KR102074157B1 - A method for pathogenesis prediction to kawasaki disease using the ITPKC and SLC11A1 genes SNP - Google Patents

Abstract

The present invention relates to a method for predicting Kawasaki disease onset using ITPKC and SLC11A1 gene polymorphism. Kawasaki disease is an acute febrile rash that occurs mainly in infants under 5 years of age. Coronary artery lesions may occur, and Kawasaki disease is the most common cause of acquired heart disease in developed countries. However, until now, there is no specific test for diagnosing Kawasaki disease, and thus the diagnosis is made according to clinical criteria.
Kawasaki disease onset prediction method using the ITPKC and SLC11A1 gene polymorphism of the present invention is characterized by applying the synergistic effect of the ITPKC gene and SLC11A1 gene and the Kawasaki disease, characterized in that it is predicted before the onset of Kawasaki disease As this is possible, it is expected to be widely used in the medical field.

Description

A method for pathogenesis prediction to kawasaki disease using the ITPKC and SLC11A1 genes SNP}

The present invention relates to a method for predicting Kawasaki disease onset using ITPKC and SLC11A1 gene polymorphism.

Kawasaki disease (KD) is an acute febrile rash that occurs mainly in infants under five years of age, although its cause is not known, but systemic vasculitis of the system is a major condition. Korea has the second highest prevalence after Japan, and coronary artery lesions can occur if not treated with proper use of intravenous immunoglobulin (IVIG). In developed countries, Kawasaki disease is the most common cause of acquired heart disease. However, until now, there is no specific test for diagnosing Kawasaki disease, and only the diagnosis is made according to clinical criteria. The most characteristic clinical symptoms for diagnosis are erythema and sclerosis at the BCG injection site.

The symptoms of Kawasaki disease are similar to those of other infectious diseases, and the progression of the disease is usually limited naturally. For this reason, Kawasaki disease was once considered an infectious disease. However, since infectious organisms are not isolated from patients, and geographic and kinetic ties are high, it has recently been regarded as an expression disease caused by genetic predisposition.

On the other hand, single-nucleotide polymorphism (SNP) refers to a genetic change or variation showing a difference of one nucleotide sequence (A, T, G, C) in the DNA sequence, the single nucleotide polymorphism Since each individual shows a lot of variation, it is mainly used for DNA fingerprint analysis.

A recent study using SNPs reported that Kawasaki's disease in Japanese infants was closely related to the inositol-trisphosphate 3-kinase C (ITPKC) gene (Onouchi Y et al., Nat Genet 2008; 40: 35-42). . In addition, polymorphisms of the natural resistance-associated macrophage protein 1 (NRAMP1 or SLC11A1) genes have been reported to be associated with Kawasaki disease (Ouchi K et al., J Infect Dis 2003; 187: 326-9). However, the relationship between Kawasaki disease and ITPKC in infants and toddlers in Korea has not been studied.

The present invention has been made to solve the above conventional technical problems, and relates to a method for predicting Kawasaki disease onset using ITPKC and SLC11A1 gene polymorphism. In particular, the correlation between the ITPKC gene and the SLC11A1 gene SNP and the synergistic effect in the development of Kawasaki disease were examined in Koreans. The onset predictive method of the present invention is expected to be widely used in the medical field because it is possible to predict the onset before Kawasaki disease.

The present invention has been made to solve the above conventional technical problems, and relates to a method for predicting Kawasaki disease onset using ITPKC and SLC11A1 gene polymorphism.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task not mentioned will be clearly understood by those skilled in the art from the following description.

Hereinafter, various embodiments described herein are described with reference to the drawings. In the following description, for a thorough understanding of the present invention, various specific details, such as specific forms, compositions and processes, are described. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and forms. In other instances, well known processes and manufacturing techniques have not been described in particular detail in order to not unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, the context of “in one embodiment” or “embodiment” expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. In addition, particular features, forms, compositions, or properties may be combined in any suitable manner in one or more embodiments.

Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment of the present invention, "Kawasaki disease (KD)" is an unexplained acute febrile vasculitis that occurs in children, and variously invades the whole body. Dysfunction of the skin, mucous membranes, lymph nodes, heart and blood vessels, joints, liver, etc., can cause gastrointestinal disorders, gallbladder edema, rarely meningitis.

The cause of Kawasaki disease is still unclear, but until now, it is estimated that if children with genetic factors are infected with pathogens, hypersensitivity reactions or abnormal immunological reactions result in Kawasaki disease. Infants under 5 years of age are the most common, accounting for 86% of all cases, with the highest incidence at 6 months to 2 years of age, with a recurrence rate of 3%.

Kawasaki disease often presents with typical clinical symptoms, but often does not show all atypical features. Typical symptoms include high fever of more than 38.5, edema of the extremities, irregular rashes of the skin, redness of the bilateral conjunctiva, redness and cracking of the lips, strawberry tongue, redness of the oral mucosa, non-purulent cervical lymph node swelling, redness of the BCG inoculation site There is this. Fever is usually unresponsive to antibiotics, fever usually lasts for more than one to two weeks, and in some cases for three to four weeks. In the early stages, they are severely ill and sometimes have diarrhea, abdominal pain, headache, digestive problems, and cough. Myocarditis, mild pericardial effusion, and valve regurgitation are commonly observed due to heart involvement. After one or two weeks of this acute phase, the subacute phase almost disappears, including the fever. Subacute phase is characterized by desquamation around the finger, toe tip and anus, increased platelet counts and the highest risk of sudden death due to coronary aneurysm. Giant coronary aneurysms are complications at risk of myocardial infarction due to rupture, narrowing, and clot closure. The recovery phase is the time when all these clinical symptoms begin to disappear, and blood test findings are normalized.

In addition to coronary complications, other clinical symptoms usually recover completely. The death rate from Kawasaki disease is reported to be about 0.01%. Large coronary aneurysms with an internal diameter of 8 mm or more are hard to recover completely, and coronary artery thrombosis or narrowing is likely to occur.

Kawasaki disease itself has no known cause, and there is no special preventive measure at this time. Therefore, there is an urgent need to develop technologies for predicting and managing Kawasaki disease.

In one embodiment of the present invention, "single nucleotide polymorphism (SNP)" has the same meaning as gene polymorphism, genetic polymorphism, nucleotide polymorphism, etc., abbreviated as SNP. SNPs are common mutations that occur in one of several DNA bases in a single region of a chromosome, with about 3 million SNPs present in the human genome, one per 500-1,000 bases, of which about 20 It is estimated that 10,000 are cSNPs present in the genes that make proteins.

SNPs are frequent, stable, and distributed throughout the genome, resulting in genetic diversity of the individual. In other words, some people in the DNA chain have adenine (A) while others have cytosine (C). These microscopic differences (SNPs) can alter the function of each gene, and they interact to make people of different shapes and create differences in susceptibility to different diseases. So, for example, if you can identify genetic differences between people with and without hepatitis, you will be able to determine the function of why the susceptibility to hepatitis changes. The ultimate goal of human genome research is to be able to develop drugs that can be used to prevent or treat hepatitis.

In one embodiment of the present invention, "real-time polymerase chain reaction (Real-time PCR)", also called real-time polymerase chain reaction, quantitative real time polymerase chain reaction (qPCR), the target DNA This is a molecular biology experiment that simultaneously measures the amplification and quantity of molecules. Commonly used RT-PCR refers to reverse transcription polymerase chain reaction, not real-time PCR. But not all those skilled in the art name this clearly. Real-time polymerase chain reaction can detect the absolute number or relative number of gene copies for one or more specific sequences in a DNA sample.

The progress of the experiment follows the general polymerase chain reaction. An important feature is that the amplified DNA is measured in real time. This is the difference from the basic polymerase chain reaction where DNA is observed at the end. Two general methods are used in real time polymerase chain reaction. (1) an unspecified fluorescence stain that can intervene in any DNA double helix, (2) a sequence-specific DNA probe consisting of oligonucleotides, labeled with the reporter, and detected after binding to complementary DNA targets. Often, real-time polymerase chain reactions are performed in combination with reverse transcription polymerase chain reactions to quantify mRNAs of cells or tissues and non-coated RNA.

In one embodiment of the present invention, "gene expression inhibition" means inhibiting gene expression with antisense oligonucleotides, siRNAs, shRNAs and microRNAs complementary to the gene sequence.

The antisense oligonucleotides are short length DNA synthesis strands (or DNA analogs) that are antisense (or complementary) to specific DNA or RNA targets and are used to achieve gene-specific inhibition in vivo as well as in vitro. Antisense oligonucleotides have been proposed to prevent the expression of a protein encoded by a DNA or RNA target by binding to the target and stopping expression at the stage of transcription, translation or splicing. Antisense oligonucleotides have been successfully used in cell culture and animal models of disease. Other modifications of antisense oligonucleotides to make them more stable and resistant to degradation of oligonucleotides are known and understood by those skilled in the art. Antisense oligonucleotides as used herein include oligonucleotides having double or single stranded DNA, double or single stranded RNA, DNA / RNA hybrids, DNA and RNA analogs and base, sugar or backbone modifications. Oligonucleotides are modified by methods known in the art to increase stability and to increase resistance to nuclease degradation. These modifications include, but are not limited to, modifications to oligonucleotide backbones, modifications of sugar moieties or bases known in the art.

The siRNA (small interfering RNA) is a nucleic acid molecule that can mediate RNA interference or gene silencing, and can be used as an efficient gene knockdown method or gene therapy method because it can suppress expression of a target gene. . When the siRNA molecule is used in the present invention, the sense strand and the antisense strand may be positioned opposite to each other to have a double-chain structure or a single-chain structure having a self-complementary sense and antisense strand. siRNAs are not limited to the complete pairing of double-stranded RNA pairs paired with RNA, but include mismatches (corresponding bases are not complementary), expansion / bulge (bases corresponding to one chain). None) may be included, such as parts that are not paired. The siRNA terminal structure can be either blunt or cohesive, as long as the expression of the target gene can be suppressed by RNA interference (RNAi) effect. The cohesive end structure can be both a 3'-end protrusion structure and a 5'-end protrusion structure. The siRNA molecule is not limited thereto, but may have a total length of 15 to 30 bases, preferably 19 to 21 bases.

The short hairpin RNA (shRNA) is a single-stranded RNA having a length of 45 to 70 nucleotides, and synthesizes oligo DNA connecting 3-10 base linkers between the sense strand of the target gene siRNA sequence and the complementary antisense strand. After cloning into plasmid vectors or inserting and expressing shRNAs into the retrovirus lentiviruses and adenoviruses, loops of hairpin structured shRNAs are produced and intracellular dicers. It is converted into siRNA by the RNAi effect.

The microRNAs regulate a variety of biological processes such as development, differentiation, proliferation, conservation and apoptosis. MicroRNAs generally regulate the expression of the gene encoding the target mRNA by destabilizing the target mRNA or disrupting translation.

Regulatory sequences useful in expression constructs / vectors with such antisense oligonucleotides, siRNAs, shRNAs or microRNAs (eg, constitutive promoters, inducible promoters, tissue specific promoters or combinations thereof) are also known in the art. The expression inhibitor of the gene may be appropriately selected from the contents, as long as it is an antisense oligonucleotide, siRNA, shRNA or microRNA, as long as the substance inhibits the expression of the gene.

In one embodiment of the present invention, "inhibiting protein activity" means inhibiting the activity of a target protein with an antibody specific for the protein or an antigen-binding fragment thereof.

The antibody means a specific protein molecule directed to an antigenic site as a term known in the art. Such an antibody can be produced by conventional methods from the proteins obtained by cloning each gene into an expression vector according to a conventional method to obtain a protein encoded by the marker gene. This includes partial peptides that can be made from the protein, and the partial peptide of the present invention includes at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited and any part thereof, including polyclonal antibodies, monoclonal antibodies, or antigen-binding agents, is included in the antibodies of the present invention and all immunoglobulin antibodies are included. Furthermore, the antibody of this invention also contains special antibodies, such as a humanized antibody. Antibodies of the invention include functional fragments of antibody molecules as well as complete forms having two full length light chains and two full length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least antigen binding function and includes Fab, F (ab '), F (ab') 2 and Fv.

In one embodiment of the present invention, "prevention" refers to the interrelation between the ITPKC gene and the SLC11A1 gene SNP, and the synergistic effect in the development of Kawasaki disease, and predicts the risk of onset before Kawasaki disease based on the analyzed data Means proper management.

In one embodiment of the present invention, "diagnosis" refers to the correlation between the ITPKC gene and the SLC11A1 gene SNP, and the synergistic effect in the development of Kawasaki disease, and to confirm Kawasaki disease based on the analyzed data.

In one embodiment of the invention, there is provided a method for predicting the onset of Kawasaki disease comprising the step of identifying the ITPKC gene polymorphism rs2290692 from a biological sample, if the sample is a sample of an individual less than 24 months, ITPKC polymorphism rs28493229 The present invention further provides a method for predicting onset, further comprising the step of identifying the ITPKC gene polymorphism rs10420685, or the SLC11A1 gene polymorphism rs2276631, and when the presence of the ITPKC gene polymorphism rs28493229 is confirmed, predicting an increase in the number of leukocytes in the individual. It provides a method for predicting the development comprising a step of predicting the erythrocyte sedimentation rate abnormality of the individual when the presence of the ITPKC gene polymorphism rs2290692 is confirmed, the presence of the ITPKC polymorphism rs10420685 Lactate dehydrogenase levels in the subject if identified It provides a method for predicting onset comprising the step of predicting a multiplicity, and when the presence of the SLC11A1 gene polymorphism rs2276631 is confirmed, predicting the occurrence of aspartate aminotransferase (Aspartate aminotransferase) abnormalities of the individual To provide.

The present invention also provides a method for predicting the onset of Kawasaki disease, further comprising the step of identifying the ITPKC polymorphism rs28493229 or the SLC11A1 polymorphism rs17235409 when the sample is a sample of an individual for 24 months or more, wherein the ITPKC gene polymorphism rs28493229 Predicting the onset comprising the step of predicting an increase in the platelet level of the subject when the presence is confirmed, and predicting the increase in the level of lactate dehydrogenase of the subject when the presence of the SLC11A1 polymorphism rs17235409 is confirmed It provides a method for predicting onset comprising a.

In another embodiment of the invention, (a) identifying the presence of the ITPKC gene polymorphism rs2561531 and SLC11A1 gene polymorphism rs17221959 from a biological sample; And (b) when the rs2561531 and rs17221959 is present, providing a method of predicting the risk of expression of Kawasaki disease symptoms comprising the step of determining that the probability of expression of Kawasaki disease is low, the sample is a sample of individuals less than 24 months Provide a prediction method.

In another embodiment of the invention, (a) confirming the presence of ITPKC gene polymorphism rs2561531 and SLC11A1 gene polymorphism rs77624405 from a biological sample; And (b) when the rs2561531 and rs77624405 present, providing a method for predicting the risk of developing Kawasaki disease symptoms comprising the step of determining that the probability of developing Kawasaki disease symptoms, the sample is a sample of individuals less than 24 months Provide a prediction method.

In another embodiment of the invention, (a) confirming the presence of SLC11A1 polymorphism rs17235409 from a biological sample; And (b) predicting the occurrence of erythema at the BCG injection site when rs17235409 is present, wherein the sample is a sample of an individual less than 24 months old. to provide.

In another embodiment of the invention, (a) identifying the presence of ITPKC gene polymorphism rs28493229 and SLC11A1 gene polymorphism rs17235409 from a biological sample; And (b) predicting the occurrence of erythema at the BCG injection site in the presence of rs28493229 and rs17235409, wherein the sample is a sample of an individual for at least 24 months. Provide a method.

In another embodiment of the invention, (a) identifying the presence of ITPKC gene polymorphism rs10420685 and SLC11A1 gene polymorphism rs17235409 from a biological sample; And (b) predicting the occurrence of erythema at the BCG injection site in the presence of rs10420685 and rs17235409, wherein the sample is a sample of an individual for at least 24 months. Provide a method.

In another embodiment of the invention, (a) confirming the presence of the gene polymorphism rs28493229 of ITPKC from a biological sample; And (b) in the presence of rs28493229, predicting a high risk of developing coronary lesions.

In another embodiment of the present invention, there is provided a kit for predicting the onset of Kawasaki disease comprising a primer for screening, or genotyping of ITPKC gene polymorphism rs2290692, the kit is ITPKC polymorphism rs28493229, rs10420685, rs2561531, SLC11A1 gene polymorphism rs2276631, rs17235409, rs17221959, and rs77624405 provides a kit further comprising any one or more screening primers, or genotyping primers selected from the group consisting of.

In still another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating Kawasaki disease comprising an inhibitor of expression of the ITPKC gene polymorphism rs2290692, or an activity inhibitor of the protein expressing the ITPKC gene polymorphism rs2290692 as an active ingredient, and the pharmaceutical composition Is a pharmaceutical composition comprising as an active ingredient any one or more expression inhibitors selected from the group consisting of ITPKC gene polymorphism rs28493229, rs10420685, rs2561531, SLC11A1 gene polymorphism rs2276631, rs17235409, rs17221959, and rs77624405, or an activity inhibitor of the expressed protein. The expression inhibitor provides a pharmaceutical composition of any one or more selected from the group consisting of antisense oligonucleotides, siRNA, shRNA and microRNA specific to the ITPKC gene polymorphism rs2290692, wherein the activity inhibitor of the expressed protein is the ITPKC gene All It provides a pharmaceutical composition comprising an antibody specific for formation rs2290692, or an antigen-binding fragment thereof.

Hereinafter, the present invention will be described in detail step by step.

Kawasaki disease onset prediction method using the ITPKC and SLC11A1 gene polymorphism of the present invention is characterized by applying the synergistic effect of the ITPKC gene and SLC11A1 gene and the Kawasaki disease, characterized in that it is predicted before the onset of Kawasaki disease As this is possible, it is expected to be widely used in the medical field.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for explaining the present invention more specifically, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example  1. From samples of patients with Kawasaki disease ITPKC  And SLC11A1  Perform sequencing of genes

Samples of 229 patients with Kawasaki disease from Severance Children's Hospital were subjected to sequencing of ITPKC (SEQ ID NO: 1) and SLC11A1 (SEQ ID NO: 2) genes. The patients were diagnosed according to the criteria of the Kawasaki Disease Research Council of Japan, except for incomplete or atypical patients with Kawasaki disease. The control group included healthy infants who had no history of Kawasaki disease and visited the hospital for cosmetic reasons. Since Kawasaki disease is highly correlated with age, patients are classified by 24 months, considering that erythema in the BCG region is mainly observed in children under 24 months of age. The age group is indicated. All experiments were performed with the approval of Yonsei University College of Medicine Ethics Committee (Approval No. 2008-0055-010).

Statistically processed information of the patients is shown in Table 1.

KD patients Controls (210) p -value All (299) <24 month (114) ≥ 24month (185) Age (month) 41.81 ± 39.49 11.81 ± 5.88 60.33 ± 40.05 115.97 ± 35.24 <.0001 ＊ Gender (M: F) 194: 105 81 (41.8%): 33 (31.4%) 113 (58.2%): 72 (68.6%) 130: 80 <.0001 ＊ BCG injection site erythema 77 62 (80.5%) 15 (19.5%) NA <0.001 † WBC 12,900.73 ± 5,315.07 13,594.09 ± 5,195.91 12,432.82 ± 5,359.14 6,910.71 ± 2,01.68 <.0001 ＊ Platelet 399.97 ± 182.73 425.72 ± 181.55 382.60 ± 182.02 304.70 ± 71.17 <.0001 ＊ ESR 63.51 ± 32.49 59.93 ± 33.15 65.98 ± 31.90 11.00 ± 9.81 <.0001 ＊ CRP 57.75 ± 53.02 51.09 ± 47.92 62.33 ± 55.95 9.152 ± 14.61 0.069 ＊ LDH 334.75 ± 145.66 334.06 ± 115.38 335.21 ± 163.21 241.21 ± 41.67 <.0001 ＊ Coronary complication 55 13 (23.6%) 42 (76.4%) NA 0.008 † Recur of KD 48 18 (37.5%) 30 (62.5%) NA 0.296 †

Genomic DNA for each sample obtained was extracted using a QIAmp DNA Blood Mini Kit (QIAGEN, Hilden, Germany) and quantified using an Epoch microplate spectrophotometer (BioTek, Winooski, VT, USA).

To identify the causative mutations, the SLC11A1 and ITPKC genes of each sample were sequenced. Genomic sequences for analysis were obtained from the GenBank (http: //www.ncbi/nlm.nih.gov/) database, and PCR primers for amplifying the exon and promoter regions of genes (2 kb upstream of exon 1) were prepared using Primer3 software ( Designed using http://frodo.wi.mit.edu/primer3/). PCR fragments were sequenced using BigDye Terminator chemistry on an ABI Prism 3730xl DNA analyzer (Applied Biosystems, Foster City, Calif., USA) according to the manufacturer's protocol. DNA polymorphism was confirmed using the PolyPhred program (http://droog.gs.washington.edu/polyphred/). Tagging SNPs were selected using Haploview (version 4.2) and TaqMan® fluorogenic 5'- for all SNP samples selected via linkage disequilibrium (LD) analysis for full gene sequencing of SLC11A1 and ITPKC. Gene typing of the tagged SNP was performed using a nuclease assay (Applied Biosystems). An rs2290692 polymorphism was added to the 3'-UTR of the ITPKC gene, which has recently been reported to be highly associated with Kawasaki disease in Han Chinese (Peng Q et al., Pediatr Cardiol 2012; 33: 1046-53). Real-time PCR was performed using QuantStudio ™ 6 Flex Real-Time PCR System (Applied Biosystems), and data were analyzed with 7500 SDS 2.3 software (Applied Biosystems).

Location information for the selected tagging SNP is shown in Table 2 below.

Corresponding gene RS name Polymorphic Information ITPKC rs2561531 Base G, located at 3,912th of the ITPKC gene (SEQ ID NO: 1), is replaced with A ITPKC rs28493229 Base C at position 6,197 of the ITPKC gene (SEQ ID NO: 1) is replaced with G. ITPKC rs7251246 Base C at position 9,099 of the ITPKC gene (SEQ ID NO: 1) is replaced with T. ITPKC rs10420685 Base A at position 17,113 of the ITPKC gene (SEQ ID NO: 1) is replaced with G. ITPKC rs2290692 Base C at position 28,371 of the ITPKC gene (SEQ ID NO: 1) is replaced with G SLC11A1 rs7573065 Base C at position 4,956 of SLC11A1 gene (SEQ ID NO: 2) is replaced by T SLC11A1 rs227663 Base T at position 7,262 of SLC11A1 gene (SEQ ID NO: 2) is replaced with C SLC11A1 rs17221959 Base C at position 10,879 of SLC11A1 gene (SEQ ID NO: 2) is replaced by T SLC11A1 rs77624405 Base A at position 16,044 of SLC11A1 gene (SEQ ID NO: 2) is replaced with G SLC11A1 rs17235409 Base A at position 17,981 of SLC11A1 gene (SEQ ID NO: 2) is replaced with G

Example  2. From samples of patients with Kawasaki disease SLC11A1 and ITPKC  Genetic Association Analysis

All statistical analyzes on the data of Example 1 were performed using SAS software (version 9.0) on the Windows 7 platform. To test the association with Kawasaki disease, the Cochran-Armitage trend test (chi-squared test) was used to compare allele and genotype frequencies (nominal variables) in the test and control groups. Statistical significance was treated with Student's t-test, where p values less than 0.05 were considered statistically significant. Continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as numbers (%).

The synergy between SLC11A1 polymorphism and ITPKC gene polymorphism was analyzed using a combination of multiple loci. In order to assess the interaction between the two genes with respect to Kawasaki disease, a search for the best combination pattern of gene polymorphism was performed according to the principle of maximizing cross-validation consistency and test balance accuracy.

For the analysis results, first, the clinical pattern of the subject is shown in Table 3. Of 299 Kawasaki's patients, 77 (25.75%) had erythema at the BCG injection site. When the patients were divided into two groups according to age, 54 out of 114 (54.39%) were older. In the case of 15 out of 185 patients (8.11%), there was a big difference according to age.

Patients with Kawasaki disease were found to have elevated leukocyte counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) compared to controls. It became.

Coronary artery lesions (CAL) were observed in 55 out of 299 patients (18.39%), in the older age group (42 out of 185, 22.70%) and in the lower age group (13 out of 114, 11.40%). The incidence rate was higher than that of (p = 0.008). Forty-eight patients (16.05%) had clinical symptoms, with age-related clinical signs being significant between the older (30 out of 185, 16.22%) and lower (18 out of 114, 15.79%) patients. No difference was found.

Genotypes p -value Alleles p -value ITPKC CC CT TT C T rs2561531 Controls 130 (61.90) 70 (33.33) 10 (4.76) 0.957 330 (78.57) 90 (21.43) 0.856 KD patients 184 (61.54) 99 (33.11) 16 (5.35) 467 (78.09) 131 (21.91) GG GC CC G C rs28493229 Controls 178 (84.76) 32 (15.24) 0 (0.00) 0.045 388 (92.38) 32 (7.62) 0.022 KD patients 231 (77.26) 64 (21.40) 4 (1.34) 526 (87.96) 72 (12.04) AA AG GG A G rs10420685 Controls 114 (54.29) 76 (36.19) 20 (9.52) 0.836 304 (72.38) 116 (27.62) 0.777 KD patients 156 (52.17) 116 (38.80) 27 (9.03) 428 (71.57) 170 (28.43) GG GC CC G C rs2290692
Controls 65 (30.95) 97 (46.19) 48 (22.86) 0.933 227 (54.05) 193 (45.95) 0.908 KD patients 89 (29.77) 143 (47.83) 67 (22.41) 321 (53.68) 277 (46.32) SLC11A1 CC CT TT C T rs7573065 Controls 194 (92.38) 15 (7.14) 1 (0.48) 0.405 403 (95.95) 17 (4.05) 0.815 KD patients 273 (91.30) 26 (8.70) 0 (0.00) 572 (95.65) 26 (4.35) GG GA AA G A rs2276631 Controls 143 (68.10) 59 (28.10) 8 (3.81) 0.909 345 (82.14) 75 (17.86) 0.688 KD patients 209 (69.90) 79 (26.42) 11 (3.68) 497 (83.11) 101 (16.89) CC CT TT C T r17221959 Controls 186 (88.57) 24 (11.43) 0 (0.00) 0.202 396 (94.29) 24 (5.71) 0.220 KD patients 253 (84.62) 46 (15.38) 0 (0.00) 552 (92.31) 46 (7.69) GG GA AA G A rs77624405 Controls 204 (97.14) 6 (2.86) 0 (0.00) 0.072 414 (98.57) 6 (1.43) 0.076 KD patients 280 (93.65) 19 (6.35) 0. (0.00) 579 (96.82) 19 (3.18) GG GA AA G A rs17235409
Controls 165 (78.57) 42 (20.00) 3 (1.43) 0.886 372 (88.57) 48 (11.43) 0.780 KD patients 239 (79.93) 55 (18.39) 5 (1.67) 533 (89.13) 65 (10.87)

In our LD analysis, four tagging SNPs in ITPKC and five tagging SNPs in SLC11A1 were selected, as shown in Table 3. The relationship between the polymorphisms of ITPKC and SLC11A1 genes and the clinical test results using the SNPs showed a significant difference only in rs28493229 in the intron of ITPKC when comparing the genotype and allele frequencies of the Kawasaki disease group and the control group (p respectively). = 0.045 and p = 0.022). Overexpression of the C allele was observed in rs28493229 of ITPKC, and similar results were observed in the low age group when dividing by age (p = 0.039, p = 0.031, respectively). Table 4 shows the rs28493229 frequency analysis result of the ITPKC.

Genotypes Alleles GG GC CC p -value G C p -value All Controls 178 (84.76) 32 (15.24) 0 (0.00) 0.045 388 (92.38) 32 (7.62) 0.022 KD patients 231 (77.26) 64 (21.40) 4 (1.34) 526 (87.96) 72 (12.04) <24 months Controls 178 (84.76) 32 (15.24) 0 (0.00) 0.039 388 (92.38) 32 (7.62) 0.031 KD patients 86 (75.44) 27 (23.68) 1 (0.88) 199 (87.28) 29 (12.71) ≥ 24 months Controls 178 (84.76) 32 (15.24) 0 (0.00) 0.065 388 (92.38) 32 (7.62) 0.052 KD patients 145 (78.38) 37 (20.00) 3 (1.62) 327 (88.38) 43 (11.62)

No significant difference was found between the control group and the control group for rs77624405 in exon 12 of SLC11A1. However, when dividing the patient group, there was a significant difference in overexpression of the A allele in the low age group (p respectively). = 0.008 and p = 0.009). Table 5 shows the rs77624405 frequency analysis results of the SLC11A1.

Genotypes Alleles GG GA p -value G A p -value All Controls 204 (97.14) 6 (2.86) 0.072 414 (98.57) 6 (1.43) 0.076 KD patients 280 (93.65) 19 (6.35) 579 (96.82) 19 (3.18) <24 months Controls 204 (97.14) 6 (2.86) 0.008 414 (98.57) 6 (1.43) 0.009 KD patients 103 (90.35) 11 (9.65) 217 (95.18) 11 (4.82) ≥ 24 months Controls 204 (97.14) 6 (2.86) 0.425 414 (98.57) 6 (1.43) 0.429 KD patients 177 (95.68) 8 (4.32) 362 (97.84) 8 (2.16)

Correlations between known SNPs and experimental data were also analyzed and found to be significantly heterogeneous in alleles of related SNPs between patient and control groups.

Specifically, the rs2290692 polymorphism of the Kawasaki disease group ITPKC was associated with an increase in leukocyte count, platelet count, and lactate dehydrogenase level compared to the control group. Differences were also found when dividing patients into age groups. In the low age group, leukocyte counts were associated with rs28493229 polymorphism, elevated lactate dehydrogenase levels were associated with rs10420685 polymorphism, and erythrocyte sedimentation rate was associated with rs2290692 polymorphism. However, there was no correlation in the whole group of patients who did not dichotomize according to age. The increase in leukocyte counts in the older age group was associated with the rs2290692 polymorphism, which was also the same in all patients who did not differentiate by age. Increased platelet counts in the older age group were associated with the rs28493229 polymorphism, but not in all the patients who did not differentiate by age. Elevated levels of lactate dehydrogenase in the older age group were associated with the polymorphism of rs17235409 in SLC111A1, and aspartate aminotransferase (AST) in the lower age group was associated with the rs2276631 polymorphism. There was no SNP associated with inflammation in SLC11A1. The results are shown in Table 6.

ITPKC gene SNP Values p -value KD Vs Control rs2290692_GC Elevation of WBC 0.021 rs2290692_GC Elevation of platelet 0.024 rs2290692_CC Elevation of LDH 0.040 <24 months vs. Controls rs28493229_CC Elevation of WBC <0.001 rs2290692_GC Elevation of platelet 0.046 rs2290692_GC Elevation of ESR 0.025 rs10420685_AG Elevation of LDH 0.014 ≥24 months vs. Controls rs2290692_GC Elevation of WBC 0.033 rs28493229_CC Elevation of platelet 0.008 SLC11A1 gene SNP Values p -value <24 months vs. Controls rs2276631_GA Elevation of AST 0.022 ≥24 months vs. Controls rs17235409_GA Elevation of LDH 0.050

No significant interaction was observed between ITPKC and SLC11A1 genes when comparing Kawasaki disease patients and controls. The interaction between and SLC11A1 rs77624405 GA was analyzed to have a strong protective effect on the manifestation of Kawasaki disease symptoms. The results are shown in Table 7.

All OR (95% CI) p -value ITPKC rs2561531_CC SLC11A1 rs17221959_CT 0.841 (0.387-1.828) 0.661 ITPKC rs2561531_CC SLC11A1 rs77624405_GA 0.249 (0.047-1.328) 0.104 <24 months OR (95% CI) p -value ITPKC rs2561531_CC SLC11A1 rs17221959_CT 0.379 (0.154-0.931) 0.034 ITPKC rs2561531_CC SLC11A1 rs77624405_GA 0.128 (0.025-0.667) 0.015

There was no ITPKC SNP associated with erythema at the BCG injection site in the Kawasaki disease group. However, the rs17235409 polymorphism of SLC11A1 was associated with erythema at the BCG injection site in patients with Kawasaki disease. The results are shown in Table 8.

Correlation between ITPKC and SLC11A1 genes for BCG injection site erythema in patients with Kawasaki disease showed that rs28493229 of ITPKC and rs17235409 (OR = 5.1, p = 0.017) of SLC11A1, or rs10420685 and SLC11A1 of ITPKC in older age Kawasaki disease patients. There was a significant correlation between rs17235409 (OR = 12.51, p = 0.008). The results are shown in Table 9.

Genotypes BCG (+) Control p -value All GG 62 (80.52) 155 (78.68) 0.90 GA 14 (18.18) 38 (19.29) AA 1 (1.30) 4 (2.03) G 138 (89.61) 348 (88.32) 0.669 A 16 (10.39) 46 (11.68) <24 months GG 53 (85.48) 32 (66.67) 0.037 GA 8 (12.90) 15 (31.25) AA 1 (1.61) 1 (2.08) G 114 (91.94) 79 (82.29) 0.031 A 10 (8.06) 17 (17.71)

All OR (95% CI) p -value ITPKC rs28493229_GG SLC11A1 rs17235409_GA 0.031 (0.093-1.031) 0.056 ITPKC rs10420685_GG SLC11A1 rs17235409_AA <0.001 (<0.001-> 999.999) 0.985 ≥ 24 months OR (95% CI) p -value ITPKC rs28493229_GG SLC11A1 rs17235409_GA 5.105 (1.345-19.372) 0.017 ITPKC rs10420685_GG SLC11A1 rs17235409_AA 12.51 (1.927-82.01) 0.008

The rs28493229 polymorphism of ITPKC was associated with the development of coronary lesion symptoms, but there was no correlation between ITPKC and SLC11A1 genes. The results are shown in Table 10.

Genotypes Alleles GG GC CC p -value G C p -value All No CAL patients 181 (78.35) 49 (21.21) 1 (0.43) 0.043 411 (88.96) 51 (11.04) 0.087 CAL patients 40 (72.73) 12 (21.82) 3 (5.45) 92 (83.64) 18 (16.36)

From the above results, it was found that Kawasaki disease is not a single disease entity, and the onset age, clinical symptoms, pattern of test data, and the like are deeply related to SNP.

<110> MEDIZEN HUMANCARE INC.          Industry-Academic Cooperation Foundation, Yonsei University <120> A method for pathogenesis prediction to kawasaki disease using          the ITPKC and SLC11A1 genes SNP <130> DPB174140 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 30758 <212> DNA <213> Homo sapiens <400> 1 atctctacct cctgggtaca agcaagtgaa tctatatttt taaaacttga accaggcggg 60 gcatggtagc tcacgcctat aatcccagca ctttgggagg ctgaggcagg tggatcacga 120 ggtgaggagt tcgagatcag cttgaccaac atggtgaaac cccatctcta ctaaaaatac 180 agaaattagc ggtcaggcac agtggctcac gtctgtaatc ctggcacttt aggaggccaa 240 ggcaggcgga tcatgaggtc aggagatcga gaccatcctg gccaacatgg tgaaaccctg 300 tctccctaag aaaaaaaaaa aaaaaaacaa caaaaaatag ttggacgtgg tggcgtgcat 360 ctgtaacccc cgctactcag gaggctgagg caggagaatt gcttgaacct gggaggtgga 420 ggttgcagtg agctgagatc atgccactgc actccagtct gggtgacaga gcaagactcc 480 atctcaaaaa caaaaacaaa aacaaaactt gaaccatgat cagcaataag aagacattta 540 cgttataacc agtgcagacc aaggtatatg tttcacgaaa caagactttc ccttgctcta 600 caggtgcatg catattttct gtcctattct tctttttaaa tgctggttgc aacccactaa 660 attatttcat gtgacttgca cgacatccgg ctgtgtaacc caaagtcaag tgacctcccc 720 tttgttagcc tcaatgtcct catgtacgga atagaacact cattgattca gtgcagcatg 780 tgtgtatatg ggacactgca cattacaggt tctcagtaaa tgttattatg gccaggagca 840 gtggctcatg cctagaaccc cagcacttcg ggaggccgag gcaggaggat cgcttgagac 900 caacttgagc aacataggga gaccctatct ctacaaaaaa atatttttta aattacccag 960 gccaggcaca gtggcttccc gggcaccgtg gctcacatct gtaaatccca acactttggg 1020 aggccgaagt gggtggatca cttgaggtca ggagttcaag accagcctgg ccaacatggt 1080 gaaattctgt ctctactaaa agtacaaaaa ttagccaggc ggccaggtgt ggtggctcac 1140 gcctgtaatc ccagcacttg ggaaggctga ggcaggcgga tcacaaagcg aggacatagc 1200 agagtcatcc cttgaaccct gggcagcctg gtgccaaagc tctaccactg cctgacaaac 1260 atggtgaaac cccgtctcta ctaaaaatac aaaaattagc cgggtgtggt ggatgcatgc 1320 ctgtaatccc agctacttgg gagtgtgagg caggagaatc ggcttgaacc cgggaggtgg 1380 aggttgcagt gagccaagat ggcgccactg cactccagcc tgggtgacag agggatactc 1440 cgtctcaaaa aaaaaaaaaa aaaaatagcc aggcatagtg gcaggcacct gtaatcccag 1500 ctactcagga ggctgtggca ggagaattgc ttgaatgtag gaggcagagg ttgcaatgag 1560 ccaagacggt gccactgcac tccagcctgg gcaacagagc gagactctgt ctcaaaggaa 1620 aaaaaaaaaa aaattacccg ggcggatggt gcacaactgt ggtcccagct actcaggagg 1680 ctgaggcgag agaattgctt gagcccagaa gtttgaggct gcagtgatcg cgccactgca 1740 ctccagcctg ggtgacaaag tgagactctg tctcaaaaaa aaaaaaaaaa attatcattt 1800 atgttcctct tgatttctct tggccttgca ggcccttgcc tttgtctctc tttttttgtc 1860 tctctctctt tcctgtctct gattcatcct ctcccttgct tcaatctgta aatgttgccc 1920 tttctaattg aggtcacacc aagatccccc aaagtcacac ctacccccaa agttggccaa 1980 gcggctgatg cgggaggcag gcaccttgcg ttctcgagag cggtcactca gctgggaaat 2040 ggggacaagg tctgagggtg ggaaagtggg catcgtggcc agagagtgca gccactctgc 2100 caccacaccc ttccccaagc tcagggggcc agcagtattc gtggggtgtt gctgggtggg 2160 tgggggtaat gatacctggg gccggggtgt cttcctggga cgggcctccc gtgccctgcg 2220 aatgtcctcc tcacccaggc ctctcccagg cccatcctgg taaaactttt gggcccaaga 2280 acctccacat ggtccctgca agagatatac tttgataagg aggggaggac atgggatcac 2340 ctggcccttc tggacccctc ctgtcctttt accctctgaa gtctccctca gcctcttccc 2400 cttggggacc tgctccctag cctcttaccc agcggtgggg cccaggcccc agggccccac 2460 aaggccaacc aacagtctgg cccagctgtc caccggtccc ccgaagtagg ccccccacct 2520 tcagccacat tgcctggagg agaagaggag ggattattca ggtgggagtt gcctggcttc 2580 ttggccaggc ccccatgttc ctctgtgtcc accctctctc attcccaccc actaaatact 2640 tcctccacta ttaatagatt cccacagttt ctcctggttc tcccctggtt gctaggaacc 2700 cttagctctt cctgcaggcc tcccaaaacc cactttcccc cctctcccaa ccctcgccgt 2760 tgctagggtc cgcccccgtt actagacacc cacagttcct caggggctac ctctccactt 2820 ctctgaaacc cccctcgttg ctatgcaccg ccttcccctc tgttggccct gtaggcaccc 2880 gcaattcctc cggtgtcccc ccgcccgatc cccaccccgt tactgagcac ctccccccgt 2940 tgctaagcac ccactgctct cagcctccga gtccgcaacc tgctggggcc ctcctgtgct 3000 tccgggagcc tctgtatgcc cgcccccttc ggccagccaa ccaatggcgc ggcagcaact 3060 cgctgactgg cacggagttt ctccatctgt gcgcggggga aggggccaga gagaggccct 3120 agcgatggag cctggaatta aggtgggcat cgggggccca tctgggggga ttgctgaggc 3180 atcgcgggag cgcaagcgtg ccctgtctgc ccttccactc acctcaaagt gccttgtacg 3240 cgacagaccc ttctgttccc tacactttct tgcaaagtct cccttacaaa cctgacgcct 3300 ctcttctgca cgaatatctt gccaaccccc cttcttattt ttacccctgg caggctcaac 3360 acaattcctt tgaatacaca ttcttcccag caaacatttc ccttgcacat ggagcccctc 3420 cactttgcac aaacacccac attctggcac ccaacctcct tccttgtgca tataaatccc 3480 ttgccttgct tgccaactgt ttcccgctca cgccttcaac tctctcgtgt acataccctc 3540 ccccccactt gcacactgag tctctgttcc ctcacacacc ctgttctctc cgctccccgc 3600 ccacctgcgg aatggtgcga ctgggagccc tctgcttcct gtaggcctga catttcccag 3660 aacacactca gccaagattc ccagtgctga gtcaggaacc ttggcatccc agaaaaccac 3720 ctcccatcct atctttcttt ctctgtgtgt gtgtgtgtgt gtgtgtgc gcgcgcgcgt 3780 tggaaagcct gctctcccca caacaggctg actcacccac ttctcacagt ctggaataga 3840 ggcatctggt tggggcatct ttcccaccac tgggagaggg agggatgccg atgcttcccc 3900 cacagaaccc cgctgcccca acccctcttg tcgggaatca ggcctctttg tctctattcc 3960 cgtactgtgt gacctcagaa aagccctcat ccctctctgg acttctcctt cccaacctgt 4020 atgaggtact aggtgggctc ctgccttcga tttctctcat tggtctgtga aaaggtgact 4080 cattttagag ccttggacct gtgcccaatg tctcccccag ttgactcaat ttcaagacaa 4140 accacctcct ctcccccttc agaggtgaac ggctgactca ggagctgggt ggcagctcag 4200 ccttgggggc aaaatatatc aaaatcacct aggacaataa ataatcctac tgggctacaa 4260 ctgacagtgc caggcccggg gccacatgct tcacatacat gagatcatgt cagatagccc 4320 cgtagctgca agcaaagggt agaggccggc agatctctga gcctctgttc tcacgtgtaa 4380 aatggagccc tggcatccct attgttcagc cttggagaat gaactgaaat cgtgtcaggg 4440 tctgatacag aacaagtact ctatacatga cagagatttc ttacggaaaa tccaatggag 4500 cgtaagtcat ttgctcaggg tagcggagct gggaactggc agaggaaggt ctcgaaccca 4560 cacccgtggg aactccaagt ctttgaaagt ccgtcccgcc cctgcgtgaa gaatgggcgc 4620 gcggctggac tcgtcaccgg gggttttagg gaaggttgaa cttgtcattc aaccgtgtag 4680 ggagggtggt ttagtcacag gggtggaggg agggggccca ctggcgcgcc accaggaccc 4740 cggtgcccta gatgcatacc tggccgcgct tcggatgctc agaggcaaac cccctcccct 4800 tgggaggcgg agtcggacaa ggctccgtct cgttccgttc cgtcacgtcc ggtggggcgg 4860 ggcttcgggg ctttcccctt tgaggggagt atcggttaac ccttgcgcgg cggggcgggc 4920 tggagctccg cgggccggaa cccgggagtc ggggctcccc agccacaccc ctcgcgggat 4980 ttaaagggat aggaggggcc gggtcggccg aagcccgaac cgaaggagcg ggcatgaggc 5040 gctgcccgtg ccgtgggagc ctgaacgagg cggaggccgg ggcgctgccc gcggcggccc 5100 gcatgggact ggaggcgccg cgaggagggc ggcggcggca gccgggacag cagcgacctg 5160 ggcccggcgc aggggccccg gcggggcggc cggagggggg cgggccctgg gcccggacag 5220 aggggtccag cctccacagc gagcctgaga gggccggcct cgggcctgcg ccggggacag 5280 agagtccgca ggcagaattc tggacagacg gacagactga gcccgcggca gctggccttg 5340 gagtagagac cgagaggccc aagcaaaaga cggagccaga caggtccagc ctccggacgc 5400 atctagaatg gagctggtca gagctggaga cgacttgtct ttggacggag accgggacag 5460 atggcctttg gactgatccg cacaggtccg acctccagtt tcagcccgag gaggccagcc 5520 cctggacaca gccaggggtt catgggccct ggacagagct ggaaacgcat gggtcacaga 5580 ctcagccaga gagggtcaag tcctgggctg ataacctctg gacccaccag aacagttcca 5640 gcctccagac tcacccagaa ggagcctgtc cctcaaaaga gccaagtgct gatggctcct 5700 ggaaagaatt gtatactgat ggctccagga cacaacagga tattgaaggt ccctggacag 5760 agccatatac tgatggctcc cagaaaaaac aggatactga agcagccagg aaacagcctg 5820 gcactggtgg tttccaaata caacaggata ctgatggctc ctggacacaa cctagcactg 5880 acggttccca gacagcacct gggacagact gcctcttggg agagcctgag gatggcccat 5940 tagaggaacc agagcctgga gaattgctga ctcacctgta ctctcacctg aagtgtagcc 6000 ccctgtgccc tgtgccccgc ctcatcatta cccctgagac ccctgagcct gaggcccagc 6060 cagtgggacc cccctcccgg gttgaggggg gcagcggcgg cttctcctct gcctcttctt 6120 tcgacgagtc tgaggatgac gtggtggccg ggggcggagg tgccagcgat cccgaggaca 6180 ggtctggggt gagtgggacc catcctgccc ttgagccaca tcacgcaaaa ctccttattc 6240 ctccgccttt gcttaggaag ttctctaccc atttactgtt agttgcccac cagcaatttc 6300 atctccggga acctcttcca tccactgacc tcctccctct gacagccagg ttactaattc 6360 actccaggca ccccttctta attctctcct ttccccttcc tgcactgtct ccactcctgg 6420 gggtctacaa tggagggcca ctgaccgact ttatggggcc caggaacccc tgaaattgta 6480 ggactaagga gcctgccgtg cgtgttcaca tacattgttg cagcgacggt ctgacatctg 6540 tctaatcctc tggaatctga agaacactgg gatagggaga caggcagggt gcactttcta 6600 ccccacattt cttaatctgg ggcctgtggc tgtcttaaag ggtcacaaac cttcaccacc 6660 ccttagccta tttgtatgta catttttcta gggagcaaag cgattccccc agcttgcatc 6720 agattcgcaa aagggctgtg tgaccccaaa cgccaaagga tccttggcct agccgggagc 6780 ccacctggtc tcccctgtga cccctacatc cccaaggagc cccctgaaca ctcttgttta 6840 ctttgtccac cgtcaccccc agcttgggtg tggctctccc ctggtgaatc aggaggaccg 6900 gccgggcagg ttcagggagg gcgggacaga gcagaggccg gtgtgaaact ggagagcctc 6960 acgtggggct gggagccgtg gggctgggag ccgagtccgg agtccatcag cttgccagct 7020 tgcctgctga ggcctctttt tgctctgggg cccctggctg gagtctgccc tgagccccgc 7080 ttcaccccac atgccttcct tggggacgtg ttcacacatg tggccctagc tgtgagagac 7140 agacctgcct tgacgtgcct gtgcctgtgt gcaggggctg accctcctgg gccccattgc 7200 ttttttctct ctgcctgccc tctcacttcc ttggcatctc agaacagctg agctggaagt 7260 gggtgaataa taataataat aataataata ataacaacaa caattagcac tcactcatgt 7320 ttagccctgt gctaagtgct gtgcttttat taactcactc actcctcgca gcaaccctaa 7380 tgaggtagat actttttttt tttttctgag acagtctcgc tctgttgccc aggctggagt 7440 gcagtggtgc catctcggct cactgcagcc ttcacttcct gggttcaagt gattgtcctg 7500 cctcagcctc ctgagtaggt gagacaccag gtgcccgcca ccacacctgg ctcatttctg 7560 tattttgagt agagacaggg tttcatcatg ttggccaggc tgacctcaag actcctgacc 7620 tcaagtgatc cacccgcctc agcctcccga agtgctggaa ttaccagcat gagccactgc 7680 acccggctga ggtagatact attattatcc ccttttacag atgaggaaac tgaggcacag 7740 agaattcaag tcacttgtcc aaggatatca ccttgcaaga tgcagatcaa ataattctaa 7800 tccttactgt acaccagaca ctgttttaag ttttttcttc tttttttttt ttagtctttt 7860 ttgtcaattt ttttctgtca ttttttatct taaaatagca tctatcttaa ttaagggctt 7920 tgtatgtgtt aactctgagt ccttatgaca gcactgagat tgtctccatt caacagatgg 7980 gggccaggct cagtggccca agcctgtaat cccagcactt tgggaggccg aggcaggggg 8040 atcacctaag gtcaggagtt caagaccagc ctggccaaca tgatgaaacc ctgtctctac 8100 taaaatacaa aaattagcca ggcgtgtgat ggcgggcacc tgtaatccca gctacttggg 8160 aggctgaggc aggagaatcg cttgaatgtg ggaggcggag gttgcagtga gccgagattg 8220 caccactgca ctccagcctg ggtgacagag caagactcgg tctcaaaaaa aaaaaaacaa 8280 aaacaacaga tggggaagct gaggcataga gaggtgagag attctttgct tagggttggc 8340 cacgtcaagt cagagccagg attctaactc agttctggct gagtttcaaa cccatcgttt 8400 aaaccctcca gtgtgtagat ctgttcctaa cttgtctccc tcccaggcct ccctatctcc 8460 agtttttttc tcatccttcc agaatctgcc tccatggccc agctttgtct gctcaggtgc 8520 cctctctgag agcagtcagg ggctcagtgc tgcgtttgga gcctccggtc tccaggcgcc 8580 ttcccagaat cgacttcctt ccctcctcct gaccccctct gctgtaacta ggcctgagta 8640 cacactgttc cttgaacact cttctgttgt cctgcctcca cgcattgctc aagccgttcc 8700 cactgcccag catacccgtg cttccttctc ccttaatttt gaaatcctct ctgaccgtaa 8760 aggctcagct tcctttctcc ctttcctcct tccttccttc tcaccatcct gtcctttttt 8820 taaaattgtg ttctctttct ttttcttttt ttggtaggga tggggtcttg ctatcttgcc 8880 caggctggtc ttgaactcct gggctcaagt gatcctcctg cctcagcctc ccaaagtgct 8940 gggattacag gtgtgctatc ctattcttct aatgagacaa aaatcactcc ctaagcccct 9000 accatgtatt tggtcctatg ttagctttgc tggggaaaca gcagtgacca agacactcat 9060 ggagctccca ggcccatgaa agagacagac caatcagccg acagtcacag ttcagagtgg 9120 tcaggaggat gtgtgagccc agaaggaggt cactggccag acacagggta tcagagaggg 9180 cttcctggag gaaggggcat ataagctgag accattgtga aaaaaatccg agaaagccca 9240 gataaaccat tggatctaac tttttttttt tttttggagg gcgtgcagtg cggagtttca 9300 ctctgttgcc taggctgaag tgcagtggcg agatctcagt tcactgcaac ctcagcctcc 9360 cgggttcaag tgattctcct gcctcggcct cccaagtagc tgggactaca agcgcacgcc 9420 accacgcccg gctaattttt ttttttagta gagagtgggt ttcactatgt tggccaggct 9480 ggttctgagc tcctgacctc aggtgatcca cccacctcag cctcccaaag tgctgggatt 9540 acaagcatga gccactgtgc ccggcccgga tctaacataa aacagagaga gaagatatta 9600 tgtttatgat taaggggcca ggtgtggtgg cttatgccta taatcccagc actttgggag 9660 gctgaggtgg gaggattgcc tgagcccaga aatttgagac caccctgggc aacacagtga 9720 gacctcatct ctactaaaag gaaaaaagaa ctagctagat gtggtggtat atgcctgttt 9780 tccagctatt cgggaggcta aagcaggagg attgcttgag cctgggaggc agaggttgca 9840 gtgagccaag atcacacctc tgcactccag cctgggcaac agagtgagat cctgtctcaa 9900 aaaaaaaaaa aattactatt aaaaaaatcc caactaacat tcttcagtcc aagcatcaaa 9960 gaatgtttct ggagcgtctg tcgtgtgcca ggccatgtgc tggggacata atcataacca 10020 tgacaacccc agtctctgcc atcatgagct tgtagtccag caagtgtgta ggggataagc 10080 cccaaggcac tgggatccaa ccagagctag aaccccagcg ctgtgtgggg tgatgttagg 10140 taagtggctt cacctctcag accctctgtt tcctcctttg taacaccgag acgataatct 10200 ccctggggtt gtgtttttag aaattaagta ggttgtggca cactgagtct ttgtcattgt 10260 gtctggaatg ttccaggtac ttagtaaaca ggaaccttta ttaatcatct cttccccagg 10320 gccggcagct ggattgggga gggactagcc cttcccgaac cctgactccc tcttaacctt 10380 cccactgtca aagagatgtc tgtgaggtag ctgggctctg agggggcggg agagatgaac 10440 acgtccctga tcctggggta ggagagggat gagccataca gtttccttct ctggaggtga 10500 cccactcttc cagtacttgc taagggactt gacatgcttg tggggtgcag aatgtattcc 10560 tgtgtgtgta tgtgttcatg aatcagacac taaccctgtc tcaaaaagct catagtttag 10620 tcggcatgat acaacgaaaa ccctgttttc tatttgcttc tctggttttc tttctttctt 10680 tcttattttt ttgagtcagg gtctcactgg gtcacccagt ctggagtgca gtggcacaat 10740 cactgctcac tgcagcctca ccctccaggg ctcaagtgat cctcccacct tagcctcctg 10800 agtagctggg actacaggtg cacaccacca cgcctagctg attcttaatt ttttatttat 10860 ttatttattt attttttgag atggagtctc gctttctcgc ccaggctgga gtgcagtggc 10920 acaatctcgg ctcactgcaa cctctgcctc tcaggttcac accattctcc tgcctcagcc 10980 tcccgagtag ctgggactgc aggtgcccgc caccatgccc agctaatttt ttgtattttt 11040 agtagagacg gggtttcact gtgttagcca ggatggtctc aatctcctga cctcatgatc 11100 cgcctgcctc agcctcccaa agtgctggga ttacaggcat gagccactgc gcccggccta 11160 atttttaaac attttgtaga gatggggtct tgctatattg cccaggctgg cctcaatctc 11220 ctgggctcag tggtcctccc accttggttt cccagtgttg agattacagg cgtaagccat 11280 cgtacccgct gcttttgtgg tttcctttgt tctctctctc tttgtctact tctgttcatc 11340 tttttctttt catcattact ttgtatctct ctcttttagt cttcctatat ttgttttgtt 11400 ttttttttgt ttttgagaca gtcttgctct gtcgcccagg ctggagtgca gtggcgtgtt 11460 cttggctcac cgcaacctct gcctctcggg ttcaaacgac tctcatgcct cagcctcctg 11520 agtagctggg actacaggtg tgtatcacca cgcccggcta atttttgtat ttttagtaga 11580 ggtggggttt caccatgttg gccaggctgg tctcaaactc ctgacctcag gtgatctgcc 11640 cacctcaccc tcccgaaatg ctgggattac aggtgagagc caccacaccc ggcctatttc 11700 tttatctttt agcaattcta tacctgtctc tgtattagtc agggtaggtc aggattttct 11760 gcagtaacaa agagccccca aatcttagtg acttagaaca acaaaggatt attttgcttt 11820 atactacaca ttggtcacag gtcagtggtg ggtcaagggc tctgcttcat gctgtcttca 11880 ctcagggtcc caggctgagg gagcttccat ttcttttctt actccctccc ccactgggga 11940 acaaacgtgg cgagtcataa actggctctt aaggctccta cccgaaagtg acacttctgc 12000 tcccagttaa ttggccaaag caaggccagg tgtggtggct cacacctata atcccagcac 12060 tttggagacc aagatgggag gattgcatga ggccaggagt tcaagaccag cctgggcaac 12120 atagcaagat gccataaagt agctgggcat ggtggcacac gcctgtagtc ctgactactc 12180 aggaggctgg gatgggagca tcgcttgagt ccaggagttg gaggttgcag tgagctatga 12240 tggtgccatt gtactgcagt ctggctgacg gagtgagacc cggtctctaa aacaaaacaa 12300 aacaaacaaa aaacaacaat ccccagttca ggagggcagg gacatccctg aactaatagc 12360 tggagctatg tggtgaacag ctgtcatgac tgccacggtc tctgtcgctg tctctgtctc 12420 tctgtcatca ctatgtcatc tgcctctctg tttctgtctc tctctgtggt ccatctccat 12480 ccatcaactc ctgcctctat aattttcccc aaaaggtctg acctggttta gggacagaga 12540 tggggcttcc aatatttgac actggtccct acataatggc ttatgcctga aaccccaaca 12600 ctttgggaga ctgaggcagg tggactgctt gaggtcagga gctcaagacc agcttgggca 12660 acatggtgaa accccatctc tactaaaaat acaaaaatta gccagacatg gtggcatgca 12720 cctgtagtcc cagctactcg gagggtgagg caggaggatc acttgaacct cggaggcaga 12780 ggttgcagtg agccaagatc ataccactgc actctggact aggtgacaga gaccctgtct 12840 caattaaaaa aaaaaaaaaa agaagatttg gaactgtgta tgtgcagtgg aagatgtaag 12900 ggttgtttgt taaaccacaa caaaacctag cctgtcctta ctcataagat ccttactcat 12960 aagagaagga cagagagaca tagatacaaa gaaagtgatg acagagggga gaaatgggca 13020 aagaatttcc cctatcttgc tgagggcttt gggcgatcat gtgattgccg aactaagtgg 13080 ggctcactca ccccaacaag cctgggaaca gtgatcccag gaagcccctg gccctggaaa 13140 gactgcaggt cccctttcgt tccctctcat ggcagcacct ctagcccctg ccttccctgg 13200 ccttggccct gaccccaccc tgctctgctc cctacagagc aaaccctgga agaagctgaa 13260 gacagttctg aagtattcac cctttgtggt ctccttccga aaacactacc cttgggtcca 13320 gctttctgga catgctggta agtggggtgg tggtggacag agctgggcag agtctcctgg 13380 gccagggaaa gggatgttct ctgtagttta gttcccccac ctagtgatgg gcttggtgac 13440 agtccccacc ttatgggact gttatgggca gtgcttaggc ctgggcctgg cccttcgtat 13500 gtcagggcag agggctattc cttgttattc tggtggagag agggagcttc agacggacct 13560 gagctcaaac cctagttctg ctctgtattc atgggtgacc ttgggcaagt tactttcctt 13620 tactgggcct cagctgcccc atctgttaat gtggagataa ccttacctcc cttgcaggat 13680 taaccgaaga gttaaaatca aaatgtatat aaagattgag gccaggcacg gtggcttaca 13740 tctgtaatcc tagcactttg gcaggccaaa acaggaggat cgcttgagcc caggagttta 13800 agaccaacct aggcaatata gtgagacccc gtttcaatta aaaaaaaaaa aagattggct 13860 gggcgcagtg gctcatgcct gtaatcccag gcctttggga ggccgaggtg ggtggatccc 13920 ctgaggtcag gagtttaaga ccagcctggc caatgtggtg aaatcccttc tctactaaaa 13980 ataaaaaaat tagccaggca tggtggcggg tgcctgtaat cccagctact caggaggctg 14040 aggcaggaga atcacttgaa cccgggaggt gaaggttgca gtgagccaag atcgcagcat 14100 tgcactgcag cctgagtgac aagagcgaaa cttcgtctca aaaaaaaaaa agactgaggc 14160 acaggactct tatgaatgga aatgatcact ccttgccttc tccgcgtgtt cagagcatag 14220 caggccttca gtaagtagca gctgtaacat tttgccccca ggaccttgca aatgcctgca 14280 gcacagagta gcacaatggt ggcatatagt gctcttttga aaggctaggc cataaatatc 14340 ttaggttttg tgggcctatg gtctctgtcg caactactca gctctgctgt tacagcagga 14400 aagctgccat agacactatg taaacatatg agtgtgtctg tattccaata aaactttatt 14460 tgcaaaaacc agcagcaggc tggactagaa aagtgtgccc attggcaaat ggcgacagta 14520 agagaatttg tctgccttgt ttgtctttag atctgacctg gaaataaggc aagaccccct 14580 aaaactgtgt caacacaagt ttgccatcta tatgtgttct ggttactatt gctgagttta 14640 ttaaaaaaac aaaactcagc agagcacagc ggctcatggc tgtagttcta gcactttggg 14700 aggctgaggt gggaggatca cttgagccca ggagtttgag accagcctgg gtgacatagt 14760 gagaccttgt ctctacgaaa aataaagaaa ttaactgggc atggtggcat gcacctgtgg 14820 tcccaggtac ttgggagctg agggtgggaa gatcacttga gtccaggagg tctgggatgc 14880 agtgagcctt gatcgcacca cagtactcta gcctagatga ccgagtgaga ccctgtctca 14940 aaaataaata cgccaggggc ggtggctcac gcctgtaatc ccagcacttt gggaggccaa 15000 ggcaggcgga tcacgaggtc aggagatcga gaccatcctg gctaacaaag tgaaaccccg 15060 tctctactaa aaatacaaaa aattagccgg gcatggtggc gggcgcctgt aatcccagct 15120 actcgggagg ctgaggcagg agaatggcgt gaacccggga ggcggaggtt gcagtgagcc 15180 gagatagcac cactgcactc cagcctgggt gacagagcga gactctgtct caaaaataaa 15240 taaataaata aaataaaata aaataaatac aaaacaaaac ccaaaaaccc caagacttag 15300 tgatggttaa aaaaaataac ttagtagaat aaaacaatca ttttattgac ctcagaagtt 15360 ttgggtcagc aattcagaca ggatggcagg gatggctttt cactgctcca caatatctgg 15420 gaactcagct agggacacct ggaggctaca agctgaaaac ttttggaggt tcattcactt 15 480 gcatgcgtgg tgattgatgc tggctattgg ctggggtctc agatggggct gccacgtggc 15540 tttgccatgt agctccttga gcttcctcac agtatggtgg cctcagagta ctcagatttc 15600 taacaagaca gctcaggact accttgaagg taagtgtctc tgccaacaga agtcatgcag 15660 tagcacttct gccataaacc gtcccatatt taatgggaga gcaatctatt ttttatttat 15720 tcatttaatt ttgagatagg atctcagtgt tgcccaggcg ggagtgcagt ggtgcagtca 15780 tagctcattg cagccttgaa ctcctggcct taaaggatcc tcctgcctca acctcccaga 15840 gtgttgggat tataggcatg agccactgca cccagcttgg gagagcaatt aagagtatac 15900 tccttgatgg gaaaattcta taagagcagg atcaggaatg ggtctgagac ccactgtgat 15960 caggagatac tgttgtagcc aactttggaa aatgtaatcc aggctggaca taatcacagc 16020 actttgggag gctgagatgg gaggatcatt tgaggccagg agttcgagac cagcctgggc 16080 atcatagcaa cactacccca acccgacatt acacattttt tttttttaga ttagctggga 16140 gtggtggggg tgcacacctg tagtcctagc tactctggtg gttgaggtgg gaggatcacc 16200 tgaatctagg agcttgaggc tgcagtgagc tatgattata ccactcaatt tcagcctggg 16260 tgacagagtg agatcctctc aaataaaaaa agaaaaagaa aatataatct gaaaatacag 16320 ctggccacta gaagaaatta gaattattat aatctataca ctctgcgtgg tccaggaaat 16380 gcttgatcta taaattaact taaataggcc ctggttgtta gcaccttggg attccaggca 16440 gcagcaaaag caaatccact ctggagagtg acgctctgga cttagatctc acagaattcc 16500 cacagatgat cacatgtgta caatcaaaaa ttacaaaaca aattaggata tcctgtgctg 16560 ggaacaggac ttggtttaag caacagagaa cagaaattcg ccctttcctt accaacccct 16620 gggcaagact tttaagagtt gcggcctggg cacagtggct cacgcttgta atcccagcac 16680 tttgggaggc caaggcgggt ggatcatctg aggtcaggag ttcaagacca gcctgaccaa 16740 caaggtgaaa ccctgtctct actaaaaata caaaaattag ctgggcttgg tggtgtgcac 16800 ctgtaatccc agctacttga gaggctgaag caggagaatt gcttgaaccc gggaggcgga 16860 ggttgcagtg agccgagatc gcaccattgc actccagcct gggcaacaga gtgggactcc 16920 atctcaaaaa aataaaataa aatcttaaaa tcattaaaaa aaaagttgca gggagagaaa 16980 gcattgcagg agggtcgggc aagataatgg tggccaggat ctgatgcaaa caggcagctg 17040 cggagaggtt ctcttcctga tccagttcct gatcctctca tttattctac cacctttagg 17100 gaacttccag gcaggagagg atggtcggat tctgaaacgt ttctgtcagt gtgagcagcg 17160 cagcctggag cagctgatga aagacccgct gcgacctttc gtgcctgcct actatggcat 17220 ggtgctgcag gatggccaga ccttcaacca gatggaagac ctcctggctg actttgaggg 17280 cccctccatt atggactgca agatgggcag caggtggggc tggggcagcc ctggggcagg 17340 gatggagggc agggggtggg cattattgaa aatattggcc tggccaggcg cggtggctca 17400 cgcctgtaat cccagcactt tgggaggccg aggctggtgg atcacctgag gttgggagtt 17460 ccaaaccagc ctgaccaacg tggtgaagcc ctgtctctac taaaaataca aaaaattagc 17520 caggcgtggt ggtgcatgcc tgtaatccca gctactcagg aggctgaggc aggagaattg 17580 cctgaacctg ggaggtggag gttgcggtga gctgagattg agccattgca ctccagcctg 17640 ggcaacaaga gtggaaccct gtctcaaaaa aaagaaaaga aaagaaaaga aaatagcgcc 17700 aagtccattt tcaaagtggt tgtaccagtg taccttccca ccaccatgta tgagtgttac 17760 agtcgtccca gattctcacc ggtgcttggt actgtctgtt ttattaactt aaaccattcc 17820 gatgggtttg gaataggatc cctttttttc ctctttgaga cagagtctta ctctatcgcc 17880 caggctggag tgcagtggca cgatctcggc tcactgcaat ctccacctcc tgggtttaag 17940 tgattctcct gtgtaaacca agtagctagg attacaagcg cccgccacca cacctggcta 18000 atttttgtat tattagtaga gatggggttt caccatgttg gccaggctgg tctggaactc 18060 ctgacctcag atgatccacc cactacggcc tcccagaatg ctgggattat aggcgtgagc 18120 caccacgcct agtctgcaag aagtgaactc taattgcttt ctccagctgg gttcagtggc 18180 tctcacctat aatcccaaca ctctgggagg ctgtatacac acacacacac agacacacac 18240 acacagacac acacatagtc ttcaactctc ccatttcatt cttttagtag tcttttgata 18300 aacatatttt tataaacaaa atagtatttg tattattact cttttttgag acagagtctc 18360 attctgttgc cccgactgaa gtgaaggagc atgattatag ctcacagtag ccttgaactc 18420 ctgggctcag gcggtccttt caccttagcc tccagagtag ctgggactat aggtatgtcc 18 480 caccaggctt ggctatattt tattttttat agagacatgg tctccctgta ctgcccaggc 18540 tggtcttgaa cccctgagct caagtgatcc tccttcttct gccccctgag tagctgggac 18600 tgtaggtgca tactatcaca cctagctaat tttcaatttt ttgtagagac aggctattta 18660 ggaaaagctc tgaatccatg cttttccgtt ctcacaccac tgccacaaca atgagagcac 18720 agaagacttc tgtgaccaaa tgtttaggtt ttttaacccc acacaccaag caacggacac 18780 cagctggatg tcctccaatt caagtctaaa accatctacc tggaaatagt gtcagatccc 18840 acaggttggg gactcagtcc ccaagactgc cccccagtta cagacaccag tcataagttc 18900 aggccttcga aacttctgac tgattggctc caagttggag ttcccatgtc ctcctctttg 18960 ggttcaaata atttgctgga gtggctcaaa taactcaggg ggatacttac ttacctttac 19020 tggtttaata taaagcaggg gtccccaacc cctgggccgc agaccagtac cggtccatgg 19080 cctcttagga acggggcccc accgtaggag gccagcgagc attaccgctt gaactccacc 19140 tcctgtcaga ctagcgggca ggagattctc tggagggcga accctattgt gaactgtgcc 19200 tgcaagggat ctagattgta tgctcctatg agaatctaat tgatacttga tgacctgagg 19260 tagaagagtt tcatccagaa accatccccc tcacagtctg tgggaaaaat tatcttctac 19320 aaaaccagtc cctggttggg tactgctaca aaggatactg caaaagatga agagaagtgt 19380 agggcaaggt atgggggaag gggtacggag cttccatgcc ctccctgggc gcaccacgct 19440 ccaggaacct ccacagggtc agctatctgg aagctcctga gcccaatcct tggttttttt 19500 tttttttttt ttttttttga gagggagtct tgctctgtgt cccaggctgg aatgcagtgg 19560 cctgatccgc ccgccttggc ctcccaaagt gctgggatta gagatgtgag ccaccatgcc 19620 cagcctaatc cttgggtttt tatggaggct ttaagacacc agcattcctt cccccagagt 19680 atagggtggg atcctctctg gggagggtcc taagacccac agtcaggaag gtggggaaag 19740 attagagtcc tgccttgggg caggtgaaag gagggcagga ggaggtcaga gattttggtt 19800 tcttgagcca gcttctgaga tctaacacac ctaaaattat aacaaaagat tgtggctggg 19860 cgcagtggct catgcctgta atcccagcac tttgggaggc caaggcaggc agatcacttg 19920 aggccagttc aagacaagcc tgggcaacat ggtgaaactc tgactctact aaaaaaatac 19980 aaaaatgtgc caggtgtggt ggtatactct tgtaattcca gctactcagg aggctgaggt 20040 gggaggatca cttgaacccg ggaggtccta gaagttgcag tgagccaaga tcacgccact 20100 gtactccagc cttggtgaca gagcaagact ccatctcaaa aaaaaaaaaa aaaaaaggct 2016 0 gggcgtagtg gctcacactt gtaaatggga ggcagaggca ggccgatcac gaggtcagga 20220 gttcgagacc agcctggcca acatcgtgaa accccatctc tactaaaaat acaaaaaatt 20280 atccgggtgt ggtggcgggc acctgtaatc ccagctactc aggaggctga ggcaggagaa 20340 tcgcttgaat ccgcgaggca gaggttgcag tgacccgaga tcaccaccat tccattgcac 20400 tctagctcgg gcgggcgtca aaaaaaaaaa aaaaaaaaaa aaaaagattg taacaagggc 20460 tatgagagtt accagccagg aaccatagag ggaaaccaat atacattgta actaacaccg 20520 ggtctcgcta tgttgccgag gctgatcttg actttctggg ctcaagtgaa cctcctgcct 20580 tggcctccca aagtgttggg gttacagatg tgaacactgc acctggccct acctttaatt 20640 tagtccagtt tgtcagtttt tttcattgtg tttaagaaat cttttcctac tccaagatca 20700 tgcaaatatt atgttttctt ctacaagctt tattgtttta gctttcatat ttagacctac 20760 attccagata gaattaatgt ttctgtgtgt gggaggtagg gatcaggttc atttttttcc 20820 atatggattg ttgacccagc actgtttatt gaaaagactt ccctttcccc actgaattgc 20880 agtgcctagt cataactgca caactctacg tgtgtgtctt tgtggactct gttgtattct 20940 gtgcattgat ttgcccattc ttgtgccaca ctgtggcttt atgtcttaat atcaggaagg 21000 gtaagccctc cagtttgttc tacataattt cctttgtcac atcctctgtg tgctcaggac 21060 ctatctggaa gaggagctag tgaaggcacg ggaacgtccc cgtccccgga aggacatgta 21120 tgagaagatg gtggctgtgg accctggggc ccctacccct gaggagcatg cccagggtgc 21180 agtcaccaag ccccgctaca tgcagtggag ggaaaccatg agctccacct ctaccctggg 21240 cttccggatc gagggcatca aggtgaggac caggaaccgc ctggcctgtc ccgggaaggc 21300 ctatagccag atcccaggca gggcttcttg gggaaagcca cgagagagtg caggagacgg 21360 cgtgggatga aaggctgggg ctggggaagc ccagcctctt tcttacctcc atacccatca 21420 gagcccaggt tctgtttatc cgtctgcctg agcatctcct gagtccatct tttcctcctc 21480 tccttctcca tggtcatgtc ctagtccagc cccatcttct cctgcctctg tctccctggg 21540 catcctggcc ctggtctccc tgcagcacaa gagctggagg gatccctttc ccccagctat 21600 ggagaaggtt tctctttttc tttcttgcat tcctttttct ttgtcaaatt aaatataatt 21660 gtatgaatag gccaggcatg gtggctcatg cctgtaatcc cagcactttg ggaggccaag 21720 gcaggaggat tgcttgaggc caggagtagt tcaggactaa gctggccaac atagggagct 21780 tctgtttcta gaagaaaaaa aaattgtttg aatagctagt cacacagttc aaaagtcaaa 21840 ataatattat aaaagggtaa atgtggagaa atttctctcc caactctgct gctgtccttc 21900 ccattctgtc cctctatccc tctacctgct catggggaac cactttgtca gtttcttgta 21960 tttcttcctg ttagtgccag taaatggagt tgtagatccg aaatgttcct cagtacgcat 22020 actgattggt actttgctat tttcacttaa tagtaacacc ctgcagagtt ttccacatca 22080 ttccatagaa agcttcctct ttctgttttt ttttccccca cagctatgta acactgtttt 22140 tgtgactgtg cctggtcccc tatagacaga cacctgggtt gtttccattt tttgccatta 22200 gcaggcctca aagaatcact ttgtatataa gacattttgc aagtatgcag attgagctgt 22260 agatttccag aagcaggact cctgggtcaa agcttaaagg catgggaaat ttgcgagaga 22320 tgaccaaact tccactctcg gtgttatgcc actgcacatc ccaccagcaa tgtatgagaa 22380 tgcctgttgc agatccgacc atgccattct cctgttcgaa acccttctgt ggctccctag 22440 taccttgaag tgaagttcca tagcctgtag ggccctctag gatctagcct cttctctctc 22500 attcttctct tttctttttt ttttgagaaa gagtctcgct ctgtcaccca ggctagagtg 22560 ccatggcaca gtctcaacta attgcaacct ccacctcttg ggttcaagcg attctcccac 22620 ctcagcttcc tgacttgacg tgattactgg cacgcactac catgcctggc taattgttgt 22680 tttttttttt ttttttgaga cagagtctcg ctctgttgcc caggctagag tgcagtagta 22740 cagtcttagc tcactgcaaa cctctgcctc ccgggttcaa gcgattcttc tgcctcagcc 22800 tcccaagtag ctgggattac aggtgtgcac caccgctcct ggctaatttt tgtattttta 22860 gtagagacag ggtttcacca tattgaccag gctggtcctg aactcctgac cttgtgatcc 22920 acccgccttg gcctcacaaa gtgctgggat gattacaggc gtgagccact gtgcccggcc 22980 taatgtttgt atttttaaga gaggcggggt ttcactatgt tgaccaggct gatcttgaac 23040 tcctggcctc aagtgatctg cctgacttag cctcccaaag tgcagggatt ataggcgtga 23100 gccaccacgc ccaacctctc attcctctca ttctttctgt gtaccttcag gcacagtgaa 23160 gcacttgcat ttacttgaaa taggcttgct ttttcctgcc acaaggcctc tgcacccctc 23220 tgccaggaat gctcttctat tttttttttt tttgagacag ggtctcactc tgtcatcccc 23280 caggctggag tacagtggcg cgatcacagc tcactgcagc ctcaatctcc taaactcaag 23340 tgatcccccc acctcagtct tttgagtagc tgggacacag gtgcgtgcca ccacaccctg 23400 gtctcttccg tctgtgcccc ctggtctggt tgattctcag tcatttttct gtctcctttc 23460 aaattttgct tcctcaggga agccctccct gatttctgtt ctactgatca gggtcccctc 23520 ttcacctcct catagctcct tatactcttt cattattctt atcttccttt ctgatcatct 23580 taatcagtgt ctgccccctc atctgactgt gtctgtcgtg ttactcccta ttgccaagtg 23640 cccacatagc acctggcaca gtgtggcaga tgacttaggt gggttctctg agccctactg 23700 aaacataaca gataacatta gtctcattag tctcaaataa ctatatgcca ggcactgtgc 23760 tgtgcatcct acacacctgg tttcctctaa tccttacacc agccttagca agtagacacc 23820 aacacaattc ccgttttcca gatgaggaaa ctgaggctga ggcagctgaa atgacttaag 23880 actgcccagc tagaaaagag cagagatggc caggtgcagt ggctcacgcc agtaatccta 23940 gcactttggg aggccaaggc gggcggagca tgaggtcagg agatcgagac catcctggct 24000 aacatggtga aaccccgttg ctactaaaaa tacaaaaaat tagccaggcg tggtggcggg 24060 agcctgtagt cccagctatc aggaggctga ggcaggagaa tggcatgaac ccagggggcg 24120 gagcttgcag tgagcccagg ttgcaccact gcactccagc ctgggtgaca gagtgagact 24180 ctgtcaaaaa aaaaaagaaa agagcagagt cacgattcac agccagctcc accctgctcc 24240 aaagcccact ttcctagatg ggttcaacca ggaggttcaa ggttggaagg gtgtggaagg 24300 actggggctc aggcatgtga cctggggctg ggttgagctg ggctgggcag gtaagctggc 24360 ttcctcctct ggcagcaagt gtgcaggcag gtgggtggcc ctgggaagtt gttttttttg 24420 agacagagtc ttgttctgtc acccaggctc gaatgtagtg gtgcaatcaa tgctcactgc 24480 aacctctgcc tcccgggttt aagcgatttt cctgcctcag cctcccgagt agctgggatt 24540 acaggcgccc gccaccacac ttggctaatt ttttgtattt ttagtagaaa cggggtttca 24600 ccgtgttggc caggctggtt gtgaactcct gacctcaagt gatcctcccg cctcggcctc 24660 ccaaagcact gggattatag gcatgatccc acacctggga ccacaggtgc atactaccac 24720 accagaattt tttttttttt taaatagaga tggggtcttg ctgtgttgcc caggctggtc 24780 ttggccaccg cgcccggcct cctgggaggt atttgaggtt gctgggtatt gggtgcggga 24840 aggaaaagcc catgaccctg cccctccaca ccctgcccta cagaaggcag atgggacctg 24900 taacaccaac ttcaagaaga cgcaggcact ggagcaggtg acaaaagtgc tggaggactt 24960 cgtggatgga gaccacgtca tcctggtgag tgggacaccc atgtcccaga atgtagcagc 25020 ttaagacagc caccatttat tcttgctcca gagtcagtgg tcttctgctt tgggtggggc 25080 tggactgata ctggctggct ttgctcagtc tgaggtcagc tggtggcttg gcaaggctgg 25140 ctggtccagg gggccctgct cccagctctg ccggttggct catgacttgg ccgcacgtct 25200 ctcgatagca ggatggcctg ggcttgctct cacagtggag gcagggggcc aagagaacaa 25260 gtaaaaatgc aaggcctctt gatgcctggg ctcagaatgg ccaccatcat ttctgccgtt 25320 cggcaagtca tgtgacccag cctggatcga ggggtctgga gacagactcc gcctccggat 25380 gggagtggaa attcatggaa tccaccactc ttctccatgc caccttgatg aatccaagcc 25440 ctcactcctc tgccctgtct tccccatggc tcccctattc catcctggct agagcctgcc 25500 tgctcctttg ggggaatggg gtgaggtcag agctcaaggt gggcaaggcc ccacaaagtc 25560 cccatgctaa ccaaagaacg ctccctgtca cacagcaaaa gtacgtggca tgcctagaag 25620 aacttcgtga agctctggag atctccccct tcttcaagac ccacgaggtg cgagccctgg 25680 cttccatggg tggatgtatg ggtgtcgggg tccaggtgca tggaggggaa accattgatg 25740 agttacaggt caaagatata aaaaggggct gggcgttgtg gcccgcacct gtaataccag 25800 cactttggga ggctgaggtg ggaggattgc tggagcccag gagtgccaag accagcctgg 25860 gaagcacagc aagaccccgt ctctatttgg aaaaaaaaaa aaaaaaaaag gccgggtgca 25920 gtggctcatg cctgtaatcc cagcactttg ggaggctgag gcgggcggat cacttgaggt 25980 cgggagtttg aggccagcct ggccaacatg gcgaaacccc gtctctatta aaaatacaaa 26040 aattggctgg gtgcggtggc tcatgcctgt aatcccagca ctttgggagg ccgaggtgag 26100 cagatcacga ggtcaggaga tcgagaccat cctggctaac acagtgaaac cccgtctcta 26160 ctaaaaaata caaaaaatta gccgggcgtg gtggcgggcg cctgtagtcc cagctacttg 26220 ggaggctgag gcaggagaat ggcatgaacc cgggaggtgg agcttgcagt gagccgagat 26280 tgtgccgctg cactccagcc tgggcaacag agtgagactc tgtctcaaca acaacaacaa 26340 caacaacaaa attagccaga aattgcttga acccagtagg cagaggttgc agtgagctga 26400 gattgtgtca ctgcactcca gcctgggcaa cagagtgaga ctctgtctca aaaaaaaagc 26460 aaagctaggc atggtggtgc acacctgtag tctcagctac tcaggaggct gaggcaggaa 26520 gagggcttga gtccaggagg tcaaggctgc agtgcatttt gattatgcct cacactgaac 26580 atttgctgtg tatttgctat gtaccaagca ctgtcttaag cacttaatgt agattaattc 26640 ctacatataa tatgcccagc agcctctgag gtaaatgatc ctacagtcga ccccttatcc 26700 tcaggtgatc tcctccaaac ccccagtgga tgccggaaac tgtggatagt actgaactat 26760 agactgtgtt ttctcgatct gataaccaag atggctccta ggtgactagt gggtgggttg 26820 cggatacagc atagacttgc tgaacaaagg gatgattcgc atcccaggtg ggacgaagcg 26880 ggatggcacg agatttcatc acagtagtta aaccaatgtg caacttaaaa cttacacatt 26940 gtttgtttct ggaattttcc acttaatatt tttggatcgc acttgactga gagtaactaa 27000 aaccaaagaa aatgaaacca cggactgggg agactaactg tattactctc actttgtata 27060 tgaggacgca gaaccacaga gaggttaaga cacctgccta aggctgcaca gacaggaggt 27120 ggcacagcca ggatatgaat caggcagcca ggctccaggg ttcatgctgt caatcaccct 27180 gctctgctgc ctgtcaggaa gggaccttgg ccagtgcctg ctcctccctt aacctcccgt 27240 ctctaccccg gcaggtggta ggcagctccc tcctcttcgt gcacgaccac accggcctgg 27300 ccaaggtctg gatgatagac ttcggcaaga cggtggcctt gcccgaccac cagacgctca 27360 gccacaggct gccctgggct gagggcaacc gtgaggacgg ctacctctgg ggcctggaca 27420 acatgatctg cctcctgcag gggctggcac agagctgagc tgctcagcca ccatcaggtt 27480 aattggatgg cgccagtctg gctggaggag ccctgagatg ccatgggagg cctgaggttg 27540 gccacggggg agctggcctc cagggacggg agagattgtg tcatgtgcca cacgagacca 27600 acgtggaaaa gtctgaaggg ccttgggaga ccaggtagca cctggcccca tcatgatgca 27660 ggggttttgg ggacctggaa ggaaggtgat gaggcagtga gtcagaaaaa ccagaacggg 27720 gtccccggat ctgccgggaa ggcttctgag gggctgccct gagagcattc agttcacatg 27780 tcacagggta tggtgtgaca gggtgcctgt ggacacatga atcacttcta acctgcctcc 27840 ctgtcagcct ccaggctgcc agctggctga ggccagggac tgggtcaggc tcatctgtgg 27900 cgcctcagag ggtcagcatc attggtgaac agatgcaggc gctgctggac catctgggga 27960 gagtgacagt ccatgtcttc accagggagc catttgagtg ctgagcgaca agaggctcag 28020 agggcatgac cccatgggac tggatgcggc ctgagggctg ataccgctgg gcggtatcct 28080 gccctgctgt ggccctgtgg gatcctccgt gttcctcggc ggactctgct gacctcctgc 28140 agacccaaac cacagccaca tcccagcttc tgtgccagca ctgtgacagt acctcgctcc 28200 tctgtgcacc agatccggcc tcaggactta cacctcctgc ctgaccccca ggcttctctc 28260 tcctttctcc cagcaaactg cagtggcaga aaggaggttc agaggctggg aaagtgggcc 28320 tccccttgca actcagagct gctgcactca ggagggcccc atccaatccc gggcccctgc 28380 agggaaaagc gctgggtgtg tgtcagaggc gcagggtggg tggggctgcc agccaggacc 28440 ctggcctgca gcctgatcca aaccaaagac tgtagaaccc tggggtgtgg ctaacggccc 28500 ctccagcacc catagccagg tcttcctggc ccttgaggct gggctggcgg acaggcacct 28560 acctcttcct taagctgaag ctcccacact gtcttccagg gctgaggaga tgctctcctt 28620 ttctactgac catcttgata cttatttata cgagaggcag ttgctggacg gggtagtact 28680 gggaagcagg aggcagaatg gctctgctga gcctcctacc catgacaaca ccccaataaa 28740 cagaacattc agagccaatg tcgtagagct ttttattttg catctggagt gtatttggac 28800 acgtgggctg ggtggggtaa caggataatg agcagtttgg gaaagaggca ggctccaagc 28860 aggctggttc actcacttgg cagtcactgg gcggctattc ttgtgcctgg atgtgttaca 28920 atgcagggga cacagtggtg agcaaggctg ctccaagccc tggctgggat gggggatgca 28980 cagacaggct gatcagggct gggatggtgg acacgcatcc tctttaccct gatcactggt 29040 tagaaatact gcactgtggc cgggctcagt ggctcacacc tgtaatccca gcactttggg 29100 aggccgaggc gggtggatta ctcaaggtca ggagttcgag accagcctgg ccaacatggc 29160 aaagccccgt ctctactaaa aatacaaaaa attagccagg catggtggtg catgcctgta 29220 atcccagtta cttggggggc tgaggcagga gaatcacttg aacctgggaa gtggaggctg 29280 gagtgagctg agatcacgcc accgcactcc agcctggacg acagaacgag actccatcta 29340 aaaaaaaaaa aagcaacagt gctctgtagt ttccctaaat gagatgggct cagttaggga 29400 cagagaagtg atccagacag gcctgttcct ccttcagagt ggaggggtca ggtattcatg 29460 aagctagtaa tcacacacac tcactagaag tttgtataag tggacaggaa agtttgtggt 29520 cagcaccata atgttcaggg agccaggaga cagcctggct gagatactga ctacctagct 29580 tgaatcctga ccttgccatg tgctagtcat gtgacctcag gccagtgatt ccacttctcc 29640 aggcctcagt cttgccatct gtcaaatcgg gtccatctag cacccccctt acagggttgc 29700 cagatctgct aacacaggta gaggggctgg cacaggtaac tgctcccaga tgggctttaa 29760 aactgtgaag acatgaggtg ggggaggggt gtcttgactg gggctgcagg actcttccct 29820 gaggtagtga tacctgagcc ccaatggaaa agttaaggag tgatccgcag cagagggctg 29880 ggggtgggac tcaatgatcc ggggatttga acaacacttc agggatctaa aaggccagta 29940 tgactagtag gtggcaagca tgaggaagac cttgggctaa ggaggggtga gctgaggctg 30000 acgcagttca gtgtccctgt cctgtgagaa gcagagggcc caggcaggag gttcctcaaa 30060 tgtctagtga gatgacagag gcggccccta gtgagaaaca gacgatgcga cattcagatg 30120 gaataggcag gccgcagggt ccgggctgtt gtcaatctct ccctagaggg accagctggt 30180 gctcaatact gcagggggtg gccctgatga aggaggactg gagacccctg agacctagct 30240 tcaatcttgt cgccatcaca cagtgggaga agtgtaggca cacttcaaat ggttaccgag 30300 ctaggctgca gcctgagacc gcagccgcag ctaatggctg cagtcctgtg gtgtgaggag 30360 cagggcctgg ccacagaggc cagcccgtac cccacccacg ggcaccacgt acacccggcc 30420 gtcagtggcc cgtgagggcg agaagtccgt cagctgcagg ttgctctccc ggacctggtc 30480 gtagtcccac agctgatagt gccaactctt gccctgcttg gacagcaggt agacagctcc 30540 cggggagccc tcctctggca gggatggtgg ttggcagggc gtgcccagca ctgggtggaa 30600 caggcccggc agctcagggt cctcagtgta gccgagactg ggcacagccc gaacacccag 30660 caggacccct gggggagagg agaaggtggt gagtggcagt gactgagcca ggaccaggtg 30720 ctggggctca ctaagttccg ccctctcccg gccctcca 30758 <210> 2 <211> 21866 <212> DNA <213> Homo sapiens <400> 2 tattaagttt tttttttttt tttttttttg agacagagtc ttactctgtt gcccaggctg 60 gagtgcagtg gctcgatctt ggcttactgc aacctccgcc tcctgggttc aagcgatcct 120 ctggcctcag cctcctgagt agctgagatt acaggaatgt gccaccacac ctagctaatt 180 tttgtatttt tagtagagac ggggtttcac catggtggcc aggctggtct cgaactcctg 240 acctcaggtg atctgcccgc cttggcctcc cgaagtgctg gacaggcatg aaccaccacg 300 cccagcctag ctgttgagtt ttaagagatt cttatatttc tagatactag acctttgtca 360 gacatgtggt ttgcaaatat gtcatccaag tctgtatcct gtctttttat cttcgtagca 420 gggtctttca ccaagcaaaa gcttttaatt tttttttttt tttttttttg agactgagtt 480 ttacttttgt tgcccaggct ggagggcaat gtcgccatct cggctcactg caacctcccc 540 tccctttgta tttttagtag agatggggtt tctccatgtt ggtcaggctg gttttgaact 600 ccagacctca ggtgatccac ccgcgtcggc ctcccaaagt gctgggatta caggcgtgag 660 ccaccgcgcc tggcctttaa ttagttttta attttgatga ggttcaattt atcaaatttt 720 ccctttatgg atcatggtct tcatatcaag tctatgaagt ctttgtctag tcctagatcc 780 taaagatttt ctcctaggtt ttttttctaa acattctata gctttatatt tagctatata 840 tggaatcttg agtgaattag acttcatgaa ctaacacccc acccatgcaa ggtttagtat 900 tcagcaacag ctccagaccc aaagagatgc ccttgcagat ttctgtaact cttcacatag 960 cttcctgctc tctgatacgt agcctaggac ctctgttctt aactattaca ctatattgcc 1020 tcttaagtta gaggttgtgc agcatattaa tcaatggctg atcaattaca attactgagt 1080 ttctaactat aggaaaggtc ccacaaaaga tgcaaaaaag gaagacatcc cagcctcaac 1140 cccagtcatc cccacatgag cccaaagcag tgattaggaa atacgtgcaa acctctgagg 1200 caagggatgg tgacagtacc gtgagcaata ggattgcaca gtgagtgaca agccatgatg 1260 ctgctgtctc ctctctggac ccatcattca tccctcttcc cacacctctc tagttcctcc 1320 agcctcgtcc atcaatgagg agccagaaaa ttggctgcct ctcccaccct agcctcccaa 1380 acttcatcta agtttttgac ggggtcaggc acggtggctc aagcctgtaa tcccagcact 1440 ttgggaggct gaggcaggcg gatcacttca gcccaggagt tcgagaccag cgtaggcaac 1500 atggcaaaac cctgcctcta caaaaaatac aaaaattagc cagtcttggt ggcatgcacc 1560 tgtagtccca gctactcggg aggctgagca tgggagttca aggctacggt actgcactct 1620 agactgggtg acagagtgag actctgtctc aaaaaaaaaa tagtttttga ctcaacatgg 1680 ggataaatta taacccaggt caattctggg cctgtaaacc tctctagaag gaaaaactct 1740 ctttctctac tctcaacagt tctaacacca aatgtgtgaa ttttccacac cagcaaaatt 1800 atccaattct ctgtggacaa caactgggtt tcctacaatt aactcaattc tgacatgaac 1860 tacctggagc cagcacaggc cccacaggtg aagagctcag tcccacaaga ctgcccccac 1920 ttcaggtgcc agttgcaggt agtgggttcc cagattaccc actctcctct ccaatttagc 1980 tacaaacagg aggtccctat gaccctcagg tttggtaact tgtagctcat agaactcaaa 2040 gaaacacttt gctctttctg gtttattatt aaggatacac ccaagaacag cctaatggac 2100 aagggatgga gggagtgccc agagcttttc tgccctttcc agacatgcca ccctccccga 2160 atctcaacgt gttcaccaac ccggaagctc cctgaaaccc acaatttagg atttacatgg 2220 aggttccatt atgtaggcat gagtgattaa atcattggcc attggccaag cctgggggcc 2280 tgtaatcctc gtgactctgt atcctggcaa tttgagaggc tgagatggga agatcaccag 2340 aggccaggag ttcaagacca gcctgggcaa catagtgaga cctgtctcta aaaaatttag 2400 aaagaaaaag taaaataaaa aatcagccag gtgcagtggt tcatgcctgt aatcccagca 2460 ctttgggagg ttgaggtggg tggatcactt gagtgggact gcaggtgagt accaccatgc 2520 ccggctaatt ttattttttg tagagacaag gtttcactat gttgcccacg ctggtctcaa 2580 actcctggac tcaaacaatc ctcccacctc agcctcccaa agtgctagga ttaacaggag 2640 tgagccacca ctcactccag tgggcatgag tcaagctgga tttcatagta ttttcttgtt 2700 ttttttgttt gtttgtttgt ttttgttgtt gttttttgtg gtggggggtg agacagagtc 2760 ttgctctgtc tcccaggctg gagtgcagtg gcttgatctc agctcactga aacctctgct 2820 tcctgggttc cagcaattct cctgcctcag cctccagagt agctgagatt acaggcatgt 2880 gccaccacgc ccagttaatt ttttgtattt ttagtagaga cggggtttca ctatgttgtc 2940 caggctggtc tcgaactcct gacctcaagt gatctgcccg cctcggcctc ccaaagttct 3000 gggatgacag cgtgagccac cacacccggc ctctttttct ttctttcatt tttttctccc 3060 ttcccatgca gtttttctta ctcccaacct ctctcatagt ttatcttacc tgcttgccat 3120 ccttgggcag ctacattttt gacctcttag ccagtttgag tctttctttt tttttttttt 3180 tcactcagtc tcactctgtc accaaagctg aagtgcaggg gcatgatcac ggctcactga 3240 tcatgccagc cccaacctcc tgggctcaag caaacctccc acctcagccc tgccccaagt 3300 aatggagact acaggtgtgg gccatcactc ccagcaaatt tttttttttt gagacggagt 3360 ctcgctctgt cacccaggct ggagtgcagt ggcgcgatct cggctctctg caagctccac 3420 ctcccgggtt cacaccattc tcctgcctca gcctcctgag tagctgggac tacaggagcc 3480 cgccaccacg cccggctaat tgttttttgt ttgtttgttt gtttattggg tttttttttg 3540 tatttttagt agagacaggg tttcaccatg ttaaccagga tggtctcgat ctcctgacct 3600 cgtgatccac cctcctcagc ctcccaaagt gctgggatta caggcatgag ccaccacacc 3660 cggtcatgcc cagctaattt ttaaattttt tgtagagatg agatctcact atgttgccca 3720 ggctggtctc aaactcctgt gagcccctca gttaatagaa gaaacagtca agcatggtgg 3780 cataggtctg tattcccagc tacccgagag gctgagaagg gaggctctct tgagctcaag 3840 agtttaaggc tatatgccag gcatggtggc tcacacctgt aatcccagca ctttgggagg 3900 ttgaggtggg tggatcactt gagaccagga gttcgagacc agcctggcca acatagtgaa 3960 accccgtctc tactaaaaaa aatacaaaaa ttggctgggc acagtggctc acacctgtaa 4020 tcccagcact ttgggagact gaggcgggcg gatcacaagg tcaggagttt gagaccagcc 4080 tggccaacat ggtgaaatcc catctctact aaaaatacaa aaattagcca ggtgtggttg 4140 gcaggtgcct gtaatcccag ctactcagga ggctgaggaa gaagaattac ttgaacccaa 4200 gaggcagagg tttcggtgag ccaaggtcgc gccattgcac ttcagcctgg gtgacagagc 4260 aagacgccat ctcaaagtaa ataaatacat acatacatac atacatacaa aaagtagccg 4320 ggtgtggtgg tgcatgcctg tagtcccagc tactcaggag gctgaggcag gagaattgct 4380 taaacatgga ggacagaggt tgcagtgagc tgagattatg ccactgcact ccagtctggg 4440 caacagagta agactctgtc tcaaaaaaaa aaaaaaaagg agtttgaggc tgcagtaaac 4500 taagatggca ccactgcact tcacat cca ctctagcctg ggtgacagag cgagaccttg 4560 tctctaaaaa aaaaaacaaa aaacgaaaaa ccaaaaaaaa aaagggtggg ggtggaatag 4620 aataaacaac tctgagaagg gacatgatct ggtgacaatc tcaagtgaat cagtggttga 4680 accaggacca gatcccagtg ccccatcttc tggggacgtc ctgggtctga atcttcaatg 4740 catgtccctt ctgcagtgcc ttcctctgtg gccctcaaag ggaaactgaa gcctttgagg 4800 acatgaagac tcgcattagg ccaacgaggg gtcttggaac tccagatcaa agagaataag 4860 aaagacctga ctctgtgtgt gtgtacgtgt gtgtgtacgt gtgtgtgtgt gtgtgtggca 4920 gaggggggtg tggtcatggg gtattgacat gaatacgcaa ggggcaggaa gcatctgaaa 4980 tcagagctaa cttgggaggc acagaacacg gggtgcctgg aaggggaaca gatgtgttgt 5040 ggggcacagg gcaggctggg aggggaacaa aggtccactc catgggtaac cagacccttc 5100 cgccagggct ggccacttct gcctttggaa aatgtttcac aacgccccat gttgtgtgtg 5160 tgtgtgaatc ggccgatgtg aaccgaatgt tgatgtaaga ggcagggcac tcggctgcgg 5220 atgggtaaca gggcgtgggc tggcacactt acttgcacca gtgcccagag agggggtgca 5280 ggctgaggag ctgcccagag caccgctcac actcccagag tacctgaagt cggcatttca 5340 atgacaggtg agtagtggcc cctagggaca gagcctgatt ggggggtgga gtggaggaga 5400 tcactaggct ggtggagact tgaggaagca agaaagccct tggtcccctg tggaagcctc 5460 tggtcccccg tgggagtcct agtctagaac acagttctgg acaccagact caatctcact 5520 gggtggagtc cttcacaccc ctaagcggtc tacctttcct ttgtctgaag tccgtggatc 5580 aaagcccctg gagctttctg ggctgccgga gaaggtgagg ggtccagcca aggggcagac 5640 atgtggcctc agcttgccct tcttagagcc tagggtctct ctgcattctc tgtggcagga 5700 gatctgcctc tgggcatctg tcctcacatg agaggacagt aattctgaag ctgccatgtc 5760 ccacacatct ggaatgtttg tttgagaggt ggaggtgatg gacccaagat gggggccagg 5820 gaccttagtt tctccacttt tccgggagga ggagggaaag gatcaggcgg ctttaactct 5880 gggccaccag aaagaggcag gacactcacc atgcttcatg ggcccccaca ggtgacaagg 5940 gtccccaaag gctaagcggg tccagctatg gttccatctc cagcccgacc agcccgacca 6000 gcccagggcc acagcaagca cctcccagag agacctacct gagtgagaag atccccatcc 6060 cagacacaaa accggtggga tgctggaaac ttcctggggg cttgcaagat tgacaggatc 6120 ctgaaggatc ccatgggctg gagaatgggg tctccttatg atcatgggtg gcaagtccct 6180 tccaggtctg agcagcagtg gtggacagtg gcaactgccc cttcctgctt ccgtccccag 6240 tgcttagctg gggtgcttca gtatttgtct aaaagcgatt aaatgacttt ctcaatgaat 6300 ctcagctttc ctatgaagga aaagaggccc agggggaatt gggattggag ccttgaggac 6360 atgttatagc atttaggaaa gggcataggg agaagtgaag gaggctgcag gctggcatct 6420 agcatctagg atgctgtcac ctgcatttcc agtatcttct ctttttttgg agatggagtc 6480 tcgctctgta gcccaggctg gagtgcagtg gcgcgatctc agctcactgc aacctccgct 6540 tcccaagttt aagcgattct cctgccccgg cctcccgagt agctgggatt acaggcatgc 6600 accaccatgc caggctaatt tttgtatttt tactagagac agggtttcac catgttggcc 6660 aggctggtct caaactcctt agctcaagtg atccacccac ctcggccttc caaagtgctg 6720 ggattacaga cacgagccaa cgctcccagc ctccaatatc ttcagcagat ttctaagtca 6780 atatgccatg ctctggaaca gggtgggggg accatagcct cagcggacca cagagaggag 6840 gccccgtggt ctgaaaagga gctggcaagg gaggagctgg gctagggaag cttggccccc 6900 tcaccccctt agacagcccc ctgtgaggtc tctgaggacc tgacaagtca gggcttgagg 6960 ggcaggcagt tcaggtgcaa gccggctgct gagcttaaca gatccagaaa aagatcctct 7020 gtgactcatc agagcatgct gcttcctcca cccatgccct ccccatccct tgggtggcag 7080 acccaggaat gggccatgga gggcagggct gggctgatga gcctgttggg gctcctctag 7140 gggatggcca aggccagctg ccaccatccc tatacccagg accccctcac tctactcctc 7200 ccacccccca acagggcacc ttcagcctgc ggaagctatg ggccttcacg gggcctggct 7260 tcctcatgag cattgctttc ctggacccag gaaacatcga gtcagatctt caggctggcg 7320 ccgtggcggg attcaaagta actaagtcgg gacctgagtg gggacacttt cgagagggag 7380 gtgaccaggc taagtgttga aggcccctgc tggccatgtt tctccaatgt ggcctgggag 7440 ctggtgttaa gttcaaatgg gcccgaaaag ggtccccagg gcagccctgc cagaaggtgg 7500 ggcatttgtg tggggggtag gggactggac tcctctcttt aaaatatata tatgtatatt 7560 tatttattta tttatttaat tttatttttt gagactcagt ctcactcggt cacccaggct 7620 ggagtgcagt ggcacaatct cggctcactg caacctctgc ctcccgggtt caagtgattc 7680 tcctgcctca gcctcctgag tagtgcatgc caccacgcct ggctaatttt tgtattttta 7740 gtagagatgg ggtttcactg tgtgggccag gctggtcttg aactcctgac ctcaagtgat 7800 ccaccgcctc ggcctcccaa agtgctggga taacaggtgt gagccacctt gcctggcgta 7860 atttatttat ttatttagag atgggggtct cactatgttg ctcaggctgc tcttgaactc 7920 ctggactcaa gcaatcctcc caccttagcc ttttaaagtg ctgggattac agggtgagct 7980 accagcgccc agccaggatg ggactccatc tctcccaccc cctccccgag gagtatgctt 8040 ggttagaggg taccacgagc tcaggggctt tctgaggctg gcctctctgg ctgaaggcct 8100 ctccctgcct cctcacagct tctctgggtg ctgctctggg ccaccgtgtt gggcttgctc 8160 tgccagcgac tggctgcacg tctgggcgtg gtgacaggca aggacttggg cgaggtctgc 8220 catctctact accctaaggt gagcttgggg ggcctggaca gggagaacca ctggccccaa 8280 accccaaaca gccattttca gcttccacga tcaaataaat acatcatctc acatggggca 8340 tcccaagtct gtttgttttt gttgttgttt gtttgttttt cagtcggagt ctcgctccgt 8400 cgcccagtca ggagtgcaat ggtgcgatgt cagctcactg caacctctac ctcccaggta 8460 caagtgattc tcctgactca gcctctcaag tagctgggat tacaggcgcc caccaccatc 8520 atcggctaat ttttgtattt ttagtagagc tggggtttca ccatgttggc caggctggtc 8580 tcaaactcct gacctcagat gatccaccca cctcagtctc ccaaagtgct gggattacag 8640 gcatgagcca ctgcatccgg ccccaattcc atttgataga tggaaagact gaggctcaaa 8700 ctgatagcac atagcctaga gggacatgag aggcatgtca tttcacagaa ggggtaatta 8760 aaatttggga aagagacttg cccaagacaa aaaatgggga ggcatcagct caggaatggt 8820 cactggttgg ggtggaccct ggggacttcg ttgttgtgag tgtccagttt ggaaaacaga 8880 aattacagca ctggacattt caaaggtatt gaatgcaggg attgaaaggt ttgggagggc 8940 ttgaggggca agggaagagg gtgttacaaa aagatcagaa agctgctaca cctctggcac 9000 aagccccaga gccatccttt gctgctgagc tcctggaagc attattgatg ctgatgaaat 9060 ggccactagt gctgccagag tccgggttgc ctggtgccac tgccagaaat acaagaagca 9120 gggggagaaa atggtttatc tcagcctggg gcggtggctc acgcctgtaa tcccagcact 9180 ttgggaggcc aaggcgggtg gatcacctga ggtcgggagt tcgagaccag cctgaccaac 9240 atggagaaac cccgtctcta ctaaaaatac aaaactagcc gggcatggtg gcacatgcct 9300 gtaatcccag ctactcggga ggctgaggca ggagaatcgc ttgaacacgg gaggcggaga 9360 ttgtggtgag ccgagatcat gccattgcac tccagcctgg gcaacaagag caaaactcta 9420 tttcgaaaaa aaaaaaaaaa gtttatctct gcctttccat ctcctgtatg ctcttcctac 9480 ataaggtagg aagcccattg gccagactgt ctagtaaatg tagtctgaga cgacagacaa 9540 atgtagtctg agacgacagg caaataaccg gcccaccctt aatgaaggat catctcctcc 9600 ccataggtgc cccgcaccgt cctctggctg accatcgagc tagccattgt gggctccgac 9660 atgcaggaag tcatcggcac ggccattgca ttcaatctgc tctcagctgg acggtaccac 9720 cccagtgtac cccaactctt caggccaggc agagaacagc tgctgctact tcccccccta 9780 accagtccct cccagagtct attttatcct gctgtcccct ctgaagcagg gctgctgccc 9840 tgttttccag aaatgtaaag tgacttgtct aaagtcacac agatgtgagt catgcaggac 9900 tttgggactg cagccccaaa ctccctgctg cgccgggtgc caggtctctc ctctagctct 9960 gccctgcctc gactgttcta tgccacactc ccactcccct tgccctagct gtctgggggc 10020 gcttagggtc ctgctcccag gaggccagat tcctgtctcc agccctgagg ctccgtagga 10080 gttagagacc cctggaccag gctgggctga cccgggccac tctggtttca gaatcccact 10140 ctggggtggc gtcctcatca ccatcgtgga caccttcttc ttcctcttcc tcgataacta 10200 cggtgggtgc acaccccacc tcatagggga gtggtggtgg tgagggtgct gtactgggag 10260 aagggctctg acatcgaaca gcctgggagc gcacctgagc tccctcactc tccctgggtg 10320 gcctctagcg agttacttgg acgtgcctct cttcacctgt aacatgggga aataatagca 10380 cagacttcag agggtggttg tgaagactga gtgaggtaac atatgttaag cacttggcac 10440 tgtgcctaga agcgctcgta gtattagcca ttacgaattg ttgatgtcac agattttttt 10500 cgttggtttg tttagtttgt ttgttctgct ccgtagggct gcggaagctg gaagcttttt 10560 ttggactcct tataaccatt atggccttga cctttggcta tgaggtagga agccagtgct 10620 gcaaccccac tgtggacctc ccaagatcat tcctctccct tccctctggc cgcgggctgc 10680 ggggggctgg ggtgggatgg aggctgagaa atggtgaccg cggcgtggtt gcgaggggcg 10740 gggcttgtcc tgaccaggct cctccctgca gtatgtggtg gcgcgtcctg agcagggagc 10800 gcttcttcgg ggcctgttcc tgccctcgtg cccgggctgc ggccaccccg agctgctgca 10860 ggcggtgggc attgttggcg ccatcatcat gccccacaac atctacctgc actcggccct 10920 ggtcaaggtg agcagagggg aggggaaagg agaccccctc actcagtcgg agccatgctg 10980 gctccgcctc caagcctgga gcccctcccc tctggctcct tccctcagga tttgcggagc 11040 ctgtaataat tgagggacag gcggggcgcc atggctcacg cctgtaatcc cagcactttg 11100 ggaggcggag gcgggcggat cacgaggtca agagatcgac accatcctgg tcaacatggc 11160 gaaaccccgt ctctactaaa aatacaaaaa ctagctgggc gtggtggcgc gcgcctgtag 11220 tcccagcggc tcgggaggct gaggcaggag aatcgcttga acccgggagg cagaggttgc 11280 ggtgagccga gatcttgcca ctgcaccact ccagcctggc gacagagcga gactctgtct 11340 caaaaaaaaa aaaaaaagaa aagaaaaagt gtctactgtg cgctgggagg aacagaccgt 11400 caaggcctct gcccttctag agtttccgtg ctagtggggt agacggatga caagcaagta 11460 aaccaacaaa ggaaagaatt ataggccggg cgcagtggct cacgcctgta atcccagcac 11520 ttcaggaggc cgaggcgggc gggcggatca cgaggtcagg agtttgagac ctcaacagcc 11580 tggccaacat ggtgaaatcc cgtctgtact aaaaatacag aaaattagcc ggaagtggtg 11640 gcgcgtgcct gtaatcccag ctactcggga ggctgaggca ggagaatcgc ttgaagccag 11700 taggcggaag ttgcagtgag gggagatggt gacattgcac tccagcctga gtgacaaagc 11760 aagactccgt ctcaaaaaaa gaaaaagaac aagaactata gagctgggcg aggtggctca 11820 cgcctgtaat cccggcactt caggaggcag aggcaggtgg atcgcttgag cccaggagtt 11880 cgagaccacc ctgggcaaca tgataaaacc ctgtctctac caacaaaaaa taaaaaataa 11940 aataaattag ttgggtgttg tgcacacctg tagtcctagt tactcaggag gttgaggctt 12000 gagccctgga ggtcgaggct gcagtgagct gagatcccac cactgcactc tcagtgacac 12060 agtgagaccc tgtcaaaata ataataataa taataataat aattgcgaaa gggactctga 12120 agtaaacaaa acagagaaat atgatagaga atgactgaaa gttggggaag tagatcaggg 12180 aaaagatatt acaagcggag ggaaagcaag tgcaaaggcc actggcagaa gtgaacaagg 12240 cttgggtccc taacagctta acagtggctc acacctgtaa tctcagcatt ttaagaggcc 12300 aagacaggag aatgcttgag cccaggagtt caaggctagc ctagcaagac cctgtctctg 12360 cagaaaattt aaaaattagc gggttgtagt ggtgtgtgtc tgtggtccca gctacttagg 12420 aggctggggc aggaggatca cttgggccca tgagttggag gctgcagtga gccatgcatt 12480 gcaccacggc actccagtct gggtgacaga acaaaacctg tctctaaaaa ataaaataaa 12540 gtaagctgga cacgtctgag gatggaacaa ggtgagtgaa ggagcgtgtc aggacctgag 12600 gtagccaggg acctcaaagg ccagccttgc ttcacccaca cagtggctta cagtggtaag 12660 gcctctgtgg caagaacaga gatgtaggaa accatcggct gacctgaacc tgccccagac 12720 tgccacgcag gggacttaag aaggtactgg gctttgggga gaacatagaa gtgtgagggt 12780 gggggacact gtggtggctc tgagggactt tggcacttcc ctctcccttt gatcttcgta 12840 gtctcgagag atagaccggg cccgccgagc agacatcaga gaagccaaca tgtacttcct 12900 gattgaggcc accatcgccc tgtccgtctc ctttatcatc aacctctttg tcatggctgt 12960 ctttgggcag gccttctacc agaaaaccaa ccaggctgcg gtgagacaca ctttcccccg 13020 cacctgaggc cacacacgta ctcatgtcct gtaagccttg ccgaggaccc taggcaatgc 13080 agctgagccc ttctgagtct ctgccctgat gatcttccct gttggcagat atcattcatt 13140 cagcaaataa tcattgagca tttgttatat accaagcaca tcctagaccc tggggataca 13200 gcagtcaatg ctacaaagac ccagctctct gcagcttaaa tagggaggga ggtgagcaga 13260 caggaatgaa tacccaaggg aagtacagag tgggaagaaa taaagggggt gaagaagcat 13320 agttgggggt atgggggtgg ggtctgcatt agcccaggtg gtcaggaaag gcttcttgga 13380 agagatgaca tttgtgctaa tactggaaaa ggaactagcc agctcctccc tgactctctg 13440 ggatctggga cctgtgtctg tctccccttc tgagtggatc tcagtcatga ggctctaaca 13500 actgcagcca gggttggggg cttcctgaat gctgagccct gtgggagaag gggtggccag 13560 gcctccaagg acctgggcac tgccactgcc ttgctctgtg accttgggag gtcacactcc 13620 tccctgggtc tcactctgtt ccttggcaca aggagggaga tcaacatcag gactgcaaac 13680 ccttgtcttc aagaccaggc aggcgcagag ttgtgggaag tggacagtgt gaagagggca 13740 tggcagccag ctgtctctgt ggtgatgcca gctcttacga acctaaaaga agctggaaac 13800 tgggttctta tgccaggcct tctcaatttt aaatgttggc aacaaatcca cattaaagaa 13860 aaaaaaaacc cggccgggtg cggtggctca cgcctgtaat cccagcactt tgggaggctg 13920 aggcagatgg ctcgcttgag cccgggagtt caagaccaac ctgggcaaca tgacaagacc 13980 cccatcgcta caaaacgtaa aagtaaaaca aaacaaaacc caacttattt tgttagccaa 14040 acaaaatatg tctggccaga ttcagccttg ggccaccagt tttggaaccc tggtcagtgc 14100 taggcagtcc agtttcccaa ggctgagcgt gctcctcaca tcttccttct actgccctgg 14160 tacccacagt tcaacatctg tgccaacagc agcctccacg actacgccaa gatcttcccc 14220 atgaacaacg ccaccgtggc cgtggacatt taccaggggg tgagcgcggg tgggtgggga 14280 gggcgtgacc cagagaggct ccccgcctcg ggcagggcca ccggtcctac cacactcgtc 14340 cctgcagggc gtgatcctgg gctgcctgtt cggccccgcg gccctctaca tctgggccat 14400 aggtctcctg gcggctgggc agagctccac catgacgggc acctacgcgg gacagttcgt 14460 gatggaggta gggcaggggg cgggcccagg agggcaaggg gtccaaggac agcaggcaca 14520 ctactggggg ctagaactcc gagccttgtg ggtcctcttt tcttttcttt cttttcttcc 14580 tttttttttg tttttgtttt tgttgttgtt gttgagacgg agtctcgctc ttgtcgccca 14640 ggctggagtg cagtggcgcg atctcggctc actgcaacct ccccctccca ggttcaagct 14700 tctcctgctt cagcctcctc agtagctggg atttcaggca cctgccacca ggcctggcta 14760 atttttgtac ttttagtaga gacagggttt cgccatgttg gccaggctag tcttgaactc 14820 ttgacctcaa gtgatccgcc tgccttggcc tcccaaagtg ctggaattac aggtgtgaac 14880 caccgcaccc ggccaatttt tgtattttta gtagagacgc agttttgctg tgttggccag 14940 gctggtctca aactcttgac ctcgtgatcc gcccgccttg gactcctgaa gtgctgggat 15000 tataggcgtg agccactgcg tccggccttt tcttttcttt ctttctttcc ttttttttga 15060 gacggcgttt cgctcttatt gcccaggctg gagtgcaatg gcgcgatctc cggctcaccg 15120 caacctccac ctcctgggtt caagcaattc tcctgcctca gcctcctgac cagctgggat 15180 tacaggccac cacacccagc taattttgta ttttcagtaa agacggggtt tctccatgtt 15240 ggtcagggtg gtctcgaact cccagcctca ggtgatctgc cctcctcagc ctcccaaagt 15300 gctgggatta caggcgtgag ccaccgcgcc cggctctttc tttctttttt gagacaggat 15360 ttcactctgt tgctcaggct ggagtgcaat ggcgccatca cagctcgctg cagcctcaac 15420 ttcagcctcc cgagtcattg ggactacagg ctcatgccac cacaccaggc taatttttaa 15480 aattatttgt agagatgtgg tcttcctatg tttcccaggc tggtctcgaa ctcctgggct 15540 caagtgatct tcccgccttg gcttcccaaa gtgctgggat tacagacgtg agccacccca 15600 ctcagctttg tttccttcat gtagcccaga gggcgacact ataagcccca ttttacagat 15660 gagaaaacag atcctgacag atgaggtgac ttgctggaag ctgcagaccc aggactaaca 15720 gaagcctttt ccccaaaact gtttagtctt cagcaaccag ctatgggatg ggagctcccc 15780 atttctcccc acccatcccc tcttgccacc tagggacaga gctgtcccag ttcaacagtg 15840 gaaaaacaga gcatgccccc agggataaat cggttgaggg actacagagg atctctcctc 15900 tggaatcccc agtcctgtct actcctcacc aaggagttca cccccacccc agggcttcct 15960 gaggctgcgg tggtcacgct tcgcccgtgt cctcctcacc cgctcctgcg ccatcctgcc 16020 caccgtgctc gtggctgtct tccgggacct gagggacttg tcgggcctca atgatctgct 16080 caacgtgctg cagagcctgc tggtgagatg cgccaacccc accagccctg cccactgctg 16140 agcgaaacag gacctccagc aacccccacg ctgagccttg catgggcctg ccaggccctg 16 200 tcccaggcac atcttgccta caaggcttcc attgtcccca cagccaccct ggggggcagg 16260 agggtaggaa tcaccattat ccttcccccc tcccaccccc cagatggtct ccctctgtca 16320 cctaggctgg agtgcagtgg ttcaatcatg gctcactgca gcctgccctc cctgtctcta 16380 gcaatcttcc cacctcaggc tcccgagtag cagggactat aggtgcatgc catcacaccc 16440 agctaatttt tttttttttt tttttgagac ggagtttcac tcttgttacc caggctagag 16500 tgcagtggtg agatcttggc tcactgcaac ctctgcctcc caggttcaag cgattcttct 16560 gcctcagcct cctaagtagc tgagattaca agcgcccacc atcacaccca gctaattttt 16620 tgtattttta gtagagacag ggtttcatca tgttggccag gctagtctca aactcctgac 16680 ctcaggtgat ccacccgcct tggcctccca aagtgcaagg attacaggca tgagccactg 16740 aggcaggtct aatttttttt tttttttaag tagagacaaa agctcattat gtttgttgcc 16800 caggctcatt attccatttt acagatggga aaactgatgc actcagttaa gttactagtg 16860 gcagggcttg gattcaaacc gaagcaacct ggtgccagag cccccaaaca ctttctcctg 16920 ctttggagcc cacaacctga taaggcagga gacggggaag taggctcagt gtggttaggg 16980 cagttgagct cacacccaca cagagggtgt caagccacgc ccatcttgcc cccacccttg 17040 ccatattctg aggcagaatt cctcagccta ggctcctgct gctctcccca gctcccgttc 17100 gccgtgctgc ccatcctcac gttcaccagc atgcccaccc tcatgcagga gtttgccaat 17160 ggcctgtgag tacccccttt cccaagtgct ggattgcatc accacatttc atcctcacag 17220 ccacccagag gtacgagcta caattctccc cattatccca atgaagccac agaggctgag 17280 agaggttaag ggacttaccc aggttcacac agctagcaag ttgaggagcc aagactggaa 17340 tccagggaag agggctgttt ctagagcctg agcgcctcac tctcgcctca gactcagctc 17400 ttgccaaatc ccgccagtgt gtagcctgga gggcccagga ggcaggaggt ggggaggggg 17460 tctgtctgct ccaggtccca cagaccagag aagcggcctc agtgtatccc cacccccagt 17520 gtgggcgctg ggagatgaag aggagttgat gcaggtgggc cagcagcaac cagccagtcc 17580 tgagcctctc tcgtgtcccc caggctgaac aaggtcgtca cctcttccat catggtgcta 17640 gtctgcgcca tcaacctcta cttcgtggtc agctatctgc ccagcctgcc ccaccctgcc 17700 tacttcggcc ttgcagcctt gctggccgca gcctacctgg gcctcagcac ctacctggta 17760 cagtagggcc aggggatgcc ttgggaatgg atgagggaag gacaagaggc aaccaatggg 17820 gagggtttgg ggggacacaa tggggcttcc ccagaggtct tggcatctcc ccaattcatg 17880 gttgcccctc ccccaggtct ggacctgttg ccttgcccac ggagccacct ttctggccca 17940 cagctcccac caccacttcc tgtatgggct ccttgaagag gaccagaaag gggagacctc 18000 tggctaggcc cacaccaggg cctggctggg agtggcatgt atgacgtgac tggcctgctg 18060 gatgtggagg gggcgcgtgc aggcagcagg atagagtggg acagttcctg agaccagcca 18120 acctgggggc tttagggacc tgctgtttcc tagcgcagcc atgtgattac cctctgggtc 18180 tcagtgtcct catctgtaaa atggagacac caccaccctt gccatggagg ttaagcactt 18240 taacacagtg tctggcactt gggacaaaaa caaacaaacg aaaaacattt caaaaggtat 18300 ttattgagca cctgcaggcg tgacctgaca gcccaagggt gggtggggtg agggcttgag 18360 gacttgggcg ggacacaggc tccaaactgg agcttgaaat agtgtctgat gaatgttaaa 18420 ttatctatct atctatttat ttatttattt gagacaggga aagggtctcc ctctgttgcc 18 480 aaggctggag tgcagtggcg caatcttaac tcattgcaac ctccaccttc tgggttcaag 18540 cgattctctt tattcagccc cgggagtggc gcgcgccacc acgcccagct aatttgtgta 18600 ttttcagcag agacggggtt tgccatgctg gccaggctgg tctcgaactg ctggattcaa 18660 gtgatccgcc catctccgtc tcccaaagtg ctgggaatta caggcgtgag ccaccaaacc 18720 cggcctgatt aaagttaaat aaatactagt tcccttctcg tccaaaggag cagggaatgg 18780 gaaccgggaa ggcacgaagt ctctaaagca tccagaagac ccctacacca gggtctggtc 18840 cgctcctatt cgccgcagcc tttctgttcc gcctgcaacc cattttccag acagtaaaac 18900 ggcggcgcac ttctttctcc gtcaggcacc aggtcataag gaacccaaga gtctgtgcct 18960 ctgaggccca aattatttgc tgtttcctca ggggagccgg cggccgcgac tcccacgccg 19020 cgccgttacc gctccctctc tgctgactgc tccccctagg ggcagagacg gtcccgacgc 19080 ccgccatccc gccccggcct cacccctccc cgccaggcgg aacgacgcgg ggaggcgggc 19140 gctcggggct cgcgccaggg gccccagaat ccttcgggga gagtgggtgg gaggaagctg 19200 tgtgggcggg gagccccctc tgccttaggg agcggctggg cacccattcg ccccattcag 19260 gggctgcact ttatagacgt tccctaggct gtttctaggc tcccccaagt ccctcctcca 19320 gcctcgtcgg gtccctcaga ccccagccca ggacctgcgg agggccgcag cgaggagagg 19380 ccaacaggcc tttccctaga gttgaacctg ggccgggtgt tgcacctgga agaacccccg 19440 atttcctggg gacccagcag ggcaggcggc ctggctccgc gctcaggtcc ggacgcttgt 19500 ttatgagaag aatttcctct ttcttaaaag ggcaacgatg cgagtgggtc cctcaaggag 19560 agaagagatg ggaccggtct ggtgcgacct gggcaagcgc tgcagagggt acctgggcaa 19620 gagggccgcc cgcctcctct gggtttggca ctggagaaga tgggtccatg ccagctgaag 19680 gaggagatgg atgggggacg tttagcgaag aaaggcatct cccagatcct ttagcctcct 19740 ggaagtgccc ccgttgtacc ccctacacac ccctcttggc attgagtgcc agtcctctgc 19800 caggctctgt gttacaagtt ggggagggcg gcaaagtccc gaattaaaga tgtcagttct 19860 caaggacccc acactccagc ggcgggagac agctgtgcaa acaagtccct gtggcaggat 19920 gcggtgaagg gcgctgcccg tgacgccagc cagggaaggg gactgaatct tgctgaaggg 19980 ggggtcggcg gtagggggga gtgttgacag gacagcccag gaggaatgag agtgccagga 20040 gcatgggggc acgtgtgtgc acatctgcca agacctgaag ctttctgggg acgtcttaga 20100 tcttgtgggg caggacgggg gacggcagag taatgggcag gttggtcaag aagacacgga 20160 gacccggcta aagggctacc caggacctgg gcaaagggct agtgatgagg tcgcgccaag 20220 gtcagtcatt tggacactgg aaggcgtcta cttagagctg cccccattcc ccccatagta 20280 gctctggttc ttccagcctg gcctcaaatc gaccctccag gaagaggggt gcagagttgc 20340 tcttctggaa gctcccttta ggcctcccag ggagggcgtg gtcgcacttg gcactcccca 20400 agagcctgct gaatgcaccc cgactttgtg cacggctccc cgcctccccc tgggttgggc 20460 ttttaccagc cctgtttggc agatggggaa actgagggac tgtgttggaa gagacgcttc 20520 caaatccaca ggtgccagac agcaccttgc tgaatcccgt tcctgcccct ccccgtttct 20580 gacttgtggc ccccatgatt ttatttttcc tggggtgcga atgataaaac agacaaaaaa 20640 tagagtgcat aaagcgacct ccacctgtag agacagaggg cagctgggtg tagacaaccc 20700 ctacagtgag gacactcgaa ggacccccct ccccccacgc aatcctggcc tctcgctcac 20760 tccgtaacta actacccgcc ccaggcgtgg ggagataagt ccagggctcc aggcagaagg 20820 cgcggctacc tctgccgctt tgggagcctg ggaggaggag ttaggtctcc ctgggaaaag 20880 aactgcacgg gcaacggctt gaagtggcga taagatgggg tggaggaggt gggggattcc 20940 tgaggaatcc tgtgagctca ggatggcgcg tctgggaatg gtgggtgtgg ggacagccgg 21000 ccaggtacca gcccccttca cagagggaga ggaaagcgcg ccacccaacc caggccaagg 21060 gcgaggccac gactccactc agtccctcgc cacacgcttc cttttggggt catgagggcc 21120 ccgcatccgg agataaagcc gaggccccac ccagggggcc ggaccgcagg ggagacagat 21180 gtcccgctcc caggctggaa tcccgccttt gcccttgccg gtagacccga agcacgtcgc 21240 ttcctttctt gaaactcagt ttcctcatct gtgaaatggg ttaagaagga ggccgttcta 21300 aggggtaaat gagattaggg ggcgcagcca gagcaggcct aggaaaacgc cagcagcgtg 21360 tggcgatcac ggtgatgaag cgcaatggtg gccgccccgt gggctaccca ggagcaggag 21420 gagggccgag ggatccagcc cggggaccgg ggtatcagtc cccgacagtc ccctcccgcc 21480 cctactccca gcctcagcgc acgaagccgc cgcgccttct ggcagacgcc gctcccctcc 21540 cttcccctcc cggcccccgc gcggggcctc ccctccccgg ctccccctcg gcagggcctg 21600 gcggacgtgc gccgcgtcgc acccggcggc cggacgggac aggacgcgcc cgccccgccc 21660 cgccacggag gcccgcggga gagggggagg ggaggaagtg ccgaggggtg tttgtcgggc 21720 ttggcattat taatttttaa atggtgaact tacaaaatag taacgacgag tgaaaagaac 21780 ttcataaacg aggaaaaaga ccaacccgca gacccacggc gcgcaccacg gaggggcttg 21840 cagcgagaag acagggacct ccgttc 21866

Claims (26)

delete delete Predicting an increase in the number of leukocytes in said individual when the genotype of ITPKC polymorphism rs28493229 is identified as a CC genotype from a biological sample of less than 24 months.
Predicting an increase in platelet count or an increase in erythrocyte sedimentation rate in the individual when the genotype of ITPKC polymorphism rs2290692 is identified as a GC genotype from a biological sample of less than 24 months.
Predicting an increase in lactate dehydrogenase level in said individual when the genotype of ITPKC polymorphism rs10420685 is identified as AG genotype from a biological sample of less than 24 months.
A method for predicting symptoms of Kawasaki disease, comprising predicting an increase in aspartate aminotransferase in a subject if the genotype of SLC11A1 polymorphism rs2276631 is identified as a GA genotype from a biological sample of less than 24 months. .
delete delete delete Determining that the genotype of the ITPKC polymorphism rs2561531 is CC genotype from a biological sample of less than 24 months, and that the genotype of the SLC11A1 polymorphism rs17221959 is CT genotype, and that the probability of developing Kawasaki disease symptoms is low. , Symptom prediction method for Kawasaki disease.
delete Determining that the genotype of the ITPKC polymorphism rs2561531 is CC genotype from a biological sample of less than 24 months, and that the genotype of the SLC11A1 polymorphism rs77624405 is identified as the GA genotype, with a low probability of developing Kawasaki disease symptoms. , Symptom prediction method for Kawasaki disease. delete delete delete delete delete delete delete delete delete delete delete delete delete delete