594, cg00005306, cg00620112 ,cg 10794502 ,cg05720 939,cg05116876, cg02694446, eg 10016885, cg26389380,cg25329589, eg 16100446, egO 6176471,cg04318178,cg05151496,cg23151508,cg06224161 ,cg04582539, eg 12032713 , cg05226462, eg 10511390, cg21342789, cg09370066, cg24051516, eg 11775367, cg0657 0207, eg 17079497, cg04867019, eg 18359780, cg05463193, eg 11325609, eg 17659363, eg 19568540, cg16220624, cg14170095, cg11789766, eg 18892132, cg06188834, cg0033619 3, cg06413461 ,cg05261851 , cg17870748, cg09327253,cg08761223, cg02405530,cg212 87819,cg08991643,cg05009464,cg05729199 cg09278623, eg 12954985, eg 11176472, cg18259290,cg13479215,cg22076118, cg08863 473, cg10269366, cg15078990, cg27420264,cg26547821 ,cg24257740,cg08735716,cg2 3063374, cg09460013, cg00040738,cg08202725, eg 17755923, cg01065821 ,cg23520889 , cg00419757, cg03245084, eg 14984143, eg 18890892, cg21486954, eg 15382743, eg 1094 1258, cg23715548, cg07517144, cg03067207, cg04655365, cg26801241 , eg 15928377, eg 14043803, cg09627043,cg04031201, cg24217756, cg08236479,cg08419827, eg 1378777 5, cg14982594, cg15299888, cg03325843,cg08699050,cg00644447,cg26886089,cg175 62226, eg 18679299, cg23529669, eg 19883936 eg 14326631 , cg23063506, cg27028085, cg06109846, cg08570343,cg26476599, eg 11725 975,cg01553063, cg01075399, cg15683497, cg24802517,cg12190504, cg10736231 ,cgO 8743199, eg 13066630, cg06268174, cg08104132, eg 14548858, cg07056537, eg 10094691 , cg07365343, eg 17423568, cg23045091 , cg05605194, eg 11953541 , cg04593828, cg2226 6824, eg 10644890, cg23599716, cg02110746, cg27506178, cg09441550, cg22238397, eg 27265307, cg05318567, cg04702535, cg02944238, eg 17415382 , cg07001420, cg2632253 5, cg00175344, cg11607949, cg07047119, cg27082627,cg24732702,cg04101495, cg130 27634, eg 13401533, cg05824762, cg22793203 cg20066347, cg24689754, eg 13823701 , cg22327778, cg02136622 ,cg24605948, eg 19843 411 , cg16701228, cg03502236,cg20966273,cg24069188, cg15393420, cg10690277, cg1 4637083, cg26031954, cg04033442, cg08864035, cg23168648, eg 19310162, eg 15499112 , cg22525105, cg20794462, cg05418395, cg23246666, cg25337691 , eg 17953249, eg 1526 0763, cg23147149, cg08640420,cg05421965, cg26504926,cg10901291, cg05275368, eg 03271936, cg02963550, eg 10705731 , cg08952523, cg07562821 , eg 14712624,cg2471521

6,cg24574793,cg21805535,cg05084811 ,cg15842898,cg16710094,cg06068118,cg242 60838, cg00321228, eg 12846407, cg27269149 cg24752923, cg18604419, cg13646708, cg24146773,cg14459543,cg04264608,cg11515 658, eg 17312501 ,cg06460866,cg 19502700, eg 10319247,cg24330902,cg 15991700, cg2 6513734, eg 11847312, cg04944900, eg 11347328, eg01293250, cg26105803, eg 13116906 , eg 10578446, cg26737458, cg24425422, cg00834536, eg01566034, eg 19992761 , eg 1707 3300, cg04203429, cg24736471 , cg23255151 , eg 15112952, cg03317075, cg08180831 , eg 13368042, cg15017865, cg13060434, cg02028388, eg 10862717, eg 10656756, cg2041750 0,cg21909475, cg05793193, cg25224376,cg23441404,cg11960334, cg22889768,cg087 52277, cg26723698,cg24320290,cg03990903 cg16161716, cg12739914, cg14737484, cg10777795, cg02156911 ,cg20823793,cg10941 966, cg11678637, cg03623532,cg01825137,cg01582438,cg10007211 ,cg17565880,cg0 0211208, eg 14935480, cg00334798, cg04318989, cg21214470, eg 13512951, cg08905969 ,cg01961881,cg07394898,cg24929264,cg00084888,cg03694515,cg16423511,cg0856 6044,cg00281099, cg13609089, cg22876519, cg23302988,cg18860292, cg15673285, eg 11414012, cg06550676,cg25773011,cg23515460,cg06975120,cg09949687,cg1415695

7, cg01635280, cg01658573, eg 11558107, cg25360211 ,cg12389943, cg00980331 ,cg185 20369 , cg05901340 , eg 11508373, cg24758814 cg03306024, cg00220302,cg26204978,cg27158675, cg00344801 ,cg08446346,cg06807 370,cg02768671 ,cg21824985,cg20235133,cg08963419,cg12777178,cg07524855,cg1 1277148, cg09121772, cg02446081 , cg24218077, cg26639596, eg 17258442, eg 16334127 ,cg09582658,cg00612715,cg04590605,cg20087295,cg04397839,cg03794166,cg1099 3924 , cg04026701 , eg 18746318, cg20912641 , cg22756142 , cg26328288, cg03901886, eg 26409237, eg 15262884, cg26025939, eg 19786686, cg08683522 ,cg20238197, eg 1013002 2, cg08097923, cg16632096, cg05869617, cg21544781 ,cg24487279,cg08107960, cg092 40793, cg25389863, eg 14210447, cg07415354 cg00409917, cg10284605, cg08503737, cg14776311,cg06696916, cg15246805, cg04055 693, cg09474092, cg10486244, cg19497511 , cg15530474, cg21057613, cg05656166, egO 8916844, cg01494384, cg25276640,cg02897359, eg 16692534, cg04555304,cg27416948 , cg21919094, cg25653103, eg 18376437, cg22448179, cg22997856, eg 16797673, eg0187 7565, cg02513147, cg12836825, cg20250189, cg07500747,cg14697930, cg16513809, eg 22009138,cg23811952, cg03124708, cg23071107, cg04672129, cg08333105, eg 1451890 7,cg22069341 ,cg00062245,cg20055316,cg06614611 ,cg27055390,cg07557612,cg199 89287, cg26981299, cg05168580, eg 14861920 cg13980795, cg20826914, cg22375082,cg18845838, cg05940536,cg08134545, cg01348 055,cg07409284,cg25027885,cg21129670, cg04438035,cg03138188, cg23516634, eg 1 6608665, cg01284776, cg06341543, cg05940386,cg15512879, eg 11571573, eg 16295988 , cg07233838, eg 11400946, cg08898868, cg00434884, cg27058052, cg20663846, cg0246 1776, cg23031444, cg21022775, cg20445807, cg08578503, cg00208000, eg 10936661 , eg 09626705, cg16889202, cg16927811, cg14725719, cg19774776, cg00147801 ,cg0996420 4, cg01026046, cg09790035,cg16613133,cg05901550,cg05870889,cg24305861 ,cg071 80834, cg03953460, cg22949077, cg23678891 cg11248254, cg25516230,cg05281126, cg06037246,cg27577583,cg11255075, cg13160 963, cg10821136, cg16706004, cg19004887, cg02566518, cg02073763,cg13854296, cg2 3104177, eg 16769791 , cg24232508, cg09247259, cg21178548, cg03061758, eg 18800948 , cg27616660, cg08844365, eg 16849481 , cg05358181, cg07465275, cg21184428, cg0650 8934, cg13991616, cg00731062, cg20992256,cg03419646, cg21546668, cg03922648, eg 16942223,cg14121701 , eg 18215280, eg 12083217, cg02399652,cg25266521 ,cg 1991433 6, eg 12426640, eg 17542296, eg 16650201 , eg 11666994, cg03432241 ,cg17193220,cg220 84381 , cg24354933,cg06237487,cg05732979 cg00029640, eg 10962977, eg 15849997, cg02407545, cg06326072 ,cg21923929, cg21611 965, cg26905126, cg05651417, cg18582824, cg08205593,cg13275515, cg01369908, cg1 0257078, cg09340485, eg 15361256, eg 16269400, eg 10446031 , cg03193079, cg26657086 , cg26693979, cg06205074, eg 18761745, cg06482783, eg 11864402, cg08476006, eg 1063 5149, cg16745969, cg26436026,cg07438660,cg05153781 ,cg05357777,cg27153942, eg 04500146,cg11848015, cg01782533, cg00058903, eg 17451493, cg09249803,cg0934011 0,cg24003866, cg13313295, cg25625860,cg01854994, cg02703198, cg16235088,cg248 36366, eg 14389884, eg 16515477, eg 17444231 cg13983277, cg02998463,cg23912455, cg19932930, cg13391067, cg07483811,cg21801 252,cg12882103,cg14971718,cg19923600,cg07060872,cg22808815,cg12841328,cg0 1183358, cg22376688, cg04205664, cg03444976, eg 11493223, eg 12557948, eg 11752061 , eg 14461613, cg03393625, eg 14061529, cg24790080, cg22680285, cg05888362, eg 1004 4193,cg15138543,cg08833509,cg04894439,cg12226865,cg07239593,cg26028595,cg 00521399,cg04341990,cg08491721,cg00280066,cg03871489, eg 16816001 ,cg0534619 3, cg26722522, eg 17260962, eg 11798723, eg 12645066, eg 10403292, eg 16899351 ,cg060 60659, eg 17435897, cg00927855, eg 11730100 cg05885483,cg05257322, cg14657710,cg22071763, cg22441338, cg10732977, cg02742 259,cg02343602,cg02259284,cg14621698,cg24329557,cg09595603,cg22659564,cg0 6340679, eg 11423290, cg06611524, eg 14558406, cg23070771 , eg 16419724, eg 12617794 , cg03047865, cg06619693, eg 19080354, cg22375689, eg 13460221 , cg23013687, eg 1479 1737, cg07327358, cg09864227, cg21940292, eg 13277298, cg00526899, eg 13335686, eg 19421370,cg20431832,cg21422336,cg05782361,cg04227087,cg24250820, eg 1319270

6,cg03608224,cg23427054,cg07245160,cg07065523,cg13197094,cg07950795,cg200 32668, cg24176288, cg09719031 ,cg24448013 cg11861579, cg08302912, cg06801852, cg01785473, cg14137707, cg01083651 ,cg05840 707,cg22222526,cg05083539,cg25401574,cg06955189,cg07914919,cg25524108,cg0 9166345, cg20231769, cg24368447,cg19194924, cg21634547, cg21031160,cg13851941 ,cg00393511 ,cg15602508, cg00676536,cg09664824,cg19883017, cg17532671 ,cg2446 5573, eg 18595198, cg21676191 , eg 11717189, cg07735194, eg 13230709, eg01807574, eg 03982487, cg08646570, eg 14862864, cg23497504, cg08938402 ,cg02594677,cg2760530

7,cg16821345,cg13121780,cg13617035,cg17019292,cg21364818,cg05256971 ,cg139 25678, eg 17538088, cg06527752, cg08384130 cg24261944, eg 19544441 , cg06705834, eg 13966558, cg26752562 ,cg24827511 ,cg 14686 165, cg01646147, cg26701270,cg02340615, cg01871682, cg17272571 , cg24324415, cg2 0217592 , cg03127584 , cg23280704 , cg04398526 , cg27441182 , eg 12124049 , eg 15167955 , eg 12552626, cg07516329, eg 15602329, eg 13571678, eg 18563599, cg03183889, cg0969 3059, eg 10704709, cg04641754, cg09239016, eg 19593401 , cg20347079, eg 14324721 , eg 23476802, eg 19309054, eg 11937448, cg06387147,cg12970154,cg13189652,cg1524783 2,cg00778921 , eg 15773049, eg 17677112,cg25296860,cg17101879, eg 14006266, cg240 12044, cg21194140, eg 10778770, cg21102555 cg18915648, cg26554230,cg23163754, cg20634074,cg26104384, cg07481097, cg08451 817, eg 10287461 ,cg 14014267,cg26979518,cg23123140,cg20851750,cg08527161 ,cgO 5812622, cg25584870, eg 19722041 , cg02212772, eg 13027206, eg 19607474, cg10054405 , eg 13106156, eg 18390991 , eg 17948136, eg 15185804, cg08038178, cg24243568, eg 1908 8961 , eg 10477938, cg05495450, cg03803009, eg 11404156, cg07277017, cg25872789, eg 20637653, cg23085167, cg02629761, cg06106126, cg07968224, eg 10526418, eg 1623672 5, cg13353339, cg00801034, cg01780245, cg18302334, cg27394794,cg19508726, cg043 74786, eg 15166718, eg 14391469, cg27538686 cg17967403,cg17802514, cg16261871 ,cg25935716,cg09623164,cg07909630,cg05063 680, cg16919501 ,cg23515269, cg16867414, cg06000233,cg12600163, cg12789958, cg1 2854979, cg05917686, cg04387969, cg22206370, cg21804045, cg05507002, cg06568789 ,cg24221965, eg 12852759, eg 16232698, eg 15583738, eg 10887224, cg08186275, cg0410 9918, eg 10441070, cg06486065, cg09900585, cg20657858, cg09969676, cg21268144, eg 04644810,cg04161194, cg01041648, cg13174522, cg14618788, eg 11235487, cg0128143 5, cg14648877, cg19514854, cg12795179, cg02217330, cg15653263, cg24734418, cg142 81144,cg23392097,cg08181610,cg03147861 cg04533919,cg00611864,cg04647953,cg22422937,cg16432308,cg09800508,cg23111 106, cg09969011,cg12580847, cg00499448,cg13106051, cg21378273, cg03773681 ,cg2 7544375, cg04857710, cg20547155, eg 10068478, cg26877462, cg02255887, eg 15686225 ,cg11861532, cg05102880, cg15088522, cg25405238,cg11032640, cg17341482, cg1669 7428 , cg03512250, cg21410961 , cg06657041 , cg02385153 , cg09972077 , eg 19084053, eg 10415514, cg04252942,cg07992259,cg14112041, cg25515798,cg25287708,cg2502760 3, eg 13422834, cg20436458,cg25240805,cg08583708,cg01109169, cg04318200, cg067 95101 , eg 15192446, cg24420703, cg05399746 cg17057934, cg04826413, cg20098251 ,cg11373451, cg01154447, cg00133448, cg26062 581, cg23975144, cg22912577, cg17336701 ,cg05999983,cg26964202,cg06739525,cg0 0113981 ,cg23025903,cg02134515,cg27153492, cg20798872,cg08953545,cg10133177 ,cg17497599, cg04187887, cg06883555,cg25755829,cg14491820,cg07485357,cg1521 2585, eg 11128476, cg24805089, cg27539352, cg21943842, cg02509086, eg 17607722, eg 05628766, eg 12397349, eg 18813588, eg 10617143, eg 19880899, cg27594282 ,cg0518622 3, cg13001919, cg24229776, cg24621629, cg24846030,cg15799080, cg17766316, cg029 73012 , eg 14209926, eg 16306964, eg 14279842 cg21543670,cg23497217,cg00686915,cg03851798,cg07131336,cg16858635,cg01224 221,cg22918133, cg22249386, cg12513920, cg19146301 ,cg24921829, cg14355694,cg1 6120796,cg04931037,cg06999661,cg24601967,cg12491257,cg22643193,cg04101806 ,cg11981744, cg08147753, cg12553864, cg02662030,cg08960830,cg27333419, cg2046 6204, cg02649940, cg25900017, cg02568123, cg07070413, eg01456736, cg20270253, eg 13835715,cg17506328,cg17639867,cg20925722,cg15172346,cg 15561305, cg2609831 2, cg09304598,cg00625026,cg07519485,cg09223513,cg11410521 , cg21421634,cg173 11063, eg 17563376, cg21690489, cg20167589 cg24806709, eg 16612097, eg 12188197, eg 14138591 , cg08801671 ,cg09865521 ,cg24168 061, cg02041470,cg01994028, cg01457612, cg26660598,cg09903556,cg25757737,cg0 8197714,cg04493899,cg09361304 List 2 "intolerance_9,676 sites" cg03188627, cg15124881 , cg01108434, cg12773992,cg16438248,cg23985209,cg11936 089,cg 19119284, cg26210521 , eg 12666614, cg05377754, eg 13960778, cg00312762, cgO 4074624, eg 13981729, eg 14398337, cg02587383, cg07769732, cg25710809, cg06143244 ,cg25653506,cg20396870,cg17317383, cg13422535, cg21422672, cg01986502, cg0356 1330, cg00047079, eg 10829210, cg20448203, eg 13388025, cg06986184, eg 17583264, eg 08242354, cg03785692,cg07221855, cg05725489, eg 17973328, eg 10332022, eg 1331547 1, cg14823860, cg02468154, cg06185789, cg08541923, cg14962050,cg23340249,cg257 58263, cg08863967,cg03445220,cg04985016,cg19218358,cg12102756,cg05230927,c g02736602,cg13020754, cg03790745, cg12902040, cg02692850,cg00321357, cg193175 65, cg09713713, cg22221266, cg03033447, cg25090002, eg 14239751 , cg00411784, cg05 457490, eg 12692919, eg 10992198, eg 12584112, cg02180798, cg04400298, cg03034552 , cg06867407, cg06015733, cg26218737, cg09416598, cg24791205,cg09766243,cg04391 685, cg17967817, cg07057636,cg03072277,cg00969254,cg13560760, cg06875308,cg1 3558954, cg22109056, cg25367559, cg02137809, cg00391332, eg 12120973, cg01198024 ,cg22598233,cg20659657,cg08173520, cg05692532,cg14235685, cg16727416, cg1120 6334, cg09666372,cg11103255, cg26856604,cg09705531 ,cg02231834, cg05736730, eg 07611279, eg 18683143, cg00866179, cg21917866, cg06523844,cg 17035266, eg 1559697 1 ,cg21389355, cg04680209,cg11277380, cg02339888,cg26997085,cg21832906, cg104 95669, cg16079716,cg07975573,cg01215169,cg23801281 ,cg02379870,cg00771490,c g21872822, cg04093065,cg24382178, cg11843700, cg05834228,cg24460383,cg027089 04, eg 17570835, eg 10249012, cg01022879, eg 11569385, cg23725024, eg 13551074, cg04 828068, cg08872579, cg21192775, eg 10712201, cg08038291 , eg 16075597, eg 18898992 , eg 18521841, cg24256830, cg21203652, cg25219896, eg 10219156, eg 12308164, cg27654 615, cg26015743, cg20753131 ,cg20272813, cg03100454, cg08266974,cg18887371 , cgO 0462492, cg01290088, cg08333703, eg 12591986, cg20246424,cg00671225, cg22996023 , eg 19354792, eg 11635401 , eg 16417091 , eg 12829473, cg26873488, cg01270230, cg2350 7676,cg06302566,cg20235510,cg02076604,cg10764492, cg20174256, cg05668945, eg 18818993, cg05129295, cg14910854, cg18356826, cg00715363, eg 16771950, cg0084163 1 ,cg08729407,cg01553388, cg03940662,cg24004745,cg08387662,cg02370770,cg036 58294,cg 16106297, cg20905902,cg07018260, cg04226314,cg27044944,cg26680763,c g 10002860, cg01824401 , eg 17217228, cg09015278, cg03086781 , eg 10231096, eg 176417 10,cg26503018, cg17367458, cg19968299, cg19145138, cg15404586, cg20965815, cg07 125482, cg26086009,cg23742887,cg09090235,cg25032499, cg10312081 , cg18631148, cg21821674,cg03232059,cg26941552,cg26233227,cg25614450,cg22199410,cg11702 503, cg23184039 , cg01756063 , eg 14963062 , cg07550016 , eg 16894314 , cg02174156 , eg 1 0633128, cg04285095, cg23047415, cg19267144, cg14105835, cg05859257, eg 10867193 , eg 14424963, cg24790600, cg07561848, eg 15385768, cg02744089, cg07607553, cg0783 1032 , cg21348486, eg 13612365, cg06733294, cg22800010, cg02879467, cg04357541 , eg 23977390, cg13680227, cg18753364, cg16932065, cg09863917, cg22282963,cg1905489 9, cg21604320, cg22978992,cg20807374,cg03337360,cg13485481 ,cg24540066,cg251 26016, cg24798727,cg27521571 ,cg07051178, cg04038879,cg22650124,cg11022944, c g11920110, cg02231095,cg04091898,cg11220663, cg25226417,cg05335707,cg028955 09, eg 17919850, eg 11021810, cg08248955, cg24392574, cg09553062, eg 16052686, cg06 868758, cg16435426, cg21830728, cg01731848, cg00777627, eg 10245314, cg21547190, cg21305774, cg25470611 ,cg00579481 ,cg25684111 ,cg00689014,cg02977168,cg14411 154, cg08038982 , eg 11719946, cg21595814, cg24559212, cg25746764, eg 14139679, egO 2907132, cg02168606, eg01927148, eg 13350768, cg07231738, cg08086264, cg03907179 , cg24191278, cg04082884, cg26938348, cg22053666, cg25059590, cg04696274, cg2651 8385,cg24291974,cg09700085,cg00391320,cg04728789,cg14279842,cg06463484,cg 22520644, eg 17162208, cg07295884, eg 18252275, cg03990906,cg05644639,cg2377287 4, cg27619454, cg21841409, cg23369179, cg03261067, cg12070516,cg09184385, cg110 50859, cg03717750,cg27564955,cg06040426,cg22346581 ,cg02404670,cg25726682,c g04421483, cg22756363, cg02232367, cg26291737, eg 14492140, eg 13339291 , eg 193509 70, cg27104437, cg04941821 , eg 14014796, eg 14863387, eg01341076, eg 13286853, cg04 737361,cg02575690,cg04501558, cg09751071, cg01634982, cg03195230, eg 19038674, cg18639129, cg14689490, cg02520910,cg01967682, cg05949203,cg14091419, cg19876 689, cg16732477, cg00145284, cg12759554, cg15302530, cg19746591 ,cg20749741 ,cg1 0037990, eg 19511222, cg06930009, eg 10821050, cg00954996, cg09563151, cg23523139 , cg06123976, cg24505802, eg 19721541, cg03213044, cg20936152, eg 17032507, cg0793 4552, cg25174439, cg02061757, cg24885631 , cg05258261 , cg27485605, cg05509584, eg 27209964, cg04957628,cg12724894, cg20345277,cg14986470, cg15176772, cg0714515 4, cg04070728,cg03079883, cg14617302, cg09253762,cg18449596, cg17919477, cg223 51824, cg03822682,cg08122789, cg06178754, cg09090068,cg02872663,cg16586648, c g15507683, cg14287883, cg10477153, cg03250393,cg19764295, cg26530630,cg029195 26, eg 14537183, eg01597747, cg23456689, cg09457057, eg 17338258, eg 11433608, eg 19 680388, cg14208721, cg13015925, cg25501720, cg00554118, cg02489379,cg03330642, cg26255281 ,cg03427193, cg02124097, cg13942897, cg08150843, cg14215390, cg26145 096,cg20411631 ,cg02787230,cg19109762, cg00102726, cg06108605, cg16383389, cg1 9692322, cg08581040, eg 17226870, cg21887246, cg09447554, eg 11099262, eg 13464955 ,cg19126007, cg25138771 ,cg13924326, cg05781311 ,cg10884975, cg02019955, cg1963 4252 , eg01219087, cg24473265, cg05571758, eg 10509965, eg01972495, eg 18762321 , eg 05151471, cg21551210,cg06261370, cg08708629, eg 10976999, cg21731033, cg2631291

6, cg13408712, cg17522324, cg24827212, cg22348183, cg20190127, cg16348962,cg065 75843, cg26577509, cg06778567, cg05622550, cg02294570, cg22836593, cg21086690, c g24273315,cg17355153,cg01249360,cg07593580,cg04754212,cg09760143,cg112025 84, cg04490136, cg13096857, cg17001032, cg24487279,cg19509579, cg00582987,cg26 592816 , cg02048791 ,cg23517944,cg03558602,cg08117110,cg24244437,cg00984985, cg04434328,cg17766219, cg24181188,cg01969330, cg25914267, cg09058955,cg04971 769, cg18745690, cg07175797, cg10157936, cg10723431 ,cg24870662,cg04869006,cg1 4236043, cg03082758,cg26766798,cg23312086, cg02548198, cg23157419, cg10690916 , cg22777949, cg07650712,cg08949815, cg15345626, cg22045714,cg01338958, cg1571 2821 , cg08610201, eg01573175, eg 19896655, cg04391789, cg00797497, cg02061130, eg 05132293, eg 19927028, eg 11407345, cg04301738, eg 12325605, cg20710898, cg2629652 4, cg26394233, cg12087432, cg03540912,cg03990998,cg06316322, cg17220690, cg143 22323, eg 19027985, eg 16856131 ,cg09021274,cg03909275,cg00297426,cg08800200,c g23954724, cg03640944,cg00124095, cg14182667, cg27151320, cg01038732, cg060204 19, cg09331206, eg 17018649, cg21238864, cg00190881 , cg20091959, cg02472224, cg21 145686,cg04391610, eg 14675248,cg06515734, eg 15372773, eg 14705879, cg24122050, cg07637175,cg13182010,cg24187971 ,cg06763375,cg20385983,cg16048537,cg01906 702, cg16318226, cg18410341 ,cg23947593,cg22229470,cg26274621 ,cg14367229,cg0 8779305, cg07173540, cg04880082,cg16631022, cg19257531 ,cg02224202,cg22231606 , cg23547656, eg 14470485, cg08159724, cg04760795, cg22614891, cg23007689, eg 1483 6889 , cg24390964, cg04984052 , cg00971396, eg 17562299, eg 12116885, eg 13853070, eg 19582046, cg24619306, cg13941555, cg18553354, cg22469173,cg10360805, cg2113922

7, cg04802018, cg05696006,cg00254679,cg19923238, cg19118037, cg08187425, cg071 73484, cg26857408,cg03910767,cg14279539,cg03660952,cg05761535,cg01111558, c g06702354,cg00476580,cg07783291 , cg17428789, cg18048897, cg25976340,cg212326 25,cg20471013,cg03999479,cg11342046, cg24618963, eg 13562602, cg04986591 ,cg02 679291,cg08698428,cg26178732, cg17751391, cg04287931 , eg 14564046, cg21621225, cg10192449,cg07383130,cg26771998,cg14502628,cg11109721 , cg11507473, cg02746 514, eg 12018809, eg 14438445, eg 16925069, eg 16348812, cg05118916, cg05496710,cg0 0205522, eg 13436907, cg00705295,cg07690796, eg 14928617, cg01719825, eg 16324369 , cg07879533,cg06601081 , cg06341100, eg 18392504, cg23685586, cg05787952, eg 1977 9005, cg10995137, cg20157484, cg23902765,cg20204784,cg06625258,cg13374648, eg 26014473, cg23955723, cg04787756, cg07660991 , eg 17189020, cg04162949, cg2572162 5, cg15384392, cg04805285,cg04481722, cg22945019, cg22807877,cg14574568, cg113 10125, eg 14622669, eg 11233236, cg02910125,cg22987568,cg27402845,cg01227239,c g17076431 ,cg10309250, cg01143056, cg19392007, cg21024085, cg12388760, cg093857 94,cg23516261,cg12114203, cg15006175, cg00044249, eg 15560209, eg 19643792, cg05 855199, cg26768419, cg23603852, cg25118283, cg11867718, cg13433446, cg18378817, cg18011945,cg24879087,cg05381183,cg09372891,cg23328938,cg00847238,cg02092 975, cg17480669, cg05128056,cg10304803, cg18085869, cg14568971, cg01069470, egO 9816855, cg08551019,cg24660631 ,cg18497489, cg23580639,cg23843264,cg06955919 cg07159286,cg11980190, cg17504584, cg08805869,cg24840787, cg17090409, cg11043 760, cg14184904, cg12480301 ,cg00950268, cg17152981 , cg15052277, cg07138962, egO 1993865, cg11021989, cg14145338, cg17236813, cg24820347,cg21095982, cg16117023 , eg 15097551 , cg26032412, cg07380384, cg07226470, cg25540078, eg 15092388, eg 1981 1608,cg02944953,cg15431287, cg23581430, cg10201785, cg27558564, eg 17048363, eg 22858733, eg 13962022 , cg00854594, eg 15268727, cg00164458, cg03099421 , cg2531475 2,cg11246580, cg25503540,cg09512080, eg 16905129, cg05874314, cg21430519, cg056 92653, cg03409737,cg07547404,cg10823595, cg17781515,cg19381819,cg07060261 ,c g17522984, cg00845942,cg15308074, cg24167264,cg01163488, cg10675120, cg194500 29, cg14277260, cg22654824,cg06905726,cg22487204,cg02611863, cg24256384,cg26 490274, cg04457572,cg05623559,cg09078100, eg 18755404, cg07199894, cg06826422, cg22015888, cg14414316, cg04195161, cg14970130, cg23601736, cg08936411 ,cg26482 905, cg00379528,cg21242417, cg11993436, cg09331011 ,cg24457531 ,cg07582070,cg2 1285782, cg08017880, cg22334543, eg 11749167, cg06398390, cg20659318, cg02552466 , cg04081153, eg 13375849, eg 17410609, cg23238790, eg 14585115, cg06721528, cg0358 5122,cg23928910,cg06765430,cg11582180, eg 16975981 ,cg20262818,cg01485268,cg 14321697, eg 14282093, cg26745471 , eg 10561843, eg 11503550, cg23857904,cg2668730 5,cg05809186,cg09303843,cg25928444,cg15212870,cg16862869,cg04537738,cg263 20080, cg01619562, cg21265536, cg01778908, cg09129772, eg 14624668, cg21756782, c g18266450, cg04117455,cg22994808,cg02457725,cg02856727,cg05802477,cg029070 49, cg04514128, eg 16121567, eg 15921637, cg09692653, cg03046573, cg06249109, cg27 471183, cg07309144,cg16013618, cg16219773, cg09021539, cg22987546,cg26989202, eg 10252138, eg 16743457, cg25637631 , eg 17368069, cg09916234, eg 14093419, cg26880 777, cg10104534, cg16841327, cg17570188, cg08679013, cg22475974,cg23276435,cg0 0504226, cg04854749, cg00960419, cg24806294, eg 11603350, cg26410148, cg23324012 , cg25880804, cg01861259, eg 18036795, cg25200887, eg 17069541 , cg02869363, cg0593 7774, cg15331837,cg08259526,cg24804652,cg05868512,cg25173392, cg17313222, eg 02326883, cg25060269, eg 17414580, cg09870092, eg 18643215,cg09442792 ,cg0540540 9, cg24498538, eg 11683390, cg05168468, cg05979549,cg04160835, cg27652249,cg200 43057, eg 16795304, eg 13053505, cg01814129, cg01911068, cg26934609,cg15541398, c g25716786,cg09095792,cg23953773,cg10207189,cg27119222,cg20489317,cg245555 28, cg21105268, cg02826687, cg09655766, eg 11082684, eg 10328783, cg07276634, cg09 352202,cg03655847,cg04260676,cg27168606,cg08834429,cg07172800,cg00750917, cg09775795,cg09367036 , cg07078269 , eg 19695521 , eg 14359606, cg09874802 , cg03655 402, cg01899581 ,cg14962283,cg06020238,cg27555894,cg21128539, cg03682865,cg2 0111107, eg 12825836, eg 10454232, eg 11660352, cg23953110, cg07720856, cg07836306 , cg08053103, eg 12387247, cg04661740, eg 11567902, cg27055366, eg 16852194, cg0397 9381, cg06204087,cg15107132, cg00750700,cg04157263, cg13660695, cg06469570, eg 07923200, eg 16894226, cg24048806, cg26779114, cg24107021 ,cg04803208,cg0461861 3,cg11527772, cg27042528, eg 16996613, eg 13701910, cg26042490,cg06182031 ,cg234 28725, cg01269405, eg 11919725, cg22040403,cg03628959,cg01036732, cg05956462,c g22122862,cg17161202,cg12053851 ,cg03646928,cg20124620,cg03087977,cg244965 23, eg 15856829, cg04539775, cg02433086, cg06708122, cg26338873, eg 15758147, cg23 165239, cg04721467, cg04403584, cg02002408, eg 12062537, cg05663891 ,cg 10973922 , cg21667042 , cg27004182 , cg22894518 , eg 18623624 , eg 13003350 , cg07023901 , cg21757 926, eg 19850406, cg00280609, cg08106887, eg01710179, eg 18962077, cg22366088, egO 1700428, cg27590781 , cg24552746, cg08188436, cg06236737, eg 14118475, cg26893523 ,cg14832223, cg20929545,cg15025227, cg01333423, cg13591497, cg15981626, cg2732 1979, eg 13448704, eg 19643390, eg 15583131, cg06335869, eg 14468497, eg 13470557, eg 20487488, cg07656988, cg24886176, cg07582379, cg26902337,cg04929736,cg2687831 8, cg09596252, eg 11454836, cg24933199, cg26617534, eg 18327423, cg09126308, eg 138 55288, cg24399162, cg01968402, cg25820220,cg00087274,cg10717750, cg06663970,c g05159604, cg15995592, cg25793425,cg19641404, cg18669213, cg07146103, cg042720 52 , cg08949862 , eg 10013971 , eg 12635578, cg07917614, eg 12071511 , eg 12100751 , cg07 125412, cg07056606, eg 15743657, eg 14032985, eg 16601489, cg08213619, cg09983885, cg04455670,cg04002038,cg01741999,cg22802720,cg14529393,cg00398767,cg09507 215,cg17301506,cg09113420, cg01790618, eg 13702695, eg 16072664, cg05538632, eg 1 8986078, cg04304300, cg07231828, cg25372239, cg00952573, cg02565297, eg 15839421 , cg25836706,cg09123677, cg09001782, cg06218726, cg25447359, cg23095634, cg0496 0492, cg07586725,cg12808636, cg25132878, cg05746523,cg01338593, cg13467484, eg 17518348, cg21084200, cg23848181, cg05622615, cg26108121, cg00996336, cg2010558 7,cg16514112, cg27329533,cg25001305, cg10839502, cg18497960, cg18467502, cg149 53636, eg 13586170, eg 18639499, eg 14281646, cg27014914, eg 12481426, cg02994863,c g14098628,cg02137495,cg14725190,cg27613057,cg01301803,cg14789642,cg273919 21 , cg08632961 , cg25914270, eg 13955622, cg25226092, cg20831690, cg22312904, cg08 557795, cg09617716, cg05658241 , eg 19541622 , eg 19388739 , eg 18946417 , eg 13259063 , cg15258121, cg04103807, cg07258524,cg10924669, cg04874129, cg22071114, cg08675 544, cg18142687,cg06548519,cg01946345,cg23276096,cg08115597, cg23449856,cg0 3102788, eg 17321723, cg07481697, cg06127374, cg22023304,cg25380415, eg 13280380 , eg 17626378, cg25924827, cg24121979, cg23332744, cg24249411 , cg07357963, eg 1075 4215, eg 17395940, eg 14023149, cg09375092, cg09280971 , eg01744248, eg01483119, eg 19926635, cg04646695, eg 14895567, cg20546765, cg09494782 , eg 12227505, eg 1285373 2, cg06583549,cg24892871,cg07103943, cg04126652, cg07805699,cg24405702,cg020 38852, cg12668782,cg15731755,cg11640208, cg01108401 , cg12260643,cg04103170,c g26804995, cg11619050, cg26612727, cg05526757,cg19656070, cg01390564, cg255578 18, cg16791767, cg14479096, cg14336011,cg03781809, cg16211224,cg16392086,cg14 556646, cg04863411,cg11623950, cg25228947,cg24097025,cg00669776,cg11986194, cg14565835, cg22161575, cg07568471,cg22460923, cg19764096, cg15266497, cg12660 062 , cg00971695 , eg 17063849 , eg01211041 , cg22162544 , eg 16334072 , eg01987196 , eg 1 7438661 ,cg04994202,cg23460212,cg10452626,cg03977449,cg09751812,cg20153322 ,cg27011024, cg10585420, cg04420600,cg08872467,cg09961177, cg06291867, cg2364 4968, cg14391622, cg02654704,cg05077334,cg22891539, cg23156962, cg14650053, eg 11037466, cg07672051 ,cg04467838,cg04959815, cg21534984, cg03421399, cg1580880 5, cg22804859,cg02152091 ,cg24147793, cg18549547, cg12847986,cg20637249,cg084 60226, cg05279086,cg27502782,cg23314893, cg09936824, eg 18413212, cg07573391,c g14177401 ,cg26942815,cg02124446,cg24796483,cg08803415,cg08276976,cg252704 98, cg18427176, cg24496841 ,cg18572653, cg09625127,cg21732460, cg01438467, cg08 305799, cg13709618, cg06985779,cg24741685, eg 19890431 ,cg04040483, eg 19575132, cg09038210,cg18978303, cg26504440,cg02555204,cg01356504, cg02764883,cg13937 686,cg27564192,cg16339797,cg20656751 ,cg23493123,cg25720688,cg02205602,cg2 4210426, eg 11589703, cg21040466 , cg21366200, eg01883322 , eg 12678667 , eg 18384890 , eg 10084370, cg20597172, cg00823789, eg 13980844, cg00952789, cg05145517, cg0225 8920, cg08830520, cg07886017, cg24403641 , cg20105087, cg23962081 , eg 11056045, eg 15032615,cg06664084,cg20890713,cg09176402,cg23580828,cg10186053,cg 1310544 5, cg00521380, eg 11459772, eg 10502431 ,cg07593903,cg23132859, cg07925687, eg 182 17284, cg01689142, eg 19726935, cg20639332,cg02023473,cg23985077,cg11664313, c g24981909,cg01716807,cg23765153,cg26441486,cg00433709,cg22553273,cg067289 61 , eg 15626881 , cg08073527, cg00047185, eg 12489322, eg 12838928, cg00963291 , eg 12 592723, cg23705487,cg22793203, cg10211383, eg 10940833, eg 12443604, cg03006960, cg27628596, cg23290343,cg11044926, cg24946253,cg02249119, cg21687008, cg19002 462,cg20839927,cg26741746,cg03530210,cg23528353,cg09536721,cg23302603,cg1 1714722, cg22145283, cg25112966, eg 18121434, cg08577194, cg26801741 , cg06900846 , eg 10504436, cg25547937, cg21494512, cg05942503, cg25057861 , eg 16606706, eg 1433 6412, cg06692408, cg04200762, cg02899190, cg05141005, cg02558474, eg 11138539, eg 03162686, cg03999165, cg21195414, cg01052411,cg26901352, eg 19205994, cg2129384 3,cg14611488, cg27575890,cg16119408, cg17841572,cg17283838, cg08485899,cg012 69575, cg11466428, cg03595951 ,cg13843791 ,cg00273658,cg09267974,cg24430189,c g18917517,cg22637307,cg01267448,cg27236648,cg26548122,cg02314586,cg250380 60, cg08340572,cg03196440, cg21261121,cg25618513,cg12551718,cg19978273,cg14 064774, cg10804216, cg16931899, cg20469575,cg22195238, cg03870394,cg03883491 , cg05753794, cg06925664, eg 14650116, eg 13541073, cg21961512 ,cg 14114912 ,cg 16696 645, cg13828047, cg15195485, cg15642225, cg12099472, cg06188870, cg07630544,cg0 5810096, eg 14522767, eg 10400226, cg00452755, cg03345504, eg 15128443, cg21942557 cg15835500, cg17949969, cg13009662, cg07079059,cg11178293, cg24776834,cg06456 738, cg18319384, cg19204234, cg10724425, cg25150799, cg26730831 ,cg03778155, cg1 9539667, cg09388499, cg24434380, eg01288977, cg08815337, cg00228496, cg23380496 ,cg05774672,cg20183619,cg08496291 ,cg22376864,cg24766555,cg24335355,cg0237 7024, eg 14665806, cg05002165, eg01911394, cg09325156, cg04275040, eg01737532, eg 25507121 , eg 18916626, eg 16275739, eg 16534508, eg 16355244, cg21205771 ,cg 1204467 1,cg10426838, cg23818931 , cg17928916, cg10749822, cg13881655, cg00170720, cg008 49570, eg 15612517, eg 17472489, eg 13951450, cg03631743, cg06947694,cg06298336,c g13826852,cg22443762,cg20679084,cg14717116, cg01578057, cg19743613, cg202485 27, cg03955826, eg 16030377, cg05592773, eg 11835462, eg 12539917, cg24272254, eg 14 039011 ,cg15127733,cg07793898,cg22021160,cg06425240,cg01998051 ,cg20597644, eg 18763854, eg 14885690, cg00570504, eg 17103243, eg 17111542 ,cg01850785, cg06944 559, cg14097855, cg26472036, cg14425609, cg15089387, cg20285559,cg08349391 ,cg1 6463460, cg23299127, eg 15609150, eg 16522113, cg00950265, cg08299282, cg27170458 , eg 18677773, eg 14037664, cg22387829, cg08626429, cg04128307, eg 14964403, cg2167 0708, cg02474109, cg14377113, cg11123501 , cg21202700, cg21265278, eg 18481241, eg 10719727, eg 17840123, eg 13926211 , eg01559259, eg 12197227, cg00796850, eg 1205751 7, cg19282987, cg07594568,cg27510671, cg09931783, cg27487344,cg04759982,cg241 05014, eg 18632018, cg05358915, cg22572902,cg00625443, eg 16690859, cg14316231, c g08175609, cg19502700, cg07266032,cg23662675,cg10962883, cg17338594, cg002922 82 , cg05013825, cg08989903, eg 15592690, cg07052700, cg24652552, cg27597505, eg 16 427743, cg06397381 ,cg05276978,cg14640621 ,cg22829375,cg12419348,cg11476985, cg19176530, cg06996396,cg23898792,cg17278062, cg02831587, cg15685144, cg22792 659, cg02371040, cg13049992, cg06299016,cg21806273, cg20670587,cg22379905,cg1 5037004, cg18055467,cg25213559,cg15876796,cg04908210,cg08680417,cg03786131 ,cg11409659, cg20132545, cg07279440,cg11709423, eg 16396580, cg06588028,cg0672 3541 , cg06807641 , eg01254719, cg22802174, cg26852032, eg 12638766, cg23137368, eg 16557092, eg 18059621 , cg21062625, cg04132534, eg 16240572 ,cg05066722 , eg 1853076 6, cg17890667, eg 17669987, cg07073960, eg 11809123, cg00793186, cg03938482, eg 198 85914,cg05914069,cg00913794, eg 17530586, eg 10721728, eg 19314856, cg25795302,c g06081952, cg06442378,cg21982455, cg22844018,cg04180864, cg23632849, eg 108348 05, cg07588996, cg08742789, cg03572284,cg00393470, eg 17091196, cg02017634, cg07 211212,cg21158027,cg12254214,cg17102411,cg08281696,cg12978143, cg13047724, cg21667367,cg03597723,cg04642971,cg22019742,cg08971592,cg02857142,cg10984 017, cg26374686, cg18261479, cg09157736, cg13630451 ,cg03144922,cg25405172, egO 1606688, cg14440047, cg01159791 ,cg24607140, cg01744760, cg08660999,cg11136969 , eg 10549831 , cg05759424, cg06127112, eg 17676428, cg07009898, cg06869158, cg0831 7252, cg25213418, cg12504027, cg01754163, cg26714915, cg08531508, cg08507178, eg 03984067, cg01622465, cg02403721 , eg 16530881, cg14730795, eg 13095865, eg 1630621 9, cg18091465, cg04904770,cg23704141 ,cg25597579,cg00804043,cg17219209, cg121 64564, cg20584801 ,cg13240253, cg02113429, cg18951718, cg01733619, cg23928123,c g17142723, cg09029293, cg16163999, cg17659271 , cg02400530,cg03995434,cg272758 21, eg 15049968, cg27278953,cg03664710,cg08182724, cg26134300, cg11450546, cg19 730687, cg11847601, cg14056975,cg01328461,cg09633881 ,cg03996001 ,cg11566199, cg18118621, cg18583828, cg15117681, cg09396308,cg21037378, cg08100687, cg04433 822, cg22281459,cg17338116, cg04815758, cg03082517, cg22495068,cg10570482, egO 3448017,cg23928643,cg17017152,cg15896833,cg14185801,cg19350162,cg21915811 , cg25655096, cg04280485, cg24051040, eg 12988118, cg05484149, eg01149202, cg0611 0522 , eg 16466850, cg09127563, cg07817783, cg26246411 , cg26685825, eg 15494597, eg 12816829,cg17228929, cg00702719, eg 16107724, cg25495217, cg20917484, cg0656797 2,cg18712752,cg05103574,cg06773554,cg04181189,cg03678860,cg12345724,cg231 92553, cg07528075, eg 12722937, cg06697471 ,cg23623458,cg06043886,cg08539737,c g17167331 ,cg10567964,cg08948898,cg12294403,cg11353300, cg11027221, cg247360 10, cg04261529, cg01896999, cg02082273, cg23983449, cg03009464, cg00783142, cg02 486086, cg10691323, cg03581262, cg25292151, cg07405919, eg 13653078, eg 14009027, cg23572228, cg12652613, cg23162834, cg06786470,cg01333532, cg10811932, cg18695 665 , eg 12564263 , cg07448457 , eg 13362546 , eg 15576861 , cg08195029 , cg00811132 , cg2 4280607, cg20090957, eg 12930251 , cg07666293, eg 10396470, cg02509086, eg 14256587 , eg 11855587, cg09426825, cg24077102, cg02267894, cg02917246, cg08977130, eg 1340 1662,cg26166770,cg10785537,cg25003531 ,cg17317561,cg08025214,cg13005086, eg 20568305, eg01357124, eg 17943075, cg02277821 , cg27249698, eg01495361 , eg 1244151 3, cg13973054, cg10521014, cg08624344,cg04902833,cg04198797, cg10015572, cg067 16807, cg21622733, cg25009366,cg02006119, eg 15681096, cg03037561 ,cg16584020, c g05348295, eg 11514705, cg27044023, cg03586803, cg03337230, eg 12598538, cg087068 37, cg17455939, cg09709592,cg27483317, cg19282586, cg09552475,cg16459120, cg01 567051, cg16568759, cg21673010,cg01204669, eg 12441893, cg01399319, cg05008435, cg27345785, cg12508856, cg22337291 ,cg01727346, cg01790344, cg12032885,cg14086 922, cg06930745,cg09478712, cg04612272, cg25995825,cg21334101 , cg14486033, cg1 9339947, cg00094901 , cg06797543, cg26987613, cg22690321 , cg24644740, eg 16786007 , cg26237050, eg 14676592, cg20401595, cg06533233, cg09697668, cg24376955, eg0105 9449, cg06336598, cg05633550, cg04490024, cg07066050, eg 11813862, cg20331494, eg 09754810, cg18515437, cg26328893,cg17300220, eg 13870435, eg 14250984, eg 1920958

8,cg20608348,cg11140440, cg12615843, cg07878171 ,cg21842033,cg16181099,cg190 23552, cg06068388, cg02619167, cg20915212, cg09454613, eg 15526094, cg02774334, c g25921112,cg02930898,cg05629723,cg00161791 ,cg03616827,cg01098921,cg260833 96, cg24167223, cg06578870,cg23612072, cg00783730, eg 16567763, cg08114317, cg04 328762, cg08043048,cg06928346,cg01220923, cg02168450, cg09567732,cg09869234, eg 19663555, cg23278908, eg 11892307, cg05226967,cg25278456, eg 11084611 ,cg04119 066, cg00737992,cg06749753, cg14473823, cg08686850,cg09265588,cg01943029, egO 1023703, cg24713063, cg22423627, eg 14607348, cg05998816, cg27032184, eg 19031510 , cg14489366, cg01535733, cg16894074, cg01443339, cg01714542, cg02979819, cg1179 6938, cg06496197, cg20596240, eg 19860154, cg20975911 , eg 10577273, eg 11223735, eg 20083113, cg20467260,cg21887591, cg06239618, cg17725163, cg03409066,cg1663707

9, cg07739966,cg08421532, cg13002809, cg12508451 ,cg19131476, cg20805757,cg093 87058, cg17218882, cg18361915, cg17423458, cg16415939, cg15643885, cg20105548, c g12400725,cg21686632,cg07042289,cg26828842,cg05199871,cg11692073, cg019005 57, eg01082601 , eg01517728, cg09984303, eg 18074016, eg 11766827, cg22757384, egOO 322866, cg23681440, cg03341523, cg08906584, eg 12552944, cg21178951 ,cg 10192340, eg01815730, eg 15494987, eg 12615235, eg 14522360, cg27531731 ,cg08924212 ,cg08255 374, eg 13865502, cg00194146, eg 14411859, eg 11243548, cg24059786,cg23086161 ,cgO 5019028, cg19188370,cg21161649, cg16709214,cg08021833,cg09448314,cg03496350 , cg00065764, eg 19537645, cg09766849, cg21913974, eg 17009189, cg21182103, cg0020 0667, cg03213100, cg04637727, cg24228964, cg06994813, cg20800359, cg20672245, eg 25564241 , eg 16855355, cg03499675, cg02954866, eg 17984932 ,cg07861865, eg 1402172 8, cg04374102,cg00786305,cg11972924, cg10423830,cg04526020,cg10291279,cg111 84021,cg03331282, eg 17965006, cg25444331 ,cg00775293,cg23729279,cg14757937, c g18845372, cg03500164, cg21301638, cg17632226, cg02495915, cg13617202, cg052894 66 , cg24353392 , cg22797971 , cg24995976, eg 15822108, eg 17631451 , eg 17044526 , cg25 618424, cg18477569, cg25782440, cg03362871 ,cg03235353,cg05228295, eg 15785534, cg13094146, cg13353472, cg25685262,cg22436126, cg10703676, cg20708125, cg04428 773, cg09431264, cg22199428, eg 12437167, eg 15955144, eg 15907278, eg 14511273,cg0 3066657, eg 11439592, cg08995089, eg 11796442, cg07276962 , eg 13383842 , eg 16198734 , cg22200067, eg 15414034, cg23016347, cg09011883, eg 10819062, cg27657633, eg 1357 6330, eg 11862768, eg 13766911 , cg26878967, eg 16530432, eg 16825133, cg23628099, eg 26165406, cg20074159, cg11176481, cg23915349, cg03749081 ,cg10984950, cg0982229 3, cg15047753, cg04284500,cg01748473, cg23193616, cg26416981,cg13490753, cg030 79104,cg04937594,cg19588519,cg12904271 , eg 12297162, eg 19819559, cg10862160, c g 17573908 , eg 16025068 , cg02426912 , eg 19481531 , cg04823952 , cg23907852 , eg 159601 55, cg18749337,cg09821214,cg04157864,cg00652027,cg11010528, cg07362860,cg00 112465, cg27657924,cg24552391,cg02866360,cg11628055, cg25587350,cg24465466, eg 18382358, eg 11416379, eg 11598034, eg 14666553, cg21973405, cg26504021 ,cg04010 165,cg00165981 ,cg04700798,cg09262666,cg04299787,cg00735744,cg16329358,cg1 4844141, cg02704345,cg24065761 , eg 12097171 ,cg23427963, eg 18549919, cg02701054 cg03792162,cg16243546,cg25412167,cg09589374,cg24914180,cg11239719, cg26311 944, cg07181843, cg18523979, cg03531211 ,cg05747038,cg24004600,cg26865409,cg2 4061931, cg00097452, eg 17079352, cg03551667, eg 10379954, cg02192028, eg 13323047 , cg07400247, eg01416578, eg 18928900, eg01678903, cg04650403, eg01008731 , cg2077 5307, eg 10071554, cg09368514, eg 14682256, eg 15673536, eg 12539249, cg23789121 , eg 16113721, cg11749177, cg16636182, cg02292720,cg27052152, cg08545854,cg0457055 1 ,cg02544837, eg 16792445, cg07414674, eg 15823064, eg 16998490, cg09227765, cg088 47140, eg 13077762, cg26433208, cg21209030, cg00249938, cg08444191, cg06603761 , c g22519691 ,cg24350612,cg03066754,cg25993248,cg24804948,cg06272611,cg003644 57, cg22185327, cg10493038, cg08586737,cg13355312, cg24577678,cg06360875,cg19 331885, cg16956345, cg03588221,cg00912972, eg 17036469, cg07699084,cg26135172, cg23397909,cg17291136,cg07326720,cg27394596,cg07311505,cg13830110,cg07724 320,cg06816651 ,cg23692497,cg04473968,cg04017513,cg13874817,cg23433503,cg2 7623562 , eg 19698585, cg00746170, cg21677767, cg08333580, cg06729701 , eg 14884197 ,cg16302816, cg22132520, cg07891774, cg12856447, cg03742705,cg00495946,cg1177 5837, cg23627620, cg08667991 , eg 11725799, cg08887721 ,cg 14405439, cg06726820, eg 05745622,cg26656208,cg12248097,cg00367438,cg26598646,cg08194519, eg 1568226 7,cg12356107,cg25675423,cg14030674,cg10109841 ,cg23551753,cg09379627,cg043 91540, cg09704401 ,cg20750930, cg11227853, cg01775354, cg25346059,cg22161299, c g11259727, cg09344100, cg27572068,cg02806824,cg16717988, cg02322159, cg080597 55, cg13644715,cg25370441 ,cg02305757,cg08773290,cg00719400,cg14831745, cg15 170386, cg22083582,cg04532834,cg16855422,cg11217840, cg03683838,cg23052670, cg13742610,cg06663068,cg05697754,cg05040544,cg09171874,cg08955792,cg06175 025, cg05070608 , egO0195796 , eg 18995560 , eg 11186468 , cg22211507 , eg 13935694 , eg 1 6902509, cg21402832,cg02840828,cg18181906,cg08733960,cg08451957,cg08795279 ,cg03619973,cg27204405,cg06697744,cg00844328,cg12826119,cg02283643,cg1815 9583,cg07050772,cg08830818,cg05459469,cg01139508, cg00931179, cg00928711, eg 06948947, cg12275605, cg27258627,cg25254573,cg12490823, cg21127534, cg0827748 6, eg 10458881 , cg20770512 , eg 18619541 , cg07461715 , eg 13455181 , eg 10256349 , cg074 67520, cg02571905,cg08364334,cg04581018,cg03403215,cg02493290,cg10977770,c g13158044, cg26345312, cg18459459, cg05180728, cg19073209, cg25391820,cg226879 02, cg19407902, cg00048832,cg00621913,cg09182686, cg04843801 ,cg03827739,cg10 833215,cg03154690,cg21343189,cg25137590,cg 19521718, cg04273811 ,cg01975510, cg03114157, cg21771250, cg15295205, cg06827611,cg08574671 , cg19779370, cg07515 367, eg 18248753, cg07985792,cg00398673,cg08336234,cg01525244, cg16711686, egO 0836302, eg 10536139, cg22196977, eg 15693483, eg 18279670, cg23768461 , cg00419220 , cg02966404,cg21850735, eg 19212399, cg04983381 , eg 15441369, cg03086235, eg 1919 0632 , eg 18330222, cg09561417, cg24835295, cg08059112, cg05820435, cg03159156, eg 02629070, cg04663017, cg25583491,cg06732395, eg 14224170, cg04136449, cg2380322 5,cg19088218,cg27502008,cg22820285,cg09879137,cg23549283,cg13667069,cg014 58659, cg00659605,cg24508168, cg27260834,cg04137003, cg07150036, cg02452635,c g 19609713,cg21384622 , eg 17217879, cg20829454, cg23697546, cg04145890, cg268430 74, cg04871207, eg 19779236, eg 18162528, eg 14833488, cg21207217, eg01897092, eg 15 018670, cg13515047, cg15527230, cg05840756, eg 16768608, cg08955448,cg03017231 , cg02534657, cg01651680, cg13711609, cg10283179, cg13269439, cg17946114, cg20149 281 , eg 19234897, cg27062116, eg 19389406, cg24303076, cg08241514, eg 15920400, egO 4320476, eg 11395271 , cg21049015, cg08832018, cg25430988, cg24691835, cg21489364 , cg27092694, cg00945735, cg04828926, cg06756291 , cg09467540, cg20837171, cg0014 1162, cg03735202,cg03649030,cg10477040, cg09950479,cg12296007,cg10920957, eg 00068174,cg04229322,cg03018486,cg27191786,cg23300810,cg20553524, eg 1545647 6,cg25175887,cg07590153,cg00108181 ,cg03502399,cg02508567,cg22784503,cg183 43870, cg03111263, cg21998745, cg20430909,cg07619960, cg17045539, cg20371505, c g 16087709, cg07260532, eg01668174, cg08831348, cg03052431 , eg 18534116, eg 197664 38, eg 11985562, cg03152385, cg24959264, cg25088621 , eg 18328334, cg00660643, eg 19 502266, cg13974715, cg12650870, cg14643075, cg09882647, eg 15735388, eg 11076544, cg17148597, cg22356432,cg03463293, cg15906214, cg10578782, cg02264733,cg13912 791, cg10587854, cg23502778,cg21222180, cg26623224,cg04144533,cg01398168, cg1 2248389, cg21899975, cg06703062, cg08077975, eg 14228343, cg25462355, cg08232135 , cg03943081 , cg04623471 , cg26417874, eg01403069, cg21459672, cg02056921 , eg 1485 0181, cg00583304,cg21283739, cg05705822, cg26066917, eg 19507638, cg25083230, eg 19163210, cg20911108, eg 16386910, cg06277784, cg21350156, cg04694744, eg 1679786 0,cg25614836, cg24253367,cg02506578,cg07717347, cg17592623, cg25318211 ,cg201 53160, cg03991533, cg05978318, cg23100671, cg05702927,cg22238600,cg13477948, c g07546878, cg12896487, cg16762000, cg01341130, cg06286127,cg26718385, cg008450 20, cg06187843, cg01423591,cg24061727, cg05166530, cg02136201, cg03040622,cg12 081027, cg13353957, cg22608296,cg00590386,cg26759077,cg08892175, eg 17226687, cg12376274, cg09653816, cg27423247,cg13624041 ,cg20417830, cg09162079,cg10430 932, cg26708220, eg 12895370, cg02996801 , cg08416569, eg 18771538, cg27459529, egO 5850008, cg04571417, cg00032376, cg07418175, cg26670249, cg22495026, eg 15094196 ,cg17352088, cg02496313, cg01614764, cg00076325,cg18959748, cg22388982,cg0130 6534 , cg24280449, cg08132303, cg07568779, eg 17940256, cg23217542, cg21816456, eg 22059430, cg23348270,cg25696000,cg21149253, cg04100967, cg22224337,cg0940833 5, cg15934839, cg16942223,cg03922963,cg02686685,cg10067398, cg05197515, cg117 72801 ,cg25070373,cg08390901 ,cg16106179, cg18139692, cg13181604, cg16655837, c g24167422, cg09891393, cg02347832,cg11736690, cg24419805, cg06075222,cg180819 79, cg08214688, cg27292563,cg03254601,cg03399794, cg17861836, cg01778872, cg11 219407,cg19310895,cg10285392,cg25790043,cg08440690, eg 12450255, eg 14222153, cg03116466, cg14935078,cg13510759,cg27086874,cg19511335, cg02261480,cg26061 548, cg01092005, cg22129402, cg24509649, cg14550985, cg02156570, cg10978061 , cg1 4903321 , eg 12848738, cg24130537, eg 14469376, cg21507528, cg00735632, cg05549122 ,cg25811320, cg24276374,cg17601216, cg25583027,cg11618438, cg06600821,cg0928 7359, eg 15826967, eg01290714, eg 11652668, cg07073593, eg 19813802, eg 11525109, eg 06378948 , cg21337120 , cg06182359, eg 19983274, eg 10159596, eg01612601 , eg0115484 9, cg08677932,cg22649546, cg19815139, cg15447562, cg05838113, cg22195509, cg020 23885, cg25910466, cg26156085, cg21968101 ,cg02620013,cg16743811 ,cg00891761 ,c g04372085,cg04596539,cg02883958, cg15739570, cg19544707, cg02768721,cg136874 22, cg05804856,cg16182479, cg07122896, cg13101072, cg11739399, cg12441038, cg26 254553,cg05871614, eg 17620694,cg 10271495, cg01340163, cg01403532, eg 19682639, cg17067993, cg16617633, cg01422683,cg22016995, cg00841693,cg02425145, cg01079 363, cg14148396, cg17280782, cg04647199, cg04950452,cg25020897,cg07122653,cg0 4671947,cg20119871, cgOOOI 5319, cg08448080,cg13507706, eg 14643191 ,cg 10788694 ,cg02131013,cg00902886,cg04669574,cg00478851 ,cg27126659, cg10571397, cg1016 6148, cg23040064, cg25833672, eg 15309393, cg07586345, eg 15774465, eg 16013173, eg 01974921 , eg 18849737, cg08406981 , eg 14639847, cg20054394 , cg07963670 , cg2492178 5,cg08854420,cg07331286,cg08581446,cg27402927,cg16347018,cg04015057,cg124 79413, cg13916146,cg07428907,cg24045431 ,cg11911560, cg00546180,cg09448951,c g10288437, cg21277972, cg09384223,cg05502271 ,cg12940337, cg05043591,cg168654 92,cg25364077,cg26894311 ,cg00610000,cg00091162, cg02474858,cg18059928, cg11 118112, cg17478776, cg10825847, cg16750082, cg23108607, cg00755234,cg01075805, cg03027739,cg09291387, cg06936956,cg25545401,cg18280962, cg07927257,cg09191 149,cg04824401 ,cg07502936,cg11157324, cg05041061 ,cg06182381 ,cg27399396,cg1 1682398, cg02330195, cg17241999, cg02106385, cg25061061 ,cg02940937,cg01456767 , cg07651728, cg08213398, cg24020698, cg09588628, cg02701112, eg 12633766, eg 1938 2027, cg18180846, cg25410641 ,cg10501096,cg03460245,cg09698228,cg05107500, eg 14630313, cg20686277,cg20789035,cg25375764, eg 12604794, eg 12967319, cg0095647 3, cg00246003,cg16782675, cg17940162, cg10589447, cg16706496, cg15065512, cg121 41388, cg25622855,cg16196348,cg03732506,cg18519030,cg01461733,cg15307496,c g26657991 ,cg00636922,cg20444098, cg12994448, cg04284610,cg22517351, cg111964 37, cg07780348,cg07887538,cg24724587, cg10648908, cg27460077,cg23586413, cg24 152297, cg11763914, cg02489677,cg22165310,cg03118745, cg01207311 ,cg18198743, cg20391606, cg07768118, cg14911472, cg01869643, cg08480449,cg12827224,cg09173 595, cg05979517, cg25721648, cg01221623, cg07612877,cg15624109, cg02921604,cg0 3301848, eg 17995119, cg26468130, eg 16279993, cg08800380, cg07718535, cg26011998 cg23883522, cg18671199, cg16962341, cg24693392,cg21280745, cg04910183, cg08144 444, cg13753149, cg03454936,cg19743721 , cg12024826, cg22827060,cg09082134, cgO 6710704, cg18738857, cg10017118, cg25251744, cg06165607,cg03711457, cg02283485 ,cg16609021, cg18899516, cg01196161, cg20102393, cg00279778,cg20460388,cg0163 0982 , eg 14986962, cg08385486, eg 12181101, cg09269620, cg21962450, cg27108452, eg 24963041 , cg01777121 , eg 16811230, eg 18913527, eg 10734849, cg06627114, eg 1984889 5, cg09280800,cg10871046, cg14505174, cg03729276,cg04177517, cg15033962, cg021 61011,cg20176212,cg05725531,cg20366236,cg00024998,cg02601341,cg02685945,c g16675583, cg02415661 ,cg25730516,cg05242257,cg17714409, cg15644404, cg078077 83,cg00415333, cg06656338,cg22093077,cg09115705, cg08344341 ,cg00817399,cg10 822097, cg17343288, cg21205463, cg06015656, cg05259000, eg 12207450, cg24016044, cg22451185, cg06385639,cg07231649, cg27529911,cg21465850, cg12490365,cg11962 082,cg26325497,cg26298281 ,cg12863621 ,cg14751177,cg04697148,cg03843892,cg2 0438142, cg24265138, cg27089875, eg 11893552, eg 16570051 , cg09744887, cg01712359 ,cg03199646, cg01805282, cg27111756,cg22892369,cg02552868,cg23132195,cg1805 0291 ,cg01156844, cg13404849, cg09938328,cg02470039,cg20545087,cg03962365, eg 09803494, cg02615582, eg 10745876, cg06720945, eg 17820065, cg09955084,cg0390019 5, cg23992697, eg 11780096, cg03912267, eg 14371649, eg 16066776, cg05203877,cg215 32200,cg 14600016, cg00200763,cg03495180, eg 12277119,cg16496398,cg01215435,c g10940099, cg11170552, cg25907190, cg05774229,cg26128898,cg23083936,cg158560 43 , eg 10243252 , cg01122799, eg 17218041 , cg00588559, eg 14170778, cg01090611 , cg03 217173,cg26712714,cg08299063,cg12210378,cg26752263,cg18365029, cg08433366, cg01640094, eg 14892570, cg03751718, cg04277172 , cg20833495, eg 17327377, cg04382 250,cg06517767,cg04853218,cg08892952,cg07086719,cg08778533,cg01729721 ,cg1 8082714, cg12504524, cg12283875, cg19071293, cg20396110,cg19134904, cg22451356 , eg 10712835, eg 13797468, eg 19390271 , cg27033231 , eg 15730281 , eg 11182465, eg 1125 0223,cg22534599,cg02072018,cg23082862,cg23250191,cg04679284,cg03799335,cg 20745684, cg05088006,cg17663845,cg03175975,cg01845087,cg12373145,cg0973012 3,cg10304922,cg14202477,cg14958560,cg02251141 ,cg07433923,cg06669700,cg197 26320, cg01947301 ,cg09182692, cg05376738,cg20497631 ,cg26163463, cg09586441,c g01231075,cg27649295,cg05684906,cg16089443,cg07728212,cg10117405, cg233204 99, cg04090022, cg03701120, cg09703318, eg 15589427, cg00664899, cg06876354, cg21 217812, cg10439209,cg19251549, cg16899265, cg21195303, cg16193078,cg23027296, cg00033818, cg19180498, cg26869609,cg01320505, cg13074295, cg06707375,cg03338 584, cg14431361 ,cg06141968, cg02046668,cg01388144, cg24399212, cg04100843, cg1 5400117, cg23965931 , eg 11580511 , cg06171637, eg 16613509, eg 16516295, cg05013422 , eg01149400, cg07268571 , cg00785312, cg05542153, cg24366105, eg 19318426, cg0473 9272, cg13483990, cg02484491 ,cg21329478, cg03825764,cg17355239, cg25147601 ,cg 06984787, eg 16851467, cg22266693, eg 10065823, cg01675512 ,cg26959982 ,cg0842561 0,cg22967180, cg23107916, cg22726349,cg17405984, cg17391508, cg20604927,cg017 24831, eg 16660359, eg 19382191 ,cg06445430, eg 17007574, eg 13396570, cg24941977, c g13741289, cg12129209,cg11027829, cg05824447, cg19987349, cg03706631,cg135673 49, cg06007291 , cg26273227, eg 10846857, cg08867464, cg00916854, cg09070261 , eg 16 872795, cg08878313,cg23314514,cg24792360,cg25859111 ,cg12133425, cg11794213, cg12963150, cg03216491, cg01788676, cg18876602, cg25763439,cg27018907, cg14872 036,cg04390341 ,cg08655589,cg23444011 ,cg13403981 ,cg06118847, cg06727980,cg0 7735969,cg08251029,cg04059838,cg20488673,cg18829125,cg16271200,cg11019740 ,cg05549575,cg05378942,cg22673320,cg04469731 ,cg23957216,cg17681750,cg0919 8085, cg26688678, cg08324906, cg20927724, cg24970016, cg08827572, eg 14020598, eg 01290229, cg13253303, cg27210919, cg24881910, eg 16640057, eg 14980188, cg0340303 2,cg04643437,cg27519330,cg26250989,cg12246353,cg02761480,cg04286377,cg210 62660, cg06388809, eg 15834054, eg 12344046, cg08516247, cg01220720, cg11524081, c g25985537, cg19173666, cg11069276, cg17059926, cg22587857,cg11915677, cg178992 03, cg04597658, eg 11330681 , cg25272394, cg03830401 , cg03780021 , cg24707065, cg24 539380, eg 14432712, cg05904869, cg24006505, eg 15637060, cg23423086, cg08315168, cg20884636,cg25413864, cg04175292, cg25754826, cg14349538, cg17036521 , cg20322 977, eg 12666768 , cg25539628 , eg 15246994 , eg 15433411 , cg22529952 , eg 11559952 , eg 1 5419852, cg09695260, eg 19384726, eg 15266604, cg03547086, cg05793987, cg26668836 , cg24717695, cg08285095,cg 18904267, cg04926431 , cg08613370, eg 17987459, cg0725 1887 , cg04367345, cg08335389, eg 17497389, cg20858308, eg01277438, eg 10880709, eg 16556397, cg02765403, cg05921138, cg26120132, cg26502609, cg00034154, eg 1808821 0,cg20149988,cg27268275,cg20056634,cg00623698,cg04200362,cg23666702,cg052 24124,cg21910588, eg 19675288, cg07431800, cg03309176,cg 16189421 ,cg15304742, c g05092787,cg05174132,cg20916434,cg14466451 ,cg23794133,cg00294885,cg254039 74,cg22890854,cg11409620, cg10143146, cg05143438, cg08882098,cg26855812, cg03 589969, cg00629289, eg 10048216, eg 18831724, cg09086380, eg01472317, cg25038295, eg 10058885, cg25347941 , cg20263096, eg 16282183, cg03793778,cg05640318,cg09936 033, cg05388821 , eg 16497424, eg01225942, cg09914198, cg25496959, eg 18124917, egO 0753676, cg24802351,cg24059612,cg14303778,cg09101753,cg06503847,cg06996423 , cg25099807,cg21251646, cg27545784, cg22221026, eg 16914425, cg05251389, cg0504 1517, eg 11296358, cg21263196, cg27055580, cg26594908, eg 14328457, cg21929761 , eg 16185636,cg03006225,cg02860599,cg03374559,cg26799806,cg05365418,cg2688080 6,cg06775669,cg09208919, cg15487687, cg14335588, cg16259714,cg09790187,cg046 79114,cg12519998,cg24544134,cg06933064,cg24549231 ,cg14422782,cg00508575,c g03704756,cg22186223, cg04786323,cg10833091 , cg16742874, cg19023847, cg112875 21,cg00566514, cg25646679,cg01575061, cg01672894, cg19026128, cg18650994, cg26 621778,cg15601244, cg22805653,cg03253073,cg22202401 , eg 13891220, cg09359834, cg24686825,cg25395022,cg26417346, cg11779646, cg08820568,cg13003513, cg07905 442,cg09809710,cg23015138,cg26556091 ,cg05163057,cg02481778,cg00538830,cg2 1386527, cg07150906, eg 18468862, eg 10366797, cg18118685, cg22317906, cg07549715 ,cg27138344, cg08041523,cg07925085,cg15157943, cg19412964,cg15154540, cg1530 6126, cg02530336, eg01005937, cg05046996, eg 11632238, cg23883404, eg 16978571 , eg 08242493, cg10093080, cg00051885, cg00563870,cg07771804, cg25892208,cg1150893 5, cg00287829,cg15040720, cg07875199, cg25324936, cg16459020, cg01613708, cg095 26452, cg21238376, cg09572816, cg09095400,cg01587630, cg02932978,cg16572540, c g24511898, cg19008468, cg01020744, cg24169771 ,cg03686366,cg22637865,cg080015 14, cg23977821,cg03159127, eg 14530983, cg05240871, cg16389358, eg 11596580, cg25 249383, cg17468855, cg07002382,cg11676223, cg25978011 ,cg04206986,cg24192933, cg19460902, cg14615893, cg18462596, cg13469346, cg00789986,cg00296079,cg14557 853, cg17988158, cg03902821 ,cg01282204, cg10592521 , cg01691057, cg20318845, cg2 4406904, cg25894839, cg02735381 , cg22153080, eg 17411455, eg 19548524, cg09475028 , cg05110943, cg26071556, cg09453280, cg20526432, cg24688655, cg06612950, eg 1509 0834, eg01390039, eg01263474, eg 14620221 , cg23295454, cg26625593, cg08736638, eg 17747781, cg06386249, cg22108292, cg10416593, cg12871384, cg01476969, eg 1939026 0,cg15113090, cg20649047,cg05540822,cg04672169,cg19663137,cg08537418,cg140 00174, cg25023215, cg25302257,cg24373596, eg 12876349, cg21954752, cg07164630, c g12581354,cg23144371 ,cg08477744,cg14683465,cg00303740,cg07549065,cg180200 72, cg02266849, cg21327887, cg26516759, eg 10317445, cg04770751 , cg02498218, eg 10 482913, cg24926008,cg10787840, cg04902671,cg02148001 ,cg06134315, eg 17202948, cg27429799,cg09431913,cg11576513,cg26704180, cg13852407, cg26908123, cg20318 252,cg11141380, cg26244225,cg26229018, cg22754654,cg01782371, cg22240409,cg1 5720019, eg 14846710, cg21639188, cg26980000, cg00383117, eg 10332523, cg06895230 , cg25073527,cg06571387, eg 15448385, eg01882222, cg08147448, cg21904978, cg0984 2728, cg17436666, cg17867835, cg04324758,cg10277956, cg19675628, cg19505659, eg 14136086, cg09929180, cg03351533, cg22881279, cg02124892, eg 19262963, cg0079781 8,cg21011267, cg03969326,cg10124442, cg16308301, cg13541101, eg 18304908, eg 105 82860, cg08051523,cg26420606,cg22112360, cg07546558,cg01211137, cg13180105,c g02798872, cg02775353,cg20237106, cg16522223, cg19562526, cg06675981,cg064791 01 , eg 12311226, cg00485090, eg 12793305, eg 12271210, eg 18614234, eg 15473007, eg 10 309776, cg00938688,cg02579136, cg15454563, eg 10765427, eg 11435035, cg01944000, cg19733740, cg19064209, cg26955580,cg13724452, cg06177446, cg19738386, cg02189 843 , eg 18341076 , eg 19831303 , eg 13499600 , eg 10655371 , eg01679663 , cg04925032 , cg2 4348114, eg 11708963, eg 19974715, cg24468492, cg23278418, cg22531904, eg 16237529 cg25640893,cg01915885, cg20931042, cg05569195, cg15167646, cg14634540,cg06224 751 ,cg25642917,cg20377999,cg07980145,cg06084557,cg27523087,cg04836485,cg1 0279667, eg 10332495, cg22298418, cg09219547, cg20743744, cg02520888, cg03808418 ,cg18283926, cg16533838, cg17177660, cg09402652,cg17172090, cg17331011 ,cg2653 3154, eg 16024529, cg02060738, cg03963837, cg00502002, cg25085038, eg 19000326, eg 10953723, cg27051171 ,cg01050213,cg25203425,cg20468815,cg04465784,cg 1139913 6,cg09763039,cg25949858,cg00061868,cg06573146,cg05019107, eg 19616844, cg254 12377, eg 10677933, cg09101902, cg09218961 , cg08694923, cg00233512, cg21928095, c g 18707868, cg21704502, cg03088878, cg26207837, eg 18985987, cg20480522, cg038952 21 , eg 13725148, cg22844265, eg 13680133, cg21056295, cg05835247, cg22003475, eg 16 170760, cg15844273, cg26648157, cg19595912, cg05704336, eg 15813048, cg05986572, cg09169514,cg03231430,cg26471121,cg14894866,cg12513294,cg14849608,cg05953 781 ,cg25837813,cg23961331 ,cg22227104, cg26295786,cg15478628, cg16526479,cg2 6439015, cg18564075, cg27550498,cg00623462,cg21803057, cg09446908,cg12151542 ,cg19069367, cg13986355, cg25561754,cg05106659, cg07952254, eg 11230523, cg0815 4612, cg02483593,cg21367307, eg 18589278 , cg05142461 , cg24115215, eg 13439195, eg 10211079, cg04768002,cg18751688, cg17356532, cg26152188, cg16150677, cg2734074

9, cg06642177, cg09104660, cg00475820,cg25413455, cg18266971 , cg16794867,cg127 77782, cg03671802, cg07224371 ,cg26334657,cg21108875, cg02357631 ,cg10384044, c g02811243 , cg09463211 , cg07197480, eg 16586402 , eg 16556504, cg22271962 , eg 164250 60, cg07431199, eg 11787828, cg25971807, cg09906402, cg08550205, cg22603569, cg02 909570, cg24187257,cg19714134,cg08207284,cg26279668,cg06214087,cg26059202, cg22799638,cg09495271 ,cg20744894, cg13144464, cg12992720, cg24898562,cg13039 021, eg 10549156, cg04904945,cg09518293, cg01496136, eg 11544714, eg 15182994, cg2 3449757, cg02610600, cg09960003, eg 12072001 , cg00197534, cg06226630, cg04694615 ,cg00564759,cg16116426, eg 14327296, eg 11060199, eg 11095027, eg 15667299, eg 1116 8534, eg 11697433, eg 18447876, eg 13772070, cg02535924, cg25422405, cg03920897, eg 22364503, cg26158133,cg03801912,cg01180772, cg00684114,cg24392132,cg2409225 3, cg05133691 ,cg06880930,cg03776372, cg16819369, cg14851496, cg19742870, cg034 11270, cg02378181, cg24856699, eg 16749093, cg05573542 , cg23623451 , cg08485302, c g13690588, cg16786144,cg07325360,cg19526740, cg14174378, cg05241596,cg079204 03, cg14691051, cg08377526,cg18001872, cg16123760, cg23650249,cg20646939,cg06 431681, cg27539176, cg18029031, cg03162314, cg20539986,cg25460716, cg01388649, cg01729862, cg18739089, cg05019168, cg24366702,cg13598673, cg24523339,cg20002 354, cg13291298,cg11237636, cg15233681 ,cg14855874,cg14214287,cg15844201 ,cg1 6312655, cg22213309, cg21854621 , eg 17768691 , cg24885794, cg05534349, cg25951430 , cg15328414, cg11745885, cg02135442, cg23096282,cg21628854,cg05636086,cg1323 1302 , eg 15481583, cg27170298, cg07209244, cg02456934, eg 16588061 , cg27021986, eg 10832476, cg03285845,cg13982417,cg10814093,cg00570594,cg05776388,cg0904345 6,cg 10170637, cg05529886, eg 10353388, cg03446675, eg 10614605, eg 11557938, cg033 40174, cg05963618, cg19879264, cg11219380, cg23894226,cg12522342, cg27197276, c g07816873, cg10632328, cg25117505, cg20724494,cg07086074,cg02525756,cg008415 33, cg00140235, cg20770922, cg27057027, cg26369484, cg03814703, cg20705358, cg22 517740, cg07788369, cg02150912, eg 12582330, eg 13350744, cg22897615, eg 12205413, cg26759515, cg19733916, cg12311132, cg15970074, cg08867767,cg10312572, cg01496 567, eg 19883905, eg 13346235, cg00622166, cg02414224, eg 18384674, cg25232967, egO 9352582, eg 15639469, eg 11857025, cg00590670, eg 11247343, eg 12235672, cg05808227 ,cg22900415,cg09240267,cg04303330,cg03648724,cg25811820,cg03061811,cg1054 4888,cg04539059,cg05001882,cg22421417, cg02403334,cg19649564, cg10726312, eg 11734009, cg12662929,cg18567504,cg14583561,cg20173193,cg17498997,cg1725575

2, cg01781266, cg02820072,cg06215939, cg07285641 ,cg23942310,cg05443407,cg161 42855, cg18175898,cg19505036,cg14976084,cg00714810,cg20052760,cg17316890,c g14650849,cg26454300,cg01729262,cg08635139,cg03861496,cg09863247,cg191058 10, eg 14841929, cg06864796, cg04028010, cg05313009, cg07882772, cg06295215, cg06 372467, eg 10734048, cg25257808,cg00457932, eg 10535411 ,cg14573389,cg16142418, cg27437304, cg24596998, cg21680161, cg04486013, cg26164767, cg27585557,cg22104 427, cg07240470, eg 10370924, cg26432044,cg05113000, cg27344740, eg 14220634, eg 1 0640327, eg 15573664, cg04260924, cg25364573, cg23353205, cg03882382 ,cg08300096 ,cg09906238,cg27617969, eg 17152177, eg 11079097, cg22541098,cg20174180, eg 1517 6213, eg 12034869, cg09552402, eg 15626828, cg25776856, eg 12075497, cg27506254, eg 09864858, eg 14780845, cg09857555, eg 12445378, cg22663117, eg 10832589, cg0456389

3, eg 13748746, cg05253759, cg09300749, eg01418090, eg 12760335, cg26764244, cg068 07002, cg22539069, eg 19050943, eg 11534519, cg09711841 , cg14033917,cg25454890,c g15689600, cg11330907, cg07310318, cg19041305, cg08365194, cg18944752, cg009497 53, cg22170260, cg12569736, cg01283343, cg02686793,cg10448011,cg12022183, egOO 794722, cg09588684,cg17250301, cg06489912, eg 19541688, eg 14065121 ,cg01362115, cg17537844, cg27591595, cg24838203,cg05642734,cg07923738,cg06798234,cg06321 562, cg19198568, cg05818685, cg27095527,cg18446895, cg05468967,cg03786920,cg0 8038037, cg13855577, cg26157020, eg 15412181 ,cg09315121,cg20656102,cg01625621 , cg21640587, eg 13354872, eg 13311930, eg01554606, eg 13838969, eg 10706072, eg 1672 2435, cg03830429, cg23314545, eg 19741231, cg03371669, cg02994900, eg 17659533, eg 23885502,cg23050254,cg03569932,cg02495670,cg26471537,cg05924191 ,cg0533227

2, cg00403246, cg25124476, cg15057214, cg21058506, cg06723057,cg19954255, cg143 32810, cg10679756,cg10954944,cg10553696,cg04638282,cg11693611 ,cg02775804,c g18950102,cg03776542,cg02019114,cg06484553,cg09476073,cg04292549,cg136927 65, cg03298286,cg03382715, cg07489204,cg14054320, cg07590922,cg09637051,cg02 766235, cg22197416, cg17344384, cg09152105, cg04087391 ,cg23429847,cg 17345703, cg22153940, cg26601590,cg20395881 ,cg01354384, cg04915079, cg01240433, eg 17753 427, cg20943499,cg13253785, cg26612648,cg05460226,cg09250727,cg26527490,cg1 3398482, cg20420783, cg20522675, eg 17606548, eg 11841450, cg24554720, cg24626164 , cg26880954, cg20919549, cg03237606, cg23839687, eg 19337413, eg 16975406, cg2032 4516, eg 17784781 , eg 17256334, cg07779423, cg00856278, eg 11056815, cg24774954, eg 01627476, cg23940322,cg01338864, cg13608726, cg14885742, cg07289133, cg0746649

3,cg07528723,cg03046332,cg03237892,cg23396057,cg22660192,cg05241586,cg061 66583, cg20999663,cg20102368, cg04140212, eg 12767937, cg22770911 ,cg21992507, c g19888485, cg03528558,cg18749901 , cg07834934,cg24863624,cg03896390,cg137082 59, cg21621464, eg 16598730, cg26102434, cg27131551, cg24516304, cg04572826, eg 10 270798, cg25323545,cg06459669,cg25156198,cg14513117, cg04795575,cg03070999, cg02034293,cg03732014, cg11620689, cg24384057,cg17147728, cg01347048, cg02350 144, cg09353063,cg02145310,cg03607359,cg16099437, cg23527621,cg12036735, cg2 0942933, cg05835228,cg21131022, eg 14694639, cg26821104,cg01904886, cg23514324 , eg 17617532, eg 13815475, cg22960135, eg 12381643, cg26225496, cg03043928, cg0097 9553, cg04100307, cg21432513, cg18429434, cg06934851 ,cg09599777,cg17484771, eg 07734047, eg 13088368, cg06315199, cg26812704, cg09090006,cg21282549, cg0087161 0,cg26062273,cg25473293,cg01948527, cg21233791 , cg10593400, cg13093012, cg013 66622, cg07664455,cg17817613,cg25551714,cg26950866,cg17502495,cg01643091,c g17411636, cg15148984, cg17181046, eg 15564098, eg 11461308, cg11478105, cg207167 03, cg21785496, cg03948437, cg21278102, cg21961904, eg 13697856, cg26165441 , cg25 739742, cg19959591, cg19324472, cg04013959, eg 17533550, eg 11791577, cg21840875, cg01363284, cg07801032, cg03320594,cg01176271 , cg17542225, cg23034818, cg12537 437, cg10785109, cg26261627,cg08159252, cg01900480, cg04960128, cg12187052, egO 6480249, cg24315629, cg21176048, eg01776144, eg 18356679, cg27129363, eg 16848717 , cg08615088, cg20431313, eg 14151409, cg05755441 , eg 14959707, eg 17659775, cg0698 0460, cg03349922,cg15385450, cg07652284,cg13067221 ,cg27110842, cg17286383, eg 22421902, cg08261871,cg25477831,cg08872596,cg02005785,cg20811659, cg2675155 0,cg05131254, cg21790657, cg07065941,cg05918682, cg21966975, cg06246552, cg109 80774, eg 18668753, cg04294052,cg22982368,cg24662062,cg02144516, cg23675000,c g25540028,cg09652405,cg21527556, cg04835925,cg05828140,cg18589102, cg100441 43, cg22779542, cg09493327, cg03695597, cg20426866, eg 11913496, eg 12753957, cg05 209514, cg23004862,cg20588285,cg00685038,cg06370287, eg 13593376, cg08125755, eg 14529095 , eg 19699832 , eg 17868910 , eg 16627915 , cg26568223 , cg07771338 , cg26246 751,cg06002198, eg 16482474, cg02855207, eg 19112349, cg02485566,cg26994023,cg0 8416023, cg02577384, eg 12489809, cg23586103, cg09831611 , eg 11463113, cg20756243 cg08342837, cg13160058, cg11453546, cg21542793, cg02527726,cg23480676,cg26557 908, cg08915936,cg05049361 ,cg11992567, cg16196762,cg09597785,cg11934849, egO 7222309, eg01194119, cg07535447, eg 14664835, cg07476653, cg09950256, cg03486961 , eg 11067338, eg 10413302, cg04683620, cg09992406, cg09713850, eg 14625636, eg 1053 8276,cg20912272,cg10131752,cg03917515,cg20171396,cg03761979,cg04662594,cg 24034289, cg11207300, cg06609182, cg12975892, cg20360251 ,cg09668022,cg0650462 4, cg04489513,cg16672637,cg11270070, cg23504815,cg09741846,cg22862193,cg208 60481 , cg02544499, eg 11798891 , eg 13426503, cg00996758, eg 12680680, eg 17540356, c g17459911 ,cg21441571 ,cg19602015,cg22457903,cg10333400,cg06004816,cg272775 32 , cg26749833,cg03255741 , cg04724866, cg08968329, eg 11885191, cg07651182, egOO 898279,cg00224465,cg12003064,cg23819087,cg 13315166,cg 16119776, cg26002259, eg 17147121 , eg 14926717 , eg 15011041 , eg 19294393 , cg06883267 , cg04043957 , eg 18456 312,cg02551145,cg12417549,cg10246296,cg09891332,cg24915511 ,cg04823124,cg1 5921869, eg 18409562, eg 14774364, cg08744915, cg23911406, cg07005934, eg 10476773 ,cg18858905, cg12688068, cg17162599, cg15604507, cg19989222, cg02521059, cg0261 8071 , cg02378763,cg05885212, cg16553796, cg03608313, cg18492647, cg15690052, eg 15710987, cg26528689,cg02645710,cg27645474, eg 18070630, eg 14208013, eg 1875130 6,cg07274194,cg20280386,cg 18317842, cg02460120, cg24485571 ,cg26858257,cg 112 41278, cg13736939,cg06275936,cg07420232,cg05824757,cg26655764,cg00936494,c g13821759, cg18215969, cg03059991 ,cg11753669, cg15143370, cg27104413,cg108790 53, cg23230486, cg05366118, cg24226400, cg25947600, eg 10480239, eg 16138752, cg07 678904, cg27298420, eg 13675330, cg24337863, cg06974458, cg25949671 , cg08316234, cg26559829,cg08565919, eg 16937477, eg 19640166, eg 12702367, eg 12828867, cg24928 391, cg10367959, cg16171428, cg17644611 ,cg22489991 ,cg03090449,cg22967523,cg1 0468253, cg05779786, eg 14851122, cg03485667, eg01720705, cg26084922 , eg 10469818 , cg20665002,cg 13168411, cg00643984, cg09639230, cg26764685, cg25144207, eg 1408 2097, eg 14139175, eg 14582888, eg 19968221 , eg 10644638, cg05638471 , eg 16356956, eg 06566077, cg00061769, cg10502175, cg03241901 ,cg15310764,cg04394362,cg2204023 9,cg24637683,cg10897384,cg24425316,cg00754989,cg23261715,cg20294080,cg100 84902, cg08769507,cg03135154, eg 11952604, eg 13714895, cg22809047,cg19813226, c g20340866, cg08027484,cg07327144,cg14489346, cg01191262, cg25581063, cg088718 97, cg27434245, eg 16380632, cg06992496, eg 11364274, eg01797488, cg20630207, eg 11 007391 , cg25923171 , eg 14148522 , eg 13205384 , cg08407007 , eg 19005640 , cg22016234 , cg05258294,cg13556468, cg21142149, cg15125762, cg08533095,cg14723307,cg08946 989, cg04043710, cg18734472, cg15290779, cg03582761 , cg12052765, cg01016030, cg2 4937747, eg 16986851, eg 17764798, cg22881435, cg21438192, eg 16397620, cg27228402 , eg 11965754, eg 17804886, cg20528695, eg 15139857, cg02413270, cg09770579, eg 1211 4599, eg 12265757, cg20812295, cg25468879, cg02672229, cg09530217, eg 10621012, eg 11492859, cg02581828,cg06804311,cg20687414,cg03420872,cg10838086,cg2444546 6, cg12459037, cg06173337, cg05021291 ,cg26712096, cg03336861 ,cg13962589, cg071 83447,cg14419560,cg24141078,cg 18038361 ,cg24438313, cg22125795, cg05816866, c g05541607,cg19626138,cg09938049,cg06704605,cg15102325,cg09118485, cg264054 75,cg15191933,cg06654628,cg20861500, cg22556485,cg27295660,cg03417766, cg05 333719, cg22712383, cg25122439, cg05457563,cg04913913, cg03939486, eg 17760982, cg16737770, cg18264062, cg05560886,cg22751650, cg06558483,cg09748306,cg03514 843, cg09848886, eg 15862119, eg 18578708, cg07746263, eg 10193193, eg 13231818, egO 0545756, cg04584630, cg21740507, eg 16030761 , cg20108204, cg21255939, cg04542869 , cg08049816, cg23593177, cg04615529, cg08595501 , cg02531193, eg 10997479, eg 1138 3894, eg 12164612, cg26731131 , cg21379196, cg20256494, cg24611996, eg01491926, eg 04238740, eg01386581 , cg25304816, eg 11380909, cg00635642 ,cg25135002 , eg 1304798 9,cg08371871 ,cg03626085,cg27493010,cg15006869,cg24009881 ,cg05661311 ,cg060 00034, cg02950364,cg23371746, eg 16449069, cg06838365,cg17626178, cg12922666, c g25350122,cg25115203, cg04528352,cg21233313,cg24768165,cg09048186,cg152655 86, cg18768509, cg12895717, cg05853769,cg15127863, cg10754941 ,cg07768486,cg20 004827, cg23057721, cg18509466, cg12243732, cg20589039, eg 17208001 ,cg21789392, cg04852826,cg26882168, cg10738026, cg16000824,cg09996288,cg22068068,cg25630 211,cg12100089,cg19175386,cg20823471 ,cg14395546,cg20094111 ,cg03473087,cg0 3760839, cg20665626, eg 14664464, cg03365548, cg04862038, cg23744393, cg23030115 , eg 11875500, cg09051393, cg04198091 ,cg05057612 ,cg25388335, eg 17463145, cg0822 0793, eg01026503, eg 11848592, eg 14285150, cg09397900, eg 18392391 , eg 12748555, eg 07009084, cg05504732 , cg20611650, eg 15898408, eg 12810221 , eg 16179054, cg0200199 1,cg26868829, cg12973651 ,cg17747924, cg18512446, cg20603548,cg07740579,cg015 43654, cg21672843, cg07010741, cg07048256, cg24654800, cg25899315, eg 18875924, c g07744152, cg10265536, cg00721125, cg01616313, cg02040583,cg13986840, cg132866 92 , cg02305358,cg21610602, eg 15416032, eg 17887685, cg03648245, cg02984063, cg07 693844 , eg01325331 , cg06681154, cg05587853, cg02715291 , cg06721796 , eg 10434361 , cg05349845,cg01025838, cg17876332, cg12148263,cg06185924, cg19694566, cg00531 400, eg 13928756, cg23412797, cg03080732, eg 17603105, cg25142308, cg26471497, egO 2328221 , eg 13001893, cg00313722, cg05873267, eg 14615946, cg05355184, cg22312296 , eg 17375901 ,cg07759237, cg24524352, eg 14046233, cg20932718, eg 16547400, eg 1463 4755, cg00061114, cg23149016, eg 13390224, cg02373061 , eg 10449839, cg00220335, eg 21396441, cg07258838,cg25567085,cg18453874,cg12816673,cg11288764, cg0933114 4 , cg26692811 , eg01373461 , eg 18190212 , cg21670451 , eg 12389889 , cg25481261 , cg218 53806, eg 15736994, cg25102136, cg06505075,cg06174407, eg 12308705, cg00121989, c g14511156, cg13686847, cg12905788, cg09504396,cg25495486,cg15775313, cg043031 39, eg 15209448, eg 19424577, eg 19271658, cg09326812 , eg 14974216,cg20584899, eg 15 353908, eg 18182399, eg 14775207, cg25969123, eg 10967532, eg 15390413, cg24859316, cg15544004, cg17755657, cg25792521,cg10857441, cg07625131 ,cg06872236,cg11824 509, cg14659956, cg18727637, cg05345149, cg00332153, cg11793977, cg01102856, egO 4143307, eg 12358298, cg00032227,cg06919709, cg21042248, cg03303747,cg24752692 , cg27379065,cg04227701 , eg 15407086, eg 12054521 , cg26996874, cg07022048, cg0859 6842 , cg06953065, cg22959512, cg05835573, eg 17136794, cg02111655, eg 18542495, eg 16970786, cg12494541 ,cg01299932,cg13533976, cg18103031 ,cg04387418,cg0900797 7, eg 11815480, cg15869128, cg24197035, cg22828783,cg02659701 , eg 13332525, eg 139 39185, cg06798572,cg13794009,cg04784633,cg09779794,cg12160011 ,cg04399091,c g01794926,cg24465376,cg01927043,cg10524283,cg22564695,cg11146114, cg087592 38, cg00183569, cg03345448,cg12152068, cg01374049, cg07003429,cg11248845, cg07 141215, cg19673125, cg01424624, cg06871863, eg 12807237, cg24800426,cg06273786, cg08130173, cg26263477,cg02725453,cg26124013, cg17642576, cg11641416, cg01307 981 , cg06404838 , cg21865687 , cg04131829 , cg02449575 , eg 15633140 , cg08062329 , cg2 1109870, cg14538189,cg03949050,cg07898631 ,cg11611544, cg03607891 ,cg01920232 ,cg07277559,cg01705052, cg15608397, cg10036510,cg08458758,cg20075315,cg2492 5698, cg09588546, eg 18103836, cg25956901 , cg20138067, eg 14914422, cg03514009, eg 16246962, cg16261823, cg03569778, cg14860917, cg17208781, cg05192440, cg1487912 7, cg21909526, cg17797859, cg19787736, cg04944283,cg19763069, cg17915286, cg179 00884, cg17000044,cg00761787,cg11129609, cg01139699, cg01097964, cg04296635,c g10604396, cg03020863,cg15841711 ,cg01791302, cg07145271, cg27141266, cg038207 79, cg21948636, cg14060863, cg16905413, cg20406576,cg02989453,cg16139228, cg22 888671,cg08379828,cg13365781,cg01510813,cg02651638, eg 17525436, cg07959027, cg18951256, cg01028469, cg09411922, cg03649476,cg27398720,cg14800351 ,cg08458 745, cg24967010, cg06735137, eg 17094923, cg00931187, cg08607032 , cg06559932 , cg2 1532590, cg27168830, cg25841970, cg10427651, cg09248887,cg22583612, cg26119845 , cg00668174, eg 15686385, eg 14671364, cg05273913, eg 17648252, eg 14364356, cg0873 5211 , eg 18192294, eg 12963241 , eg01827908, cg09446329, eg 10663353, eg 16341592, eg 00196810, cg03526652,cg13596297,cg18177613,cg20168063,cg11144351 ,cg0523208 9, eg 00463885, eg 13917047, eg 14621784, eg 10101634, eg 11252372, eg 16257804, cg243 39092, cg23124641 ,cg07139438,cg21437208,cg14447871 ,cg16688911 ,cg10529387,c g03041730,cg12239602,cg14037082,cg03552597,cg25924217,cg05200046,cg120503 08, cg08684551 , eg 15529703, eg01916685, eg 14975786, cg02693505, cg05065319, egOO 963378, cg10391895, cg17953249, cg09414262,cg27299406, cg12504163, cg01117833, eg 13206224, cg25039753, cg02814525, cg25653659, eg 18786809, cg21040775, cg22448 360, cg18717967, cg04178523, cg01441738, cg13426224, cg06063324,cg25827351 ,cg2 1775265, cg20177485, cg23391173, cg00184390, cg20756284, eg01336809, eg 16353201 cg09276883,cg18753695, cg05352767,cg04018315, cg03107409, cg03940688,cg04448 061,cg07080244,cg23312168,cg16359174,cg09272488,cg08337959,cg21850069,cg0 8951638, cg13001913,cg00161715,cg25282776,cg03228554,cg01255315, cg01012339 , eg 15282743, cg08005697,cg05921834, cg01164819,cg20647694,cg20318536, eg 1536 4725, cg19754622, cg26671652, cg03251293, cg03694644,cg06053850,cg22488718, eg 05972398, cg19519624, cg00345230,cg23599913, cg04931630, cg20359445, eg 1897352 1, cg14860494, cg15815726, cg27144223,cg03953980,cg25793931 ,cg22459988,cg224 92274, eg 15358690, eg 17734803, cg27225457, eg 13283330, cg21534574, cg06999891 , c g13527707, cg15890103, cg16948367,cg26050366,cg27340796,cg07269491,cg098560 68 , cg05468483, cg05530288, cg05740381 , eg 11769476, eg 13242667, cg27092986, cg03 786092, cg01858205, cg10442442, cg12006399, cg03547487,cg20169906, cg04027805, cg05587288, cg02288296,cg24313279, cg16747828, cg06893491 , cg15508380, cg14819 618, cg00145863,cg09225237, cg12591404, cg16322262, cg24059976,cg16496699,cg1 0924691 , eg 19093680, eg 11679186, eg01807303, cg02238928, eg01433347, cg24641186 , cg26494252,cg22560214, cg06480942, eg 17978124, eg01674530, eg 17365369, cg2103 3709, eg 17267835, eg 19579117, cg26269038, cg25453686, cg06694826, cg20431201 , eg 26373942, cg25734977,cg17759082, cg08959725, eg 19800096, eg 15430294, cg2721685 3, cg22061636, cg13769719, cg04297246,cg24149237, cg10638657, cg08249750,cg250 09947, eg 10024446, eg 12364461 ,cg09719563,cg08910474, cg21897425, cg03689540,c g21549415,cg07342403, cg05567294, cg00345965, cg07464886, cg27449836, cg053038 69, eg 15427448, eg 18845984, cg07702689, cg07678644, eg 11085283, eg 12877190, eg 19 635580, cg19758958, cg10508217, cg02074714, cg07519863,cg02018802, cg17815891 , cg25090653, cg07320380, cg04594452, cg03417473, cg24791257, cg21674727, cg24372 185, cg21556904, cg25691772, cg07771579, cg10508439, cg02948264,cg08534459,cg2 6764362, cg21561712,cg18331515,cg09322555,cg24760414,cg17792882, cg09008322 ,cg24805411,cg00231239, cg26606916, cg21943938, cg04132379, cg26833883,cg0714 0660, eg 11064966, cg26702212 , cg25059497, cg09338965,cg08043233, eg 15856662, eg 12500891, cg07605241 , cg06492005, cg06348136, eg 18142940 , cg21184847 , eg 1096271 3,cg02167757,cg06512514,cg10157663,cg16836355,cg00070380,cg26451234,cg007 60200, eg 19287858, cg22867118, cg25639084,cg22279720,cg09657982,cg16799111, c g 10689512 , eg 17072755, eg 11006597, eg 16817229, cg02881516, cg09035349, cg031767 88, cg23555866, cg25748726, cg22475869, cg03116355, cg20486246, cg04478606, eg 19 237818, cg23234674,cg14125846, cg15684600, eg 16094925, cg02902741 ,cg02098816, cg02407342,cg25459450,cg07784478,cg02084259,cg03875330,cg24522809,cg27511 235,cg03543319,cg09259179,cg03681008,cg16436225,cg22257056,cg10519093,cg0 7463455, cg21958241 , cg06574159, cg05513806, cg25011763, cg23146882, eg 13362837 ,cg09724374,cg00252422,cg11174740, cg08720503,cg23135706, cg23898951 ,cg0709 1062 , cg07380773, eg 10544884, eg 14459420, cg02523938, eg 12666976, eg 12458587, eg 12853948, cg02493486,cg04783624, cg18231229, cg21270847, eg 17665104, cg0250512 6, cg10799705, cg14552106, cg03993550,cg13570928, cg03978269,cg24502901 ,cg205 56458, cg01573804, cg09460490,cg06168992, cg16785441, cg14868694, cg04776892,c g08480903,cg08089977,cg24051057, cg06721255, cg10281728, cg00368059,cg046267 21 , cg20270703, eg 12337884, cg00060796, eg 17522986, eg 19106967, eg 12251943,cg01 084425, cg27555130, cg05028244,cg06352807, eg 12012865, cg02434007,cg21100958, cg15693281 ,cg26425933,cg03722901 ,cg01728993, cg08274556,cg09624466,cg01874 871 , cg24086600, cg02184644, cg05239425, eg 16801797, cg17980699, cg02017257, egO 2288088, cg26122129, cg05051950, eg 12425787, cg23068772, cg04311599, eg 10339241 , cg26970173, cg11558107, cg01516459, cg10767665, cg03765396,cg13613167, cg1647 9957, eg 14304960, cg24695972, cg02233849, eg 19853434, cg23436282, cg24491328, eg 20881888, cg26910619, cg08978953,cg16565890, eg 18850918, eg 15439733, eg 1593321 6,cg24524850,cg23930923,cg12255061 ,cg10130460,cg05934090,cg03225208,cg021 72885, eg 15598719, cg07424295, eg 15431537, cg21833655, cg09564132, cg20851790, c g20421764, cg06521357, cg03727842, cg21231909, cg19773045, cg16399182, cg233487 64, cg09940832, cg09693433, eg 12851609, eg 16106427, eg 14869203, cg23966473, cg03 637781, cg22698108, cg00863353,cg25838091 ,cg09427574, cg12454161 ,cg07742381 , eg01217131 , cg08506775, eg 16495621 , eg 13843417, eg 14934413 , egO0146676 , eg 19800 370, cg17840833, cg17968523, cg25228422,cg08288955,cg23812100, cg07522190, egO 0150030, cg21907004, cg07434077,cg00442507,cg23010183,cg08853316,cg21305021 ,cg13246328, cg10862587, cg22226852,cg23031969, cg08255044, eg 17220544, cg0421 0714, cg08438705, eg 15069362, cg20727483, cg23094236, cg26698347, eg 14888270, eg 25356621 , cg22798984, cg23068499, cg20935933, eg 10211626, eg01315063, cg0091700 3, cg21952723, cg13981787, cg14289093, cg14757543, cg20116574, cg24084706,cg101 09747,cg 16101156, cg02058807, eg 12615398, eg 13095216,cg09583753,cg21384789,c g20834681 , cg21955154 , cg27064692 , eg 19092032 , eg 19459454, eg 16016036, eg 194164 17, cg27529175, cg26679668, eg 15634739, cg06237697, eg01530202, eg 10473508, cg25 424383, cg17370481, cg16510709, cg12447688, cg03648666,cg08595249,cg21550483, cg06339126, cg02032125, eg 10588135, cg22056558, cg24364343,cg06037365,cg 11698 252, cg20890215, cg09309496, eg 18501421 , cg07198782, cg07983706, cg09063936, egO 4411044, eg 16726643, cg06483699,cg13391652, cg27416204, cg26570448,cg01632230 , cg00151810, cg09080721 , cg20817824, cg07169295, cg21747559, eg 15347131 , eg 1361 9852 , cg02893015, eg 16812600, cg05835416, eg 17597176, cg05208381 , eg 17910071 , eg 16698679, cg01439105, cg19901734, cg20696737,cg23216184, eg 18860682, cg0106491 8, cg17234979, cg20093198, cg06822704,cg02319097, cg17880376, cg01453114,cg072 87030, cg21606102,cg26744308,cg04220116, cg26843401 ,cg25523559,cg02737727,c g10911967, cg26133736, cg14023926, cg20897667,cg02673107, cg10095608, cg189027 42, cg03604939,cg15683488, cg12590791 , cg15836394, cg19941483, cg23931412, egOO 810351, cg22775501,cg25740500,cg15125994, cg08078204,cg00366223,cg03938777, cg13954265, cg00357062,cg27247702,cg03048529, cg10583499, cg17600065, cg09452 478, cg01936565, cg02452585,cg15741764, cg03392960,cg12124543,cg09083171 , cg1 5052719, eg 18165540, eg 18939666, cg05744332, cg02390588, cg20506745, eg 11913696 , cg24254658, cg00348538, eg 14666354, cg27496793, eg 10377621 , cg20683221 , cg2601 1448, cg00518495, cg19149222, cg16974878, cg00277502,cg05105913, cg02921269, eg 11688616, cg17918184, cg20040709,cg06881996, cg01879805, cg03627071 ,cg1880609 3,cg16063162,cg05226125,cg05993353,cg03821987,cg04698187,cg08277453,cg079 06276, cg05081346,cg21211357, cg20704560,cg24396605,cg13735959,cg21975040,c g07298692,cg02997922, cg15490715, cg02974491 ,cg21986239, cg22039482,cg267014 08, eg 14346162, eg 16066871 , cg20896439, cg20514110, eg 18965980, cg03018530, cg20 281040, cg13685273,cg06817639,cg10695145,cg01185411 ,cg16593418,cg21641209, cg18590839, cg16168328, cg15787712, cg18415382, cg16130600, cg13177959, cg07010 297,cg17431362,cg08743107,cg26529712,cg03335434,cg00985388,cg01918255,cg1 7300750, cg25561913, eg 18410358, cg17087899, cg23375552,cg09316688, cg03137972 , cg06377929,cg06567355,cg09869882,cg03019277, cg23279681 , cg09174690, cg2208 0027, cg16133643, cg00053769,cg20116166, cg22333016, eg 10880209, cg01893560, eg 07086492, cg14062612, cg16196087, cg14454127, cg01337593, cg08248366, eg 1122690 1,cg26881686,cg02854449,cg26969933,cg14855425,cg00120998,cg27482076,cg056 07089, cg18291238,cg18194110, cg24523650,cg19102858,cg05065100,cg01712007,c g06270975,cg27389290,cg27074985,cg27386006,cg14281756,cg21408513,cg006149 69, cg08122685, cg17834060, cg21665057, cg24641901, cg23801475, cg12133118, cg02 294631, cg02525108, cg25949961,cg27325314, cg07475244, cg11791526, cg24116779, cg27570517, cg01505148, cg16055075, cg04651602,cg01553699, cg07996447,cg19272 382, eg 13714844, cg01396176,cg27663468,cg00813027, cg06219927, eg 15476227, cg2 1343292, cg03231960, cg22792022,cg19631792, cg02933679,cg09956442,cg00364026 , cg23394480, eg 16819803, cg20577468, cg03707948, cg04122422, cg21573947, cg2612 1789,cg00853296,cg06875832,cg06978336,cg25414967,cg14240348,cg00499201,cg 15801815, cg01700290, cg17405687, cg03618290, cg09503635, eg 17878511 ,cg2618913 9,cg20248140,cg20175506, cg26974415, cg15981571 ,cg11685432, cg03437770,cg065 75541, cg11381113, cg02418294,cg15710143,cg04554033,cg13368423,cg01312997,c g07416030, cg22433190, cg02974628, cg21832731 , cg08504214, cg22664150, eg 141899 88, cg18455776, cg17716463,cg21194942, cg11894856, cg22509422,cg17287767, cg18 083817, cg04314825, cg00634229,cg24983367, eg 19711602, cg21385821 ,cg25619607, cg14593306, cg04976850,cg20364320,cg07093942, cg12815937, cg00744431 ,cg03777 405,cg22840018,cg05055171 ,cg05250673,cg02871995,cg05185311 ,cg23851030,cg0 1967448, cg02422627, eg 17692096, eg 13764830, cg00106211 , cg06454126, cg01932519 cg10417571, cg22252462, cg09463890,cg21154059, cg17238970, cg18093448, cg23982 427, cg05813612, cg23663698, cg16005461 , cg10704534, cg16217610,cg01229452, egO 8287175, cg10127162, cg25471472, cg06282811,cg25631746, cg08385375,cg26820118 , cg06721486, cg21911021 , cg23414211 , eg 10167235, cg26260386, cg07987890, cg0049 0209, cg10354850, eg 13611934, cg05777919, cg01234929, cg08871809, cg02009228, eg 15793218, cg07689821 , eg 12319836, eg 19207856, eg 13993643, cg07570142 , eg 1086189 7, cg22432933,cg02353484,cg01539201 ,cg25577821 ,cg09856869,cg13996962, cg084 05405, eg 17954957, eg 16362170, cg02353767, eg 14726652, eg 13432154, cg04542030, c g03840678, cg13295972, cg15636365, cg04025590,cg23149423, cg25027863,cg264738 44, cg23332327, cg07248874, cg21287597, cg09701712, cg26009554, cg22798756, cg09 065199,cg05095427,cg19946064,cg01664843,cg07238698,cg24328520, eg 18671773, cg04728775, cg00041083,cg09015115, cg16554099, cg02366534,cg25310104,cg26066 315, cg10590964, cg26544774,cg05060949,cg03114573, cg21171772, cg08092333,cg0 5017199, eg 16500987, cg26346230, cg03605064, cg26677783, cg25404263, cg04681958 , cg24253461 , eg 18851966, eg 18798099, cg06762750, cg03957671 , eg01258771 , cg2541 7913, cg06692384, cg01732449, cg15531800, cg25132161 ,cg08528826,cg19298856, eg 11994425, eg 18272878, eg 17767659, cg26476630, cg22061831 ,cg23360700,cg2707472 0, cg00432937,cg00019759, cg09111835, cg04571965, cg02425511 ,cg26432459,cg270 93835, eg 16963062, cg26993848,cg24504518, cg24726200,cg27076861,cg27054524,c g23415810, cg13050390, cg13526756, cg02780269,cg22754452,cg05361750, cg114087 29, cg23776294, cg07159847, cg27460824, cg24304000, cg04608253, cg26945996, eg 12 880685, eg 12970547, cg24660199, eg 18752987, cg00374078,cg00148252 , eg 19294038, cg08962625,cg00741650,cg16926102,cg00761069,cg26046467,cg03744604,cg08148 545, cg11399955, cg14832349,cg21671329,cg15107117, cg00470280,cg11681126, cg2 2751438,cg09322678,cg12278705,cg01714452,cg15172007,cg18273412,cg13530105 , eg 18742678, cg21935549, eg 16001495, eg 11894282, cg21908635, cg23307658, eg 1300 9981 , eg 19684059, cg02922879, cg22922226, cg02441765, cg10276302, cg02425263, eg 02810494,cg20006006,cg09961732,cg14959659,cg11605222, eg 15408073, eg 1270696 5, cg10422824, cg22192762, cg05242561 ,cg22456891 ,cg04474928,cg23297125, cg166 22176, cg05797685, cg07056623, cg27040005, cg26398691 , cg06798092, eg 17294065, c g03198203, cg21355791, cg15131282, cg03292069,cg24525340,cg05465169,cg038747 28,cg19091986, eg 18239300, cg00447867,cg02132670, eg 17739967, cg04398759,cg03 645899, cg09916232, cg11722376, cg09770075,cg02994773,cg08431062, cg08816705, cg15455280, cg24612772,cg21840434, cg16046951, cg05006142, cg19494464, cg19691 894, cg15846643, cg14906843, cg20950465,cg10720699, cg07117038, cg00113554, egO 0063959, cg18013056, cg22032947,cg24157349, cg11804724, cg01951637, cg27484529 ,cg21873674, cg20056648,cg17180313, eg 16082007, eg 18668327, cg05337739,cg0211 2027, cg16105303, cg17010972, cg25020373,cg14139078, cg11992550, eg 17320237, eg 07522516, cg24154132, cg20148881, cg05116545, cg05826823,cg22744180, eg 1427600 6, eg 11180303, eg 14262433, cg09368360, cg04064559, eg01410991 , cg03142258, cg020 23043, cg23311950, cg11220060, cg10088519,cg23982868,cg22374901 ,cg06447154,c g05530566, cg20833901 ,cg03874222, cg10591825, cg14507132, cg02227919, cg199233 61 , cg00410534, eg 11920122, eg01294263, eg 17809284, cg08734918, eg 15239238, eg 14 929913,cg02810516,cg16524216,cg14584529,cg18832411,cg01707127, eg 17497965, cg16407692,cg27328469,cg19967622,cg17611193,cg16268707,cg16317961 ,cg08705 406, eg 10941180, cg26114254, cg08305378, cg00560072, cg03444889, eg01495834, egO 0668949, cg09012337, eg 14948912, cg22974210, eg 16283010,cg22684008,cg01439876 , cg25461290, cg24913115, cg25144913, eg 19903333, cg25757393, cg09230950, eg 1886 0301 , cg06347643,cg26961386, cg04192862, cg01058879, cg14481263, cg18731014, eg 07439098, cg06580745, eg 16347155, cg08000684, cg20632567,cg02063736,cg2516927

8, cg14708311 ,cg19793034, cg00206185, cg00004747, cg16179594, cg25142794,cg171 03081,cg01561506, cg07869048,cg08292559, eg 10734164, cg03721808, cg14854358, c g02727678,cg06491456,cg10693251 ,cg18468219, cg23892580,cg17864040, cg183419 24,cg02867530,cg05151185,cg15796200,cg02644889,cg03401312,cg02017417,cg16 725723, cg15080477, cg04205753,cg15425541, cg02047170, eg 12481560, cg25579774, cg24639754,cg14358879, cg05407433,cg20993361,cg09245419, cg04151444, cg16533 314, cg24157994,cg23351943,cg11199428, cg21368511 , eg 14675871 ,cg26102806, eg 1 7073323, eg 11744817, eg 14881459, cg04927113 , eg 18656829 , eg 17944412 , cg23406699 , eg01927645, cg04406573, cg00801049, cg00767069, cg07655487, eg 13501181, cg0855 0283, eg 14098744, eg 16953128, eg 14897419, cg02193580, cg24783167, cg21593606, eg 09461094, eg 15880741 ,cg15306254, cg02862059,cg26031613, cg25308885,cg0821803 6, cg21349645, cg13848960, cg20293888,cg23646888,cg03302807,cg06304167, cg063 62543,cg08772028,cg15130076,cg00415827,cg22157199,cg06446719,cg21484914,c g21427854, cg10648763, cg10181968, cg10883069, cg06402789,cg00902415, cg144585 63, cg06035250,cg13295463, cg02370248,cg05796492,cg17250863, cg16934178, cg14 292841 ,cg15727647, cg25856411 ,cg24732856,cg01976469, cg19439706, cg20594401 , cg06070749,cg01094950, cg07295964,cg00125100, cg07339662,cg14885904,cg05857 826, eg 10580083, eg 13530254, cg07229600, eg 14692213, cg03609058, eg 13118906, eg 1 3254080, cg26062223,cg13489874, cg26194015,cg22551912,cg25927219,cg14231073 , eg 15411927, eg 17131435, eg 12093891 , eg 11843781 , cg26223654, cg03326597, cg0542 2897, cg12313892, cg10108001, cg05928053,cg25083792,cg03157659, cg21512370, eg 11046985, eg 19582344 , cg09092901 , cg23657686 , cg04775302 , eg 10641721 , cg0691574

9,cg23817981 ,cg07582470,cg14935271 ,cg06931695,cg05817664,cg13109634,cg159 59167, cg00298910 , eg 16864256 , cg26219051 ,cg02629205,cg11112021 ,cg22325332,c g15351341,cg00261647,cg27339840,cg02370877,cg07934732,cg16441919,cg085274 48, cg01431482, cg21276695, cg12361046, cg14360897, cg10766367, cg24566917, cg07 160014, cg22737823,cg23965588,cg09304460,cg25317233, cg21154759, eg 13766172, cg17328472,cg24815154,cg22214335,cg00486036,cg14343953,cg04736140,cg01513 081 , cg16957997, cg24765579,cg12609403, cg12530021 , cg21877714, cg10348384, cg1 7934894, cg27544871 , cg00759699, cg26609342, cg26881663, cg25974422, eg 11774413 , eg 12166811 , eg 15029032, cg22896904, eg 13640690, cg25087487, cg21660597, eg 1893 8204, eg 13391271 , eg 17690694, cg21620540, eg 17592292 , eg 10583180, cg09372755, eg 12150111 , cg09466904 , cg08330183, cg27427565, cg26247841 , eg 19934294 , cg0857686

4,cg00026731 ,cg08684546,cg22755008,cg22991379,cg12629359,cg14321859,cg015 39854, eg 16914946, cg27411858, cg13143688,cg26488590,cg13453253,cg07678960,c g07341624 , eg01369599 , eg 11018769 , cg02698668 , eg 17395885 , cg00666772 , cg264888 37, eg 18074562, eg 17320866, eg 14148735, cg24579424, cg21489873, cg09751583, cg02 066925, eg 17029300, cg25446676, eg 16613500, eg 11376709, cg19934590,cg12811215, cg18521772, cg05350601 ,cg27536151 ,cg04550371 , eg 16087060, eg 17462356, cg26073 815, eg 11614585, eg 15139063, cg25043477,cg00780282,cg06361057, eg 13999099, egO 1417537, eg 12286351 , eg 12572059, eg 13465470, eg 16585380, cg06740613, eg 15604777 ,cg14224553, cg15232652, cg10181028, cg17328880, cg24191189,cg23796525,cg1696 5936, cg01624068, cg21307843, cg03647327,cg14182166, cg19252199, cg10921077, eg 15006246, cg06269001,cg08572394,cg06115614, cg05767306,cg01151966, cg1120605 2, eg 11237883, cg07439975,cg27517702, cg03264209,cg09848493, eg 12760786, cg075 07115, cg23431892, cg08485389,cg17475456, cg10405794, cg09203650,cg15467503, c g18388972, cg08767710,cg20928554,cg06662976,cg08270964,cg16215996, cg103224 43, cg04302433, eg 14087524, eg 18098089, cg00802396, cg04804241 , eg 16812519, cg05 810476, cg09337511,cg00183468, cg03976768,cg03950441 ,cg04102547, cg15874113, cg27491896, cg10897231 ,cg22849482,cg03751356,cg23577104, cg21958251 ,cg02511 456, cg20656556,cg22748407,cg00986590,cg25110943, eg 18813390, cg06645772, eg 1 5980689, cg07573085, cg02032027, eg 17027101, cg07139577, cg26680750, eg01077779 , cg20059467, cg16572354, cg09716038, cg20962215, cg03212568, cg15381433, cg1566 3348, cg23305943, eg 18234145, cg27297051 , cg24005131, cg02310103, cg09270675, eg 05669550, cg26459588, eg 15633661 , eg01239928, cg02065953, eg 17877485, cg2213432

5,cg16916204,cg05063097,cg02949838,cg27501451,cg24825974,cg00446488,cg262 03256, cg22519184, cg02926266, eg 11689323, eg 17594757, cg23805457, eg 11291798, c g06489367,cg22564021 ,cg23370536,cg04443039,cg08675654,cg09507697,cg010834 75, cg21787291 , eg 17625635, cg25946722, cg24830619, eg01011154, cg24214471 , eg 19 530176,cg09678150,cg00078676,cg02374817, cg19944463, cg21834547, cg01995852, cg11992265, cg26221796, cg06506040,cg01722584, cg01498160, cg18207141 , cg25598 530,cg08041019, eg 14886990, cg06442089,cg22734126, cg20122635, eg 11028747, cg2 3299262, eg 14545212, cg22496450, cg20409587, cg22813366, cg25618981, cg03052128 cg11857320, cg23027580,cg18203764, cg25721516, cg07691152, cg03419140, cg03177 231, cg17447502, cg27614445, cg21669441 ,cg25336853,cg21281009, cg05035143, cg2 5509621 , eg 14666404, eg 12312252, eg 18477248, cg00530710, eg 11059341 , cg22514863 , eg01462681 , cg26147746, cg23477849, cg22923827, cg25349828, eg 19546397, cg2613 5012 , eg 15641060, cg23316188, eg01957881 , cg09574807, eg 14527423, eg 14565408, eg 23656707, cg07594209,cg27199414, cg21888135, eg 16010788, eg 13795856, cg0906255 0, cg11356990, cg09748973,cg25771041 , cg12479696, cg18318655, cg02616470, cg072 17924, cg16438392,cg03359503,cg11468826, cg13537752, cg01928231, cg11164846, c g09600529, cg15281505, cg05638174, cg13983442, cg18333807, cg14426525, cg144143 38, cg17477442, cg06049528,cg22807732,cg06931253, cg07048479,cg24172946, cg07 238401,cg14071758,cg16137250,cg25296860, eg 14163334, cg24320643,cg03628820, cg03187894, cg16940805, cg24924210,cg21545840, cg07721547, cg18763536, cg18244 589, cg07287563,cg10852119, cg14209987, cg19091146, cg25306257,cg20716945, cg1 2402495, cg09926135, cg03654588, cg07345999, eg 15205435, eg 10210928, cg20533393 , cg23833878,cg21925748, cg18488207, cg02757645,cg07946633,cg22705929,cg2077 8915, cg19129369, cg07760720,cg21228269, cg01105362, cg25580978,cg04800682, eg 06584619, cg06255299,cg20962356,cg11251063, eg 16051599, cg03289369,cg2100630 1, cg07244980, cg16226899, cg08314795, cg02283106, cg17470061 ,cg01673299, cg135 38006, cg02389566,cg04446986,cg00145507, cg06688502, eg 18727880, cg09694281,c g21843573, cg15109150, cg18838958, cg08412584, cg27328882,cg13201254, cg149127 51 , eg 14663767, eg 10836173, cg24413727, eg 11138794, cg21473748,cg15710018,cg04 930630, cg08282679,cg14324694, cg07351084, eg 10278149, cg00563487,cg05729783, cg13643886, cg15281956,cg25341963,cg27186528, cg08213792, cg05258027,cg09727 928,cg02935802,cg11988964, cg07263984,cg11296933, cg03804847, eg 17373848, eg 1 6931052, eg 10949240, cg25284089, eg 11752061, cg23751761 , eg 13886772 , eg 14721545 , cg24401487, cg02045388, cg22783262 , eg 10695848, cg07590344, eg 15154232 , cg0398 6322 , cg26539688, cg23086890, cg22306928, eg 18476993, cg00946032, eg 13595604, eg 20515423,cg14654158,cg12140144,cg01636591,cg 17328138, cg04132252, cg0380181 9, cg23131559, cg19995471, cg25083270,cg00467326,cg01977838, cg24107886, cg011 34309, cg20312821 ,cg23877380,cg01025233, cg06636678, eg 19368762, cg13915219, c g24947540, eg 15803261 , cg20367788, eg 11270237, cg26594205, cg25538530, eg 114083

95, cg04134826, cg20857275,cg23093217, cg16993186, cg01998014, cg17345366, cg20 356664, cg23293329,cg13509954,cg24977338,cg23096826,cg10160407,cg01721538, cg07195261, cg14369329, cg11173148, cg19910128, cg02897366,cg15660070, cg11026 333, cg12459316, cg25233887,cg08813539, cg14037728, cg13628171 , cg16389252,cg2 7428051 ,cg23500850,cg07661340, cg20758929,cg09107937, cg22405728,cg03267321 , cg22361181 , eg 18029596, eg01991875, cg27553780, cg23007775, eg 19350812, cg0861 8021 , eg 13234417, cg23513567, cg05822495, eg 13142499, cg03059073, eg 18129327, eg 22979163, cg00251443, cg19772747, cg06476463,cg00777331 ,cg16983788, cg0473882 7,cg04027111 ,cg12990832,cg27280313,cg27641084,cg23713813,cg19698348,cg011 78013, eg 12865142, eg 17813775, cg02809409,cg22778788,cg20983046,cg26351764, c g 16063308 , cg24138650 , cg07918562 , cg22974212 , eg 13916266, eg 10768206, eg 148338

96,cg05767299,cg18144076,cg17181660,cg02054776,cg00423487,cg08780218,cg22 134054, cg04795700,cg14810357, cg13951576, cg03345106, eg 12570942, cg06535121 , cg15417365, cg26534477,cg02932233,cg02701653,cg06106763, cg12631766, cg04732 856, cg24317735, cg02645338, eg 14262439, eg 15038241 , cg03300335, cg05503532 , eg 1 3912318, eg 18989224, eg 10731295, cg02346057, eg 17769069, eg 12425380, eg01495890 ,cg13447527, cg11041034, cg27388298,cg01302067, cg04275390,cg17171407, cg1685 5845, cg24542777,cg10892794, cg02367850,cg21350115, cg25608569,cg15016597, eg 15076990, eg 16246347, cg02246928, eg 13513171 , cg25531618 , eg 19761269 , cg2664059 4, cg13906416, cg07308943,cg27273054, cg14933899, cg06306198, cg18549994, cg090 89682, eg 17930183, cg25865387,cg21467108, cg27563027,cg20747393, cg19216414, c g22371845,cg25304659,cg23756219,cg26036466,cg01063615,cg27555365,cg251816 99, cg03169856, eg 15701900, cg05568797, cg08965656, eg 12380609, cg09545552, cg20 938359, cg04613057, eg 12856112, cg17863024,cg19146924,cg03350825,cg03630756, cg22692692,cg22552602,cg20263570,cg07103917,cg09376238,cg00616417,cg04393 170, cg03286467,cg08823780,cg09111258, cg15496741 ,cg26197784,cg27228191 ,cg0 0021264, cg09996240, cg09249657, eg 15576031 , cg03637901 , cg02882044, eg 18361375 ,cg16112129, cg12043747, cg06741989, cg00672228,cg04252513, cg05280786,cg1806 6055, eg 15422103, cg24554621 , cg20826576, eg 19214331, cg02524954, cg02072231 , eg 09168066, cg03121717,cg11859821 ,cg03605037,cg10871818,cg05060901 ,cg1385963 9, cg01570589, cg17059136, cg02986878,cg07000551 ,cg12716639, cg03548386,cg114 55120, cg08415838,cg25154075,cg06710735,cg23484358,cg22315149,cg21023831,c g17872064, cg19681356, cg17471193, cg24721673, cg27282264,cg03701609, cg057089 63, eg 13246199, cg27176948, eg 16473703, eg 17833257, cg26007223, cg23865853, egOO 151675, cg19901551, cg01908874, cg24073782,cg09491570, eg 18880005, cg25189085, cg07615678, cg06776823,cg27417609, cg13523072, cg04498312,cg08476985,cg26848 718, cg09873533, eg 17237287, eg01620942, cg21846823, cg07244783, cg08795648, egO 9934894, cg26358400, cg07892425, eg 18858418, eg 12190423, eg 18970844, cg05965902 , cg06336578, cg06220449, eg 13825239, eg01145544, cg07028608 , eg 14371153 , eg 1791 3504, cg09063989, eg 14003655, eg 15988983, eg 11934333, eg 18766795, cg02737621 , eg 13921570, cg05639405,cg11656817, cg18613866, eg 13226160, eg 12492289, cg2325300 6,cg19757493,cg12975127,cg05000987,cg02835038,cg04020930,cg06238169,cg185 65809, cg04643858,cg11639001 , cg03445516,cg01591132, cg20280170, cg12009803, c g26552746,cg23522915,cg10974104,cg23324081 ,cg20743628,cg22505386,cg237270 72, cg06178492, cg17588003, cg11736903, cg18567944, eg 18499441 ,cg27021709,cg16 873710,cg10539631 , eg 15531433, cg23738734, eg 19856728, cg23922643, eg 16559448, cg18776876, cg13580027, cg22378252, cg16317459, cg17685473, cg24605046,cg08853 050,cg07044140, cg24286887,cg23766867,cg09533368,cg23873654,cg21828923, egO 0162969, cg03881200, eg 15697470, cg24577191, cg02162556, cg04828458, cg04784898 ,cg06516769,cg11911610, cg01630199, cg18916423, cg08842412,cg04493793,cg1410 0131 , cg05450586, eg01219924, cg02462941 , cg00803088, eg 12441066, eg 18785274, eg 07719604, cg13233355, cg03652525,cg11509284, cg06919159, cg26076249,cg0515103 0,cg00242627,cg11059800, cg22763897,cg24725079,cg00760872,cg24051798, cg098 37467, cg26571093,cg01867663,cg16964082,cg07041883,cg03812693,cg03125754,c g24046935,cg07139076, cg02031618, cg19780389, cg04619341, cg04624228,cg170280 39, cg02282833, cg03340148, cg26619384, eg 17063018, cg25708069, cg20415643, cg05 081674, cg10427988, cg26589036, eg 14519696, eg 15796753, cg09745309,cg01870865, cg07846697,cg20578501,cg06915098, cg04223671,cg17072983, cg13416204, cg00123 906, cg13349651 ,cg26382678, cg12259792, cg01058850, cg10244047, cg04093751 ,cg0 4130851, eg 16651334, cg26837569,cg13764516, cg22381068, eg 16901394, eg 15950273 , cg00421221, cg22179082, eg 16402534, cg25433614, cg07230018, cg26299086, eg 1074 4805,cg24547137,cg18500830,cg00605777,cg18181070,cg01758312,cg24428016,cg 05632555, cg22718031, cg09948076,cg26132947, cg11500101 ,cg02983813, cg2117246 4, cg18648641 , cg14128582, cg07058086,cg26505300,cg13466072, cg06307169,cg187 91136, eg 13436449 , eg 16449464 , cg24295138 , eg 12646754 , cg22090773 , cg04133879, c g15875062, cg26227027,cg17252669, cg15295766, cg18886630, cg14014485, cg114259 27, cg12352038, cg24032414, cg18225485, cg26185859, cg26551417, cg24798795,cg05 157731, cg09080523,cg21283867, cg16255150, cg00522034, eg 12635937, cg07369174, cg02594615, cg18235835, cg21148404, cg26061772, cg26718808, cg24132632, cg07702 853, cg03296424,cg21147708, eg 10959866, eg 14063176, eg 12580583, cg07539543,cg2 0945221 , eg 19708055, cg21037892, eg 16425342, eg 14469684, cg21533727, cg01811438 , cg25696921 , cg07637672, eg 19590140, cg24166022, cg24569447, eg 10052118, cg0987 7593, eg 19891476, eg 18412499, cg07872799, cg23081781 , eg 16696002, cg24995503, eg 19304108, eg 17339550, cg07499477, eg 15931557, eg 17882499, eg 17573882 ,cg0329933 1 ,cg 16290082 , cg27581604, cg20046236, eg 18870865, cg07329667, eg 17951157, cg093 74375, cg04344069,cg05000761 ,cg12780470,cg15512469,cg11391543, cg01106366, c g00337803,cg25582403, cg11467732, cg08073764,cg00185853, cg24910189, cg058817 76, cg16004911,cg14455466, cg10894156, cg13320318, cg08748437,cg09213987, cg12 363248, cg15288800, cg09006366,cg03144494, eg 19914904, eg 17516138, eg 12894672, cg05013027, cg09852744,cg06657721,cg10906602, cg01311654,cg25998564,cg02910 011 ,cg09989659,cg07208518,cg 13582001 ,cg25720885,cg05993512,cg02065003,cg1 6267343, eg01162512, eg 11417653, cg23448348, cg20352394, cg07360792, cg20125159 cg20216030,cg02018101,cg27047406,cg01352551,cg21386213,cg14761552,cg15262 516, cg15448245, cg02478379,cg03547245, cg14947466, cg21298915, cg23960868,cg1 2083965, cg09409539,cg22605348,cg09621945, cg18391491 ,cg04198215,cg03194151 , eg 10072850, eg 15945448, cg25836239, eg01349615, eg 11549094, cg08513541, cg2182 4460, cg26999579, cg21153881 , eg 13582921 , cg07098722, cg20350289, cg24052541 , eg 19533804, cg22906524, cg02752076, eg 18544450, eg 12274082, cg07312504, cg0890290 5,cg25401083, eg 11861387, cg07312710, eg 17130580, eg 16607615, eg 16763552, cg227 63008, cg22726698, cg21812918, eg 19792427, cg02927448, cg22367165, cg27372170, c g17344060,cg25579735,cg21045171 ,cg12211843, cg04173521, cg22215642, cg221483 88,cg26109017,cg24865292,cg20267823,cg23912171 ,cg04485799,cg12193250,cg16 121525,cg24805898,cg05953285,cg21146184,cg05462328, eg 16607181 , eg 10951859, cg23049226, cg16297444, cg12923613, cg10474919, cg08802497,cg19280225, cg13713 218,cg13571582,cg21164440, eg 10220060, cg25423822,cg04729594, eg 10154626, cg2 6727693, cg03275734,cg19019913, cg19805894, cg24891034, cg22985635, eg 19945092 , eg 15077372, cg09552063, cg02254469, cg09146459, eg 12719233, eg 17009890, eg 1276 2683, cg16708774, cg01799854, cg15543154, cg18935353, cg22851092, cg17032723, eg 25902666, cg26326061 , eg 14630685, cg02699540, cg21933078, eg 17390355, cg0319291 9, cg10364459, cg04626414,cg07705135, cg23972767,cg10373866, cg05952098,cg074 24646, eg 10438487, eg 19400055, cg06570167, eg 13718185, eg 10609984, cg24353236,c g21611682, cg15118519, cg14613594,cg22175849,cg23913078,cg09245907,cg126606 63, cg02688848, eg 11267527, cg26680187, eg 13692860, eg 12349571 , eg 14446955, eg 16 038402, cg22113966, cg18711979, cg23032598,cg14490552,cg27287167,cg12524884, cg02208902,cg12692042, cg09848079,cg24805654,cg24728542,cg26114035, cg13106 389,cg06156729, cg07007062, eg 13702217, eg 14400946, cg23429235, cg06499892 , egO 7982934, eg 17774764, eg 17764685, cg27088150, cg08666333, cg04628197, eg 10227327 , eg 10649130, cg25310447, cg27251694, eg 10057245, cg24603297, cg21408734, cg2589 5818, cg26830038,cg10935882, cg23569632,cg07099107, cg02665968,cg18009691 , eg 21083214, cg22145996, cg18970534, cg12701184, cg21934323, cg20737880,cg0842506 5,cg27269190,cg16278661 ,cg02278864,cg10875041 ,cg00487351 ,cg20137347,cg104 75689, eg 18652923, cg08830139, cg03037864,cg22711621 ,cg04979435, cg19146001, c g08394248,cg27158243, cg22175345, cg06645674,cg19528703, cg04721302, cg184311 19, cg24756756, cg09585968, cg09315240, cg09934565, cg22345137, cg06207201 , cg22 535773, cg03286662,cg09246211,cg09203469, cg08605641 ,cg10832470, cg17528170, cg07939646,cg03881369, cg25374813, cg19741619, cg08929398,cg08143260, cg14801 768,cg27152890, cg08382497,cg06177801 ,cg03683031 ,cg22265110, eg 13763267, eg 1 1845045, cg02702524, eg 15665517, cg25354169, eg01261535, cg02467794, eg01965939 , cg06385000, cg09886946, eg 12302797, eg 13099150, eg 12408083, cg27038067, eg 1071 7991,cg07494518,cg07476236,cg14488391 ,cg09444868,cg13332183,cg08725039,cg 26572073, eg 11890956, cg03448396, cg06090630, cg20874992 ,cg23656415, eg 1173651 0, cg14638209, cg01590198, cg13065262, cg02281970, cg12231009, cg21588792, cg008 80656,cg07751757, cg20825437,cg01049691 ,cg02482035, eg 18443412, cg24590430,c g06982805,cg20749185, cg21757650, eg 15447479, eg 13426542, cg24331354,cg007719 75, cg09789636,cg13396037, cg10327647, cg26945938,cg08156066, cg03820843,cg27 310486, cg00028429,cg26185554, cg20135341, cg22829917, cg04344225,cg08278246, cg12403996, cg17843212, cg19453154, cg24014805,cg07902051 ,cg24491774, cg10955 825, cg08553820,cg20162696, cg13407435, cg19564029, cg05375160,cg15658392, cg2 1574271 , eg 11031701 , eg 18428707, cg02655549, eg 19008216, eg 16134369, cg21668194 , cg00257453,cg02641865, cg12662091, cg15274466, cg18574112,cg06907588,cg0499 7743, cg04217952, cg17065772, cg09921707, cg13116098,cg13408795, cg08142858, eg 12071544, cg01804043, cg21086810, cg14986136, eg 14952224, cg20244953, eg 1069499 2,cg11118520, cg07754999,cg08124495,cg00064347,cg04733855,cg23852542,cg245 36250, eg 19008692, cg20439056,cg09039893,cg07385114, cg25597976,cg26340740,c g01371348, cg01396022, cg13072241 , cg06153298, cg05842669,cg14468658, cg114537 12, cg20955693,cg11810719, cg23287017,cg09712616,cg22234080,cg11229862, cg11 910296, cg27072561 , eg01780596, eg 10374534, cg22566663, eg01860944, cg09578794, cg02643433, cg07796735, cg04353763, eg 10305311 , cg05921699, eg 16706840, cg02285 715,cg27410534, cg02614525, cg27016549, eg 18371284,cg07017737, eg 11357768,cg0 2357741 , cg07281640, cg00759508, cg22578792, cg25832569, cg27097806, cg25501712 ,cg07278165,cg23748463,cg06977347,cg22745167,cg03580819,cg03147584,cg2229 2478, eg 13022888, cg05630667, cg02556345, cg05377034, cg09378499, eg 12154153, eg 06955856, cg05543972 , eg 11351746, eg 13150766, eg 10328157, eg 19654118, cg2697631 5, eg 12909277, eg 18350024, cg01726621 ,cg08947542,cg01171329,cg08204159,cg266 87811,cg20852378,cg02891048,cg26551865,cg14195117, cg27267310,cg11331655, c g17278057, cg12658805, cg23916646, cg23378497,cg26963545,cg17889199, cg156434 28, cg10974027, cg12812803, cg18796990, cg04691829, cg14460816, cg13780065, cg14 028652, cg10465028, cg24237600,cg08893641 , cg00710857, cg21543705, eg 10695490, cg13447813,cg08332875,cg25318189,cg24363947,cg07508942,cg21211608,cg01371 799, cg00221096, eg 16910569, cg03914922, cg09806943, cg27330542 , cg24358657, egO 4756597, cg06167721, cg27409364,cg08519239, cg05216766, cg08882738,cg26672076 ,cg05715828, cg16633923, cg01765406, cg06372718, cg23056713, cg13919438, cg1687 3848, cg02674186, eg 13974773, cg26551975, cg06366627, cg08577743, cg02987621 , eg 10978544, cg01132834, cg27626141,cg09541539, cg09244635,cg11209279, cg1209571 2, cg04391175, cg22689075,cg00488988,cg11876566, cg25450986,cg09122308,cg083 65738,cg 18115575, eg 15776918, cg01602376, cg03966514,cg24406917,cg02862761,c g20490811 , cg10624768, cg25924583,cg03522910,cg10467201, cg13985688, cg008942 89, cg15251311,cg07661177, cg06884199, cg26956975,cg01647346, cg01786216, cg06 032329, cg14560144, cg20950724,cg09348353,cg07150874, cg06969233, eg 16676734, cg05267739,cg15911612, cg25416347,cg23716690,cg11024200, cg04753856,cg02194 223,cg07441122,cg23426614,cg08607001 ,cg07166601 ,cg22548031 ,cg14020076, cg2 7507919, cg02727674,cg03017269, cg04391641, cg17715222, cg03436546,cg01488306 , cg10371464, cg05974788,cg21354621, cg01597135, cg14281535, cg09286183, cg1455 5669, cg09091433, eg01937819, eg 17635579, eg01691530, eg 15769424, eg 11584277, eg 24007084, eg01137782 , cg07982263, eg 17522207, eg01219048, eg 10754528, cg0473088 2, cg09740560,cg24100957, cg18370151 ,cg03812323, cg24253464,cg14909834,cg222 05539, cg22989407,cg07148452, cg07834364,cg07348311 ,cg01270001 ,cg05624300,c g25320889, cg10946644, cg10880177, cg10386813, cg05814555,cg21853250, cg252824 54, cg20417180, cg22780058,cg01561528, cg15732230, cg03554028,cg00938920,cg25 903143, cg01026803,cg25019378,cg20784500,cg02836046,cg27409073,cg13071210, cg26833060,cg23460084,cg08680266,cg12180270, cg25358137, cg09086835,cg03442 867, cg13921420, cg04651914, cg26053068,cg18015622, cg00992586,cg01037217, egO 9662887, eg 18357279, cg08329777, cg02151704, cg08629372 , cg02359506,cg08205993 ,cg25098068,cg02965699,cg25138713, cg09408023,cg15478863, cg11546529, cg0558 6701 , eg 16537295, cg02434860, cg21776419, cg05791738, eg 19769844, eg 15115797, eg 19159092, cg04839881,cg11691705, cg21287806, cg07238630,cg23776186, eg 1590995 1,cg21501987,cg03448068,cg23036508,cg04290563,cg09118417, cg24347498,cg124 27286, cg09429924, eg 14304014, cg22930187, cg23818937, eg 16590189, cg25953012, c g19470138, cg23103127, cg01835394, cg13657095, cg17768819, cg07992918, cg143838 15, cg04364453, eg 14312115, cg06547788, eg 14374913, cg08814800, cg21354959, cg22 349573, cg25729713, cg13709876, cg02021485, cg08216426, cg00703260,cg00688756, cg26889990, cg06577604, cg11671771, cg21836370, cg17177455, cg08101054, cg01807 820, cg22183626, cg03605444,cg14963027, cg09820318, cg09290941,cg25736125,cg0 3331924, cg09603030, cg00550214, cg09224619, eg 15372842, eg 14009051 , cg25342496 , cg07149347, eg 17300736, eg 15656702, cg26670245, cg21383151 , eg 17138539, cg2105 7249, eg 16789129, cg06114035, eg 15229773, eg 19410626, cg02402209, cg23355725, eg 25096847, cg02682760,cg04041654, cg08960285,cg07996785,cg00227490,cg0459926

5,cg17113955, cg27065685,cg13980944 cg22905282,cg07233389,cg08937831,cg27370351, cg19460042, cg05362548,cg22450 574, cg23565505,cg26986180, cg26464446,cg04800909,cg22205937,cg22159954, egO 2230701 , cg24676409, cg07364264, cg04141094, cg05612656, eg 15389153, eg 16927781 , cg02267795,cg24834823,cg20025595,cg00078197, cg09359114, cg06879152, cg0030 7584, cg22460123,cg15843719,cg00064261 ,cg09581517,cg22865640,cg16234274, eg 09151842, cg10717754, cg19871494, cg00641348, cg18763121 ,cg08789695,cg0223321

6, cg00776752,cg10464462, cg15257469, cg14239366, cg00275132, cg09193988, cg007 21951, cg05777536, eg 14500472, eg 10626768, cg21902325, eg 15875995, eg 10349616, c g26188818, cg01736403, cg25189904, cg25844787,cg08288312, cg21054441, cg051520 67, cg02504690,cg09713090, cg19487894, cg07538293,cg18559799, cg02368481,cg09 163442, cg04576710,cg02384170, cg25012864, eg 13076169, cg03164805, cg22498251 , cg05805733, eg 14200725, eg 18486906, eg 13811315, eg 14707392 , eg 10201685,cg24065 328, cg19033308, cg16041959, cg01809281 ,cg21972958, cg06822697,cg24189359, egO 9344607, eg 12749057, eg 18059652, cg07508787, cg06049736, eg 10025908, eg 17265923 , eg 17420078, eg 19655569, cg00466873, cg02147989, cg24839008, eg 10593758, cg0275 0308, cg20480783,cg21267652,cg17499426,cg06925203,cg12930304,cg11516875, eg 07147544,cg27633903,cg04008542,cg01317818,cg25148230,cg07056299,cg 1602610 3, cg03732055,cg12491225,cg11265916, cg02682829,cg06160397,cg08266366,cg045 81753, eg 17308762, cg23933032,cg22725112,cg27010947,cg04843660,cg08833675,c g26322749,cg05586556, cg19086599, cg10801607, cg00648203,cg15129299, cg272500 37, cg18873878, cg09121721 ,cg03911515,cg07060721 ,cg15320416,cg17713448, cg08 952497, cg11258076, cg10320618, cg27297120,cg02245193, cg25144657,cg25590826, eg 18339589, cg00295339, eg 14911202, cg23836747, cg21703056, cg06752928, cg08581 928,cg27001747, cg13693328, cg08726005,cg15521326, cg22179905, cg08260569,cg0 2076747, cg27183386, cg05310303, cg06605803, cg24656834, eg01438892, eg 11777782 , eg 19090784, eg 10267872, eg01839850, cg07022650, eg 11301827, cg26114884, cg2168 2902 , cg23324957, eg 19771465, eg 14606680, cg02598872, cg03395088, eg 11760644, eg 01240566,cg07626533,cg26169020,cg19139589,cg13629304,cg24300099, eg 1264201 8,cg23453622,cg20781380,cg24248776,cg01336716,cg25876906,cg14521373,cg104 02321,cg07011025, eg 12944659, eg 17698634, cg03897851 ,cg07435331 ,cg20441553,c g23762433, cg24989489, eg 14813923, eg 17369438, eg 15260349, eg 17299745, cg057427 84, cg00999835, cg03219968, cg26687579, eg 15000998, cg04453628, cg21156815, cg05 014952,cg12285003,cg13369952,cg24833737,cg09409209,cg11472297, cg16411188, cg24592391 , cg26680656,cg02659914,cg10849092, cg06232266,cg23719318, cg16002 305, eg 13946335, eg 17714573, eg 10591753, cg20433531 ,cg22266602,cg 11078810,cg2 4518599, cg03162410, cg08484676, cg22578935, cg00032661 , cg09923715, cg25966745 , cg26139435, eg01747792, cg27033919, cg25512179, cg23740938, cg24607653, cg0363 7719, cg26594796, eg 19610869, eg 18096388, cg27260636,cg14355192, cg01134436, eg 16240500, cg04219001, cg23147996, cg16226644, cg24342565,cg03791058, cg0527255

6, cg23362260,cg01748496, cg24804117, cg23779574,cg11835098, cg26968942,cg186 51840, cg27203437,cg23492789, eg 14477227, eg 16259069, eg 12994003, cg01877937, c g19357865,cg02339970,cg02672827,cg05924780,cg17747553,cg16289611,cg109943 70, eg 19056444, cg08516400, cg09860050, cg26495092, cg25637824, cg04391954, cg02 169889, cg26692224,cg20124376, cg27216087, eg 13017319, cg20054085,cg22755839, cg03601896,cg03573529,cg09186667,cg16924263,cg09621573,cg04111551 ,cg00896 182, eg 15437231 , eg 13779868, cg03021377, eg 12623045, cg04663168, cg04360080, egO 3603808, cg22495058, cg23520422, cg04158884, eg 10482224, cg21939482, eg 13793438 ,cg22468316,cg21881364,cg23996508,cg15111822, cg05357039,cg11188741 ,cg0613 2170, eg 11601000, cg24514230, cg02085640, eg 15079885, cg02892961 , cg21684773, eg 23832259, eg 18218855, cg23640903, cg06904548, eg 10360769, eg 15221912 ,cg 1992137

7, cg04616422, cg17778607, cg01620248, cg07765813, cg05336276,cg25874611 ,cg144 03603, eg 16567087, eg 15042942, eg 13783387, eg01724443, cg25376688, cg03796175, c g24550880,cg03738328,cg14380892,cg15842218, cg07232729,cg05231888, cg049686 42,cg15661310,cg04251872, cg19828298, cg19911854,cg20712856,cg03551456, cg19 980912 , cg04242728, eg 11385938, cg26227107, eg01439854, cg08594100, eg 15609410, cg09097524,cg04735745,cg04371726,cg18648122,cg05913672,cg07374306,cg12613 020, cg03752430,cg12191152, cg03622386,cg27665985,cg05106206, cg08815978, cg1 0239039, cgOO018212, cg06740892, cg02016207, cg04819775, cg02263206, cg26705472 ,cg04592292,cg10835015, cg16268778, cg12949547, cg14840536, cg17428748, cg0408 7789, eg 17370195, eg 12457451 , cg24008009, cg07713538, cg05685296, eg 16653173, eg 27229596, cg04254320,cg05221748, cg03431741 ,cg21939017,cg19045191 ,cg2265976

5, cg01706819, cg01409736, cg02224147, cg15715049, cg24625115, cg16437222, cg012 96889, eg 12495593, cg02353258, eg 15818306, cg05307301 ,cg25977683,cg16015362, c g03327386,cg19324950, cg23266487,cg15598425, cg15208375, cg12627454, cg238702 82 , eg 14545975, cg23539933, cg07556134, cg24076968, cg00508851 , cg22661866, cg09 935466, eg 11333568, eg01953119, cg15481223,cg11691561, eg 17342064, cg23026896, cg17457115, cg17118809, cg05421238, cg09972420,cg22063434,cg06857441 ,cg25869 317, cg25280876,cg09862928,cg19432600, cg11282584, cg06313880, cg18392215, cg1

1207405, cg04514683, cg24046884,cg04513673, cg03142841, eg 17424101, cg08393972 , eg 16606674, eg 13751113, eg01443426, cg03032532, cg25021939, cg06948629, eg 1477 6016, cg07397572, eg 16351998, cg20935025, cg06821936, eg 14923623, cg00029648, eg 14522049, cg02148922, cg09673523,cg19363499, cg07481886, cg02821832, cg0170997 7, cg13753463, cg24720361 ,cg18221991 ,cg27053692,cg00195179,cg01635193,cg234 62943, cg21594304, cg25678125, eg 13039115, eg 14630164, cg27427357,cg17420862, c g17983640, cg24392970,cg08715466, cg18892096, cg21835046, cg08845042,cg097062 77, cg24517978, eg 11130692 , eg 13592570, cg24714742 ,cg05304851 , eg 13135288, cg07 273698, cg00330375,cg21661974,cg14157170,cg05257275,cg00809353,cg06305175, cg07355446,cg05235248, cg19502694, cg03342804,cg05984320,cg24375835,cg05372 260, cg14429175, cg00448395,cg15543238, cg07774424,cg23616046, cg10565589, egO 5605147, eg 12833465, eg 10039928, eg 10678071 , cg21410629, eg 17587071 , eg 12294454 , eg 12155199, cg09755924, cg09298920, cg02626665, cg03553278, cg09411076, cg2699 2539, eg 11567041 , eg 18806378, cg00026703, eg 11945717, cg07548607, cg24053343, eg 25932329 , cg04578149, cg03099208, cg07355791 , cg06994238 , eg 19169377 , cg0534310

6,cg23237607,cg05971911 ,cg24689196,cg15711208,cg16943635,cg27632704,cg045 11182, cg10643233, cg19426522, cg25197654, cg12850165, cg09441852,cg18500714, c g16387581 ,cg25115812, cg06058668,cg12860109,cg06066640,cg06846812,cg055511 70, eg 17800788, eg 11746597, eg 11225642 , eg 18823633, cg00088007, cg08380556, cg27 120228, cg01181009, cg11603705, cg24524245,cg19288226,cg07163845,cg22820426, eg 18776248, cg02836586, cg04823676, cg24377604, eg 19135362 ,cg08657093, eg 10056 356, cg18265147, cg06174330, cg03602233,cg13592931 , cg12332167,cg22992573,cg0 8401938, cg11210881, cg16906765,cg17831882, cg21473894,cg24717490, cg09840645 , cg21058822, cg27016609, cg02275294, cg01086406, cg04957803, cg21224834, eg 1614 3121 , eg 11562552, cg07638904, cg22446709, cg08231648, cg07808087, eg 11399214, eg 11968713, cg12682061,cg18601682,cg18925548,cg11523799, cg07458065,cg0918481 9, cg01837631 ,cg08584628, cg14589148, cg19907796, cg15096079, cg04647494,cg002 12058, eg 16739796, cg20185723, cg06126483, eg 10777596, eg 19434889, cg05308380,c g15789334, cg24531698,cg22329152, cg14478430,cg07072507,cg06348430,cg237606 49, cg26429783, cg20910568, cg24610763, cg21040115, cg05906871 , eg01954701 , cg09 661548, cg03146865, cg05046209,cg12615275, cg09960881 , eg 14975358, cg02051077, cg04885698,cg06830503,cg09112623, cg11528392, cg26971783, cg26178272, cg01029 450, eg 14954668, cg01766908, cg17186744, cg26327216, cg11773265, cg00543751 ,cg2 3013931 , eg 14846648, eg 18613031, cg09066349, cg00406098, cg24278036, cg06793505 ,cg00530925,cg19459542, cg08493621 ,cg13103163,cg04330730,cg04743916,cg1599 6289, cg21735344, cg08823113, cg00345443, cg02031303, cg27394127, cg25499044, eg 01098010, cg00957609, eg01167697, eg 13794868, cg03649122 ,cg24082072 ,cg0385003 5, eg 18142026, eg 14375807, eg 14336003, eg 15749836, eg 14594834, cg07004372 , eg 101 35894, cg26061898, cg18341493, cg11190156, cg22598744,cg03037033,cg26477549,c g04895205,cg01889897, cg22530822,cg03625627,cg17903549, cg15951362, cg017363 89, cg03833558, cg20953563, eg 12507168, eg 18569825, eg 15543769, eg 17606881 , eg 11 202464,cg26121436,cg09619146,cg25248507,cg01612220, cg07215653, eg 13534892, cg13107348, cg04319462, cg20979799,cg07137606, cg20280258,cg24346914, cg01972 350, cg19291253, cg14707162, cg10027917, cg08987887,cg24275855,cg24537734,cg0 5782417, cg05714729, eg 17866352, cg16287796, cg19073531 ,cg03904551 ,cg07953034 cg11656478,cg21984111,cg01273580, cg18936283, cg25061131 , cg12213003, cg11725 640, cg11791613, cg17705343,cg12168164,cg12872311 ,cg23396432,cg05389053,cg0 1048585, cg27329659, eg 13598677, cg25183890, eg01883247, cg26038749, cg00655702 , cg06731137, eg 18606005, cg03310453, eg01065605, eg 12608633, eg 15575498, cg0915 9123,cg00041903,cg25373297,cg06823805,cg23572455,cg02287436,cg12714421,cg 25090514, cg01356463, cg15486645, cg19186409, cg03909494, eg 18851071 , eg 1644918 4, eg 17524637 , eg 18844158 , cg08393445 , eg01135754 , cg27642710 , eg 14943827 , cg071 15761, cg07279485, cg27229764, eg 18112163, eg 11580759, eg 13971652, eg 15215681 , c g26428191 , eg 16598411 , cg26270195, cg23600944, eg01434694, eg 13461890, cg053858 79, cg04615654, cg03466670, cg23574277, cg27290629, eg 14979946, eg 19995434, cg25 824265, cg26436829,cg10861863, cg03416035, cg01274233, cg27000977,cg05995607, cg19426827, cg08239540,cg21748271 , cg10319399, cg26006870,cg17362434, cg07639 550,cg27470537,cg16131304,cg15131074,cg10861017,cg22174486,cg05756489,cg2 2452520, cg05172122, cg08545493, cg08924488, cg08376211 , cg06644451 , cg08530253 , cg24904145, cg02121672, cg00787282, cg00679908, cg06550420, cg20979128, eg 1452 5527, cg11293126, cg07083806,cg23224342,cg26932552,cg04314114, cg11529663, eg 12967093, cg23843407,cg23805785,cg20912517, cg02585699,cg21593513, eg 1833773 5,cg14931686,cg03799283,cg02490907,cg05836555,cg00954039,cg18416705,cg274 34143, eg 11871038, cg06381905, cg02216061, cg06091475, eg 19697512 , cg03413202 , c g02452328,cg14424559,cg07282879,cg02080641 ,cg07859728,cg07354515,cg153524 31 , cg22154493, eg 13247069, cg09112262, cg03723321 , eg 16619994, eg01364894, eg 10 960375, cg15970156, cg01566287, cg07935832, eg 14613365, cg00533933,cg00370820, cg26222765, cg14857823, cg19685672, cg00479180, cg21666002, cg17468749, cg22202 703, cg16667710,cg08357990,cg01800926, cg03864326,cg03406609,cg01754267, cg1 2549956, cg25770267,cg14823429, cg10975449, cg05681376, cg17591725,cg20922251 ,cg12100721,cg08898873,cg02124383,cg22376913,cg11858114, cg02169278, eg 1640 6707, cg00597076, cg08368624, eg 14153654, eg 13826470, cg06715672, eg 16852894, eg 19260329, eg 15811904, cg13662195, cg13598426, cg24433045,cg19975482, cg2224412 2,cg16599965,cg15136742,cg08735147,cg00189887,cg09926463,cg02582973,cg088 02607, cg23995169, cg09902272 , eg 11614342, cg25665203, cg25659938, eg 16977711 , c g09829164, cg08123738, cg14425141, cg05451060, cg15435778, cg10994819, cg261442 65, cg20634266, eg 19769080, eg 19368946, cg03379552, eg 16890796, eg 12601237, eg 17 245846, cg13356342, cg22718050, cg08919634, eg 15727690, cg27562431 ,cg07037019, cg02713153, cg02216060, cg27648567, cg09537268, cg20237731 ,cg27210998,cg22470 465, eg01326135 , eg 15292446 , eg 17881203 , eg 14536269 , eg 13914054 , cg03874689 , eg 1 9378602, cg26831081 , cg22616126, cg20286377, cg20628049, cg20126158, eg 14371731 ,cg10646711 ,cg02891359, cg08062273,cg16301311 ,cg18475643, cg27461800, cg1010 7117, cg03319419, cg18592215, cg12038091, cg12205729, cg13482172, cg02896266, eg 00732328, cg15237857, cg23268417, cg18623931, cg00616952, eg 18225895, eg 1371756 2, cg20748350,cg05751189, cg06035333,cg00809335,cg20431135, cg14729205, cg271 06909, cg22929787,cg20992769, eg 16834320, cg22812005, cg05214548, cg19385628, c g03580297,cg08959144,cg08511678,cg26401058,cg05941027,cg03709938,cg257193 74, cg27544223, eg 12134806, eg 10780191, cg25770033, cg25678178, eg01183579, eg 10 362426, cg15507271 ,cg25445017, cg03946826,cg09925823,cg01742897, cg09169615, eg 17832562, eg 15793877, cg21180793, cg22996004, eg 18195352 ,cg07752650, eg 19238 398, cg01421019, cg01782790, cg06673826,cg16437933, cg07163475, cg08576274,cg0 9223516, cg07830167, cg20085065, cg24817471 , eg 18090431 , eg 18212777, cg00042409 , cg26763945, cg23842386, eg 16959766, cg25736986, cg03985360, cg20588438, eg0186 7647, cg25880154, cg08443279, cg09863028,cg02198878, eg 10257545, eg01093151 , eg 01800521,cg18383538,cg19302283,cg25233894,cg05654338, eg 17019898, cg0886112 7,cg02013655,cg14886849,cg15893070,cg21719817,cg07369278,cg26023087,cg012 95646, cg03592955,cg22648135, cg05624564,cg03001119, cg00924484, cg23586839,c g00644777, cg03432697, eg 10043753, cg04994953, cg22846807, cg00470144, eg 111662 95, cg07074473, cg22210061, cg26341283, eg 14847983, eg 12253828, cg03924800, eg 17 515737,cg00539943,cg02672116, cg09773473,cg26544188,cg11960458, cg20638696, cg13799941, cg13361393, cg14548158, cg11233384, cg23872464,cg27321311,cg26257 241 ,cg25114011 ,cg27027478,cg02926785,cg07063089,cg15447511 ,cg26990351 ,cg2 6665224, cg24308654,cg09761088, cg01939236, cg23576842,cg13617248, cg17103761 , eg 19906131, cg22685658, cg07777694, eg01152441 , eg 17360196, cg02727104, cg0827 1918, cg22476645, eg 10775157, cg08547793, cg05335944, cg24856733, cg25406755, eg 02830903, eg 11464464, cg06963451 , eg 12593204, eg 10838531 , cg24317857, eg 1343646 4, cg08579279, cg13173369, cg24791666, cg10114235, cg15319382, cg26315233, cg107 36902, eg 19550904, cg24205633,cg18483322, cg11858213, cg17967224, cg02288859,c g07317117, cg17779824, cg07928502,cg05629892,cg11947981, cg22277972,cg221513 87, cg00544788, cg21846970, cg07242215, cg20066716, eg 17066909, eg 18812668, cg20 846962, cg06378100, cg09704765,cg04951797, cg22528172, cg03693330, eg 12881226, cg07841849 , eg 19662870, cg24645247 , eg 19676671 , eg 12616125, eg 11200297, eg 18399 896, cg27049761 , cg22026457, eg01011530, cg06600429, eg 18693985, cg25889797, cg2 5331250, cg00967405, eg 10049251 , cg27176197, cg23083455, eg 12950732, cg04148945 , cg14481935, cg27634195, cg13109911,cg05878073, cg07536704,cg13805951 , cg1106 9461 , cg08729927, eg 19903532, cg21873971 , cg03415497, cg20822553, cg27414535, eg 08468449, cg21964466, cg23116986, cg12531614, cg08136938, cg21659725, cg0551610 0, cg26253397 , eg 13185046 , cg03521696 , cg09773514 , eg 12578844 , eg 10992704 , cg271 39064, cg06338562,cg07908403,cg01190484, cg19629843, cg06170961 ,cg08633313,c g04016160, eg 11337697, eg 16784468, eg 11637898, cg26808810,cg08936078,cg119703 49, eg 15726378, cg03446427,cg00029979,cg25022086,cg07196225, eg 14116465, cg25 307902, cg14899088, cg26995715, cg26147657, cg24521087, eg 13559984, eg 16659151 , cg13854296, cg16208682, cg09387559,cg04106935, cg01917295, cg21570403, cg09662 329, cg05109877, cg18180710, cg15102575, cg17904897, cg23090632,cg25781755, cg1 9284211 , eg 11943735, cg06673956, cg20211448, cg21971919, cg20144521 , cg07580975 , cg00089142,cg09332592,cg22189856, cg01692463, cg21491915, cg03923277,cg0231 4019, eg01754756, cg06161933, cg08294373, eg 14614469, cg05004337, cg02994291 , eg 03597143, cg14889768, cg07068674,cg21774136, cg18182575, cg09937039,cg1526408 3, cg09412390, cg02518245, cg09201525, cg05251814, cg27256423,cg16495681, cg265 85560, eg 11732322, cg06019865, eg 18392644, cg25345561 ,cg09400392,cg07921030,c g25889905,cg10902270, cg06473094,cg15498349, cg16319427, cg09163196, cg019465 74,cg09724798,cg24441872,cg10995359,cg00488842,cg02083546,cg26023112,cg15 817026,cg21616935,cg12302110, eg 14738329, cg04166748, cg20257013, eg 19583819, cg08869785,cg06294220,cg27618701, cg23997493, eg 17884425, eg 19775372 ,cg05224 524, cg14078385, cg07177039, cg13323701 , cg10053073, cg08553572,cg02059047,cg1 0758328, cg22070406,cg07614783, cg19743103, cg19302347, eg 17986346, cg07696690 , cg21105227, eg 10169241 , eg 15092772, cg05660764, cg02012703, cg06035531 , cg0297 8150,cg13132769, cg27409651 ,cg03990811 ,cg07526717,cg12534466, cg26587014, eg 05131483, cg00416162,cg27494124,cg13202578,cg11816444, eg 16703576, cg0056579 0, cg19056506, cg18028808, cg15465242, cg20654385,cg04584023,cg26535547,cg191 22581,cg23291305, cg02425741 ,cg27055296,cg01721255,cg13913917,cg11100386, c g03947261 ,cg00530199, cg09482195, cg16665765, cg03258272,cg14942928, cg173296 15,cg13899452,cg26676332,cg03889890,cg04791659,cg20866393,cg00833747,cg13 505393, cg14533192, cg09841598, cg07515251, eg 16541031 ,cg25085950,cg02544037, cg08832594,cg01191058, cg15981620, cg06971381, cg16659413, cg16157435, cg03947 832, cg18764240, cg16856436, cg24828582,cg04262961 ,cg06297642, cg12036419, cg1 2597112, cg02167713,cg19170009,cg05208812,cg02889469,cg22865404,cg08871495 , eg 12473382, cg24711626, cg22144328, cg08536417, eg 10689438, eg 15395240, eg 1875 6579, cg01247522, cg26481727, cg14300730, cg14123750, cg07181582, cg15144888, eg 05728135,cg11831564, cg13423282, cg20709530, eg 18713852, cg07504172, cg0597751 7, cg25779154, cg24141153, cg18046087, cg11959630, cg06060962,cg24968185, cg178 92331, cg03746823,cg11729361 ,cg06656994,cg22647566,cg25623532,cg02065310,c g17559034,cg11920745, cg19086488,cg10929024,cg21497202,cg13338799,cg031438 49, cg00686429,cg11363476, cg24199381 , eg 17397836, cg22144875, cg00070722,cg21 285804, cg18443786, cg20024609.

Items

The invention may further be defined by the following items:

1. A method of predicting whether an individual is able to respond to metformin treatment or not and/or whether an individual is able to tolerate metformin treatment or not, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) Identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of sequences, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment.

2. A method for treating a patient suffering from type 2 diabetes, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin, and administering to the responder and tolerant individuals a therapeutically effective amount of a medicament that comprises metformin. A method for identifying a patient for treatment with an anti-diabetic medicament which does not comprise metformin, wherein said patient suffers from type 2 diabetes, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, d) identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of CpG sites, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, e) administering to the non-responder and/or non-tolerant individuals a therapeutically effective amount of an anti-diabetes medicament that does not comprise metformin. A method of predicting whether an individual is able to respond to metformin treatment of type 2 diabetes or not and/or whether an individual is able to tolerate metformin treatment or not, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, wherein the normal methylation level is the average methylation level of said CpG site as observed in at least 15 individuals suffering from type 2 diabetes and known to be able to respond to and/or tolerate metformin; d) Identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of sequences, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and wherein said individual suffers from or is at risk of developing type 2 diabetes. The method according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; and iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment. The method according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

9. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii., wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to metformin treatment.

10. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to tolerate metformin treatment. The method according to any one of the preceding items, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

14. The method according to any one of the preceding items, wherein said panel of CpG sites comprises or consists of at least 1 CpG site, such as at least 4 CpG sites, for example at least 7 CpG sites, such as at least 11 CpG sites, for example in the range of 5 to 20 CpG sites, such as in the range of 7 to 11 CpG sites.

15. The method according to item 11, wherein said panel of CpG sites comprises or consists of at least 1 CpG site, such as at least 4 CpG sites, for example at least 7 CpG sites, such as at least 11 CpG sites, such as in the range of 7 to 11 CpG sites, wherein said CpG sites are located on one or more DNA sequences according to item 11.

16. The method according to item 12, wherein said panel of CpG sites comprises or consists of at least 1 CpG site, such as at least 4 CpG sites, for example at least 7 CpG sites, for example in the range of 5 to 7 CpG sites, wherein said CpG sites are located on one or more DNA sequences according to item 12.

17. The method according to any one of the preceding items, wherein said normal methylation level is the average methylation level of a CpG site of said panel of CpG sites as observed in at least 15 individuals, such as in at least 20 individuals, such as in at least 30 individuals, such as in at least 40 individuals, such as in at least 50 individuals suffering from type 2 diabetes and that are able to respond and/or tolerate metformin.

18. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein the method further comprises calculating a response methylation risk score (rMRS) for the panel of CpG sites, wherein said rMRS is the sum of the standardized methylation values at each CpG site, weighted by CpG-specific effect size.

19. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein the method further comprises calculating a tolerance methylation risk score (tMRS) for the panel of CpG sites, wherein said tMRS is the sum of the standardized methylation values at each CpG site, weighted by CpG-specific effect size.

20. The method according to any one of the preceding items, wherein step c) comprises or consists of comparing the rMRS calculated for the panel of CpG sites to a predefined response cut-point calculated for said panel of CpG sites, wherein a rMRS being higher than or equal to the predefined response cut-point indicates that the individual is not able to respond to metformin treatment, and wherein a rMRS being lower than the predefined response cut-point indicates that the individual is able to respond to metformin treatment.

21. The method according to any one of the preceding items, wherein step c) comprises or consists of comparing the tMRS calculated for the panel of CpG sites with a predefined tolerance cut-point calculated for said panel of CpG sites, wherein a tMRS being higher than or equal to the predefined tolerance cut-point indicates that the individual is not able to tolerate metformin treatment, and wherein a tMRS being lower than the predefined tolerance cut-point indicates that the individual is able to tolerate metformin treatment.

22. The method according to any one of the preceding items, wherein said predefined response cut-point is determined from a Receiver-Operating- Characteristic (ROC) curve for metformin response including at least 100 individuals suffering from T2D, wherein at least a portion of the individuals are responders and at least a portion of the individuals are non-responders to metformin.

23. The method according to any one of the preceding items, wherein said predefined tolerance cut-point is determined from a Receiver-Operating- Characteristic (ROC) curve for metformin tolerance including at least 100 individuals suffering from T2D, wherein at least a portion of the individuals are tolerant and at least a portion of the individuals are intolerant to metformin.

24. The method according to any one of the preceding items, wherein step e) comprises administering to non-responder and/or non-tolerant individuals a therapeutically effective amount of a medicament selected from the group consisting of sulfonylureas, pioglitazone, alpha-glucosidase inhibitors, gliptins, Bromocriptine, colesevalam, SGLT2 inhibitors, GLP1 analogues, insulin and/or any other glycemic lowering drugs that can be used as second-line treatments according to the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) and/or International Diabetes Federation (IDF).

25. The method according to any one of the preceding items, wherein an individual is able to respond to metformin if the hemoglobin A1c (HbA1c) is reduced to:

- below 53 mmol/mol, if the basal HbA1c was equal to or higher than 53 mmol/mol, or

- below 48 mmol/mol if the basal HbA1c was equal to or higher than 48 mmol/mol, upon treating the individual with metformin for in the range of 3 months to 24 months.

26. The method according to any one of the preceding items, wherein an individual is able to respond to metformin if the hemoglobin A1c (HbA1c) is reduced of 8 mmol/mol or more, such as of 11 mmol/mol or more, from baseline upon treating the individual with metformin for in the range of 3 months to 24 months.

27. The method according to any one of the preceding items, wherein an individual is not able to tolerate metformin, if the individual suffers from severe adverse effects when administered with a daily dose of metformin of 500 mg or more, wherein said severe adverse effects comprise gastrointestinal adverse effects.

28. The method according to any one of the preceding items, wherein the methylation level is determined by pyrosequencing, PCR based methods, methylation-based methods, microarray-based methods, MALDI-TOF mass spectrometry-based methods, or combinations thereof. The method according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 , wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 ; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites ofTable A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The method according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site. The method of predicting whether an individual is able to respond to metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site. The method of predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding items, wherein the methylation level in b) is determined by contacting the sample with a plurality of DNA sequences, wherein each DNA sequence comprises at least one CpG site, said DNA sequences each being selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site. The method according to any one of the preceding items, wherein said one or more DNA sequences are single-stranded DNA sequences. The method according to any one of the preceding items, wherein the sample is a body tissue, a body cell or a body fluid, wherein the body fluid is selected from blood, serum, plasma, saliva, amniotic fluid or urine sample. The method according to any one of the preceding items, wherein said sample is treated with an agent that modifies unmethylated cytosines, prior to determining the methylation level. The method according to any one of the preceding items, wherein the methylation level is determined by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the one or more DNA sequences in the panel. The method according to any one of the preceding items, wherein said individual suffers from or is at risk of developing type 2 diabetes. 43. The method according to any one of the preceding items, wherein the individual has not been treated with metformin for at least 6 months prior to obtaining a sample, such as for at least 12 months, for example for at least 2 years, such as wherein the individual has never been treated with metformin prior to obtaining the sample.

44. The method according to any one of the preceding items, wherein said method is conducted in vitro.

45. An array comprising a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

46. The array according to item 44, wherein each of the plurality of DNA sequences is selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein said consecutive sequence comprises at least one CpG site, and wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein said consecutive sequence comprises at least one CpG site, and wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.. The array according to any one of items 44 to 45, wherein the panel of nucleotide sequences comprises or consists of one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said consecutive sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises at least one CpG site. The array according to any one of items 44 to 46, wherein said array comprises in the range of 1 to 900.000 DNA sequences. 49. The array according to any one of items 44 to 47, wherein said array is fixed to a carrier material.

50. The array according to any one of items 44 to 48, wherein the one or more DNA sequences are labelled, such as labelled with a fluorescent moiety.

51. Use of an array according to any one of the items 44 to 49, for determining the methylation level of a DNA molecule of an individual.

52. A method of determining the methylation level of DNA of an individual, the method comprising the steps of: a) Providing a sample obtained from said individual, wherein said sample comprises one or more DNA molecules; b) Treating said sample with an agent that modifies unmethylated cytosines in said one or more DNA molecules; c) Contacting said sample with an array comprising a plurality of DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.; d) Determining the methylation level of the DNA by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the plurality of DNA sequences in the panel.

53. Use of the methylation level of blood DNA of an individual for the manufacture of a diagnostic agent for predicting whether said individual is able to respond to metformin treatment or not and/or whether said individual is able to tolerate metformin treatment or not, wherein said diagnostic agent is manufactured to measure the methylation level of a panel of CpG sites, wherein said measured methylation level is compared to a normal methylation level of each of said CpG sites, and wherein a measured methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment.

54. The use according to item 52, wherein the panel of CpG sites is according to any one of items 4 to 15.

Claims

1. A method of predicting whether an individual is able to respond to metformin treatment of type 2 diabetes or not and/or whether an individual is able to tolerate metformin treatment or not, the method comprising the steps of: a) Providing a sample obtained from said individual; b) Determining in the sample the methylation level of a panel of CpG sites; c) Comparing the methylation level of each CpG site of the panel with a normal methylation level of each of said CpG sites, wherein the normal methylation level is the average methylation level of said CpG site as observed in at least 15 individuals suffering from type 2 diabetes and known to be able to respond to and/or tolerate metformin; d) Identifying an individual as non-responder and/or non-tolerant to metformin based on the methylation level of the panel of sequences, wherein a methylation level of the majority of the CpG sites being higher or lower than the normal methylation level of said CpG sites indicates that the individual is not able to respond to and/or not able to tolerate metformin treatment, and wherein a methylation level of the majority of the CpG sites being essentially equal to the normal methylation level of said CpG sites indicates that the individual is able to respond to and/or tolerate metformin treatment, and wherein said individual suffers from or is at risk of developing type 2 diabetes.

2. The method according to claim 1 , wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; and iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

3. The method according to any one of the preceding claims, wherein said panel of CpG sites comprises one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of Table A and/or Table B, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

4. The method according to any one of the preceding claims, wherein said panel of CpG sites comprises or consists of one or more CpG sites located on one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises or consists of in the range of 10 to 100 nucleotides of any one of i, ii and iii, wherein said sequence comprises at least one CpG site.

5. The method according to any one of the preceding claims, wherein said panel of CpG sites comprises or consists of at least 1 CpG site, such as at least 4 CpG sites, for example at least 7 CpG sites, such as at least 11 CpG sites, for example in the range of 5 to 20 CpG sites, such as in the range of 7 to 11 CpG sites.

6. The method of predicting whether an individual is able to respond to metformin treatment or not or predicting whether an individual is able to tolerate metformin treatment or not according to any one of the preceding claims, wherein the method further comprises calculating a response methylation risk score (rMRS) or a tolerance methylation risk score (tMRS) for the panel of CpG sites, wherein said rMRS or tMRS is the sum of the standardized methylation values at each CpG site, weighted by CpG-specific effect size.

7. The method according to any one of the preceding claims, wherein the methylation level is determined by pyrosequencing, PCR based methods, methylation-based methods, microarray-based methods, MALDI-TOF mass spectrometry-based methods, or combinations thereof.

8. The method according to any one of the preceding claims, wherein the individual is a human.

9. An array comprising a plurality of DNA sequences each selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii..

10. The array according to claim 9, wherein the panel of nucleotide sequences comprises or consists of one or more DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of any one of the nucleotide probe sequences of Table A and/or Table B; ii. DNA sequences comprising or consisting of a sequence being complementary to any one of the nucleotide probe sequences of Table A and/or Table B; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to any one of i. and ii., wherein said consecutive sequence comprises at least one CpG site; iv. a fragment of any one i, ii and iii, wherein said fragment comprises at least one CpG site.

11. A method of determining the methylation level of DNA of an individual, the method comprising the steps of: a) Providing a sample obtained from said individual, wherein said sample comprises one or more DNA molecules; b) Treating said sample with an agent that modifies unmethylated cytosines in said one or more DNA molecules; c) Contacting said sample with an array comprising a plurality of DNA sequences selected from the group consisting of: i. DNA sequences comprising or consisting of a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; ii. DNA sequences comprising or consisting of a sequence being complementary to a consecutive sequence of in the range of 10 to 100 nucleotides of any one of the surrounding genomic regions of any one of the CpG sites of List 1 and/or List 2, wherein a surrounding genomic region consists of 750 consecutive nucleotides located upstream and 750 consecutive nucleotides located downstream to each of the CpG sites of List 1 and/or List 2, wherein said consecutive sequence comprises at least one CpG site; iii. DNA sequences comprising or consisting of a sequence having at least 90% sequence identity to a consecutive sequence of in the range of 10 to 100 nucleotides as defined in any one of i. and ii.; d) Determining the methylation level of the DNA by measuring an amplification product resulting from hybridization between the one or more nucleic acid molecules in the sample and the plurality of DNA sequences in the panel.