KR101832160B1 - Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia - Google Patents
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Abstract
The present invention relates to a method for providing information on the diagnosis or prediction of familial hypercholesterolemia using a novel single nucleotide polymorphism combination, wherein the combination of single nucleotide polymorphic markers according to the present invention is a family- In the case of patients not diagnosed with the diagnosis of cholesterolemia, the diagnosis of familial hypercholesterolemia can be made. Therefore, the accuracy and sensitivity of the method can be improved compared with the conventional method, thereby enabling early diagnosis of the patients with familial hypercholesterolemia It is expected to play an important role in preventing the occurrence of various complications.
Description
The present invention relates to multifunctional causalities in Korean familial hypercholesterolemia, and more particularly to methods for providing information about the diagnosis or prediction of familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is known to be caused by defects in the LDL receptor (LDLR) that regulate blood cholesterol levels by transferring low-density lipoprotein (LDL-C) into cells Is a type of dominant inherited disease (Cell (1984) 39: 27-38). In patients with familial hypercholesterolemia, blood cholesterol levels are more than two times higher than normal, and as a result, cholesterol accumulates in the endothelium and the inner wall of the blood vessels (Achilles tendon xanthoma), arteriosclerosis, cardiovascular disease The risk of the onset of the disease is very high. In particular, patients with homozygous genetic traits for familial hypercholesterolemia are known to die from cardiovascular disease due to excessive cholesterol in their infancy. Therefore, it is very important to prevent complications by early diagnosis and treatment in patients with familial hypercholesterolemia.
However, in spite of these risks, the current method of diagnosing familial hypercholesterolemia is to measure the blood cholesterol level, which is a low density lipoprotein receptor (HDL) known to have a high association with familial hypercholesterolemia receptor, LDLR), apolipoprotein B (APOB), and PCSK9 (proprotein convertase subtilisin / kexin type 9) are measured to diagnose familial hypercholesterolemia. However, There is a possibility of being a patient with genetic hypercholesterolemia. Therefore, new diagnostic methods using single nucleotide polymorphism (SNP) as a method for diagnosing familial hypercholesterolemia have been developed worldwide, but Korean family members have a high level of familial hypercholesterolemia - associated single nucleotide polymorphism There is a lack of research on this subject.
Therefore, there is a desperate need to develop a method for diagnosis of familial hypercholesterolemia for Koreans, which is diagnosable, accurate and sensitive, in addition to the existing method for diagnosing familial hypercholesterolemia.
Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide information on the diagnosis or prediction of familial hypercholesterolemia using a novel single nucleotide polymorphism combination.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions, and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to 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 at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" an embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the present invention. In addition, a particular feature, form, composition, or characteristic may be combined in any suitable manner in one or more embodiments.
As used herein, the term "biological sample" refers to all samples for which gene information of a patient can be confirmed. Preferably, the sample is blood, plasma, serum, and the like, but is not limited thereto as long as it can identify single nucleotide polymorphisms.
As used herein, "a method of providing information on the diagnosis of familial hypercholesterolemia" is a method of providing information on a high-risk group or a low-risk group on familial hypercholesterolemia, This is a method of obtaining information on the possibility (risk) of developing familial hypercholesterolemia by identifying a single nucleotide polymorphism that has an association.
As used herein, the term "kit" means a device for examining a single nucleotide polymorphism associated with familial hypercholesterolemia in Korea and providing information on the diagnosis of familial hypercholesterolemia, As long as it can confirm the single nucleotide polymorphism. Preferably a set of probes or primers having a sequence complementary to the single nucleotide polymorphic gene, wherein the "probe or primer" is an oligonucleotide having a sequence complementary to a single nucleotide polymorphism oliogonucleotide), and it is not limited as long as it can identify the single nucleotide polymorphism of the present invention.
As used herein, the term "diagnostic device " means a device capable of diagnosing a disease in vitro based on a substance generated from the human body such as blood, saliva, urine, and the like. none. Preferably, the analyzing unit may include an input unit for receiving the gene sequence, a detecting unit for analyzing the gene, a calculating unit for calculating the weighted average single nucleotide polymorphism value, and an output unit for displaying the analysis result. However, by analyzing the single base polymorphism from the biological sample, But is not limited to, equipment of a type capable of predicting whether or not sexually hypercholesterolemia is present.
(A) identifying a mutation in the gene of low density lipoprotein receptor (LDLR), apolipoprotein B (APL), and PCSK9 (proprotein convertase subtilisin / kexin type 9) from a biological sample isolated from a human; b) selecting a sample in which no mutation has been observed in said step; And c) determining a single nucleotide polymorphism (SNP) of the selected sample, rs629301, rs1367117, rs6544713, rs6511720, rs429358, and rs7412, and measuring a weighted mean SNP score And a method for providing information about the diagnosis of familial hypercholesterolemia.
The present invention also relates to a method for detecting a mutation of a low-density lipoprotein receptor (LDLR), apolipoprotein B (APL), and PCSK9 (proprotein convertase subtilisin / kexin type 9) from a biological sample isolated from a human. b) selecting a sample in which no mutation has been observed in said step; And c) single nucleotide polymorphism (SNP) of the selected sample. rs599839. identifying rs12654264, and rs2738446, and determining a weighted mean SNP score. < RTI ID = 0.0 > [0030] < / RTI >
The present invention also relates to a method for detecting a mutation of a low-density lipoprotein receptor (LDLR), apolipoprotein B (APL), and PCSK9 (proprotein convertase subtilisin / kexin type 9) from a biological sample isolated from a human. b) selecting a sample in which no mutation has been observed in said step; c) determining a single nucleotide polymorphism (SNP) of the selected sample, rs629301, rs1367117, rs6544713, rs6511720, rs429358, and rs7412, and measuring a weighted mean SNP score; And d) a single nucleotide polymorphism (SNP) of the selected sample. rs599839. identifying rs12654264, and rs2738446, and determining a weighted mean SNP score. < RTI ID = 0.0 > [0030] < / RTI >
In one embodiment of the invention, the method of measuring the weighted mean SNP score is preferably a weighted sum of the risk allele of the experimental and control individual (LDL-C) on the basis of increased risk alleles and beta coef- ficients, but the SNP risk score is lower than that of low-density lipoprotein (LDL-C) There is no limitation as long as it can be calculated.
In another embodiment of the present invention, the gene mutation is preferably a mutation in the gene sequence associated with the pathogenicity of familial hypercholesterolemia, but is not limited to any mutation in the sequence of LDLR, APOB, or PCSK9 Do not.
In yet another embodiment of the present invention, providing information about the diagnosis of the familial hypercholesterolemia comprises providing the weighted average single base polymorphism value of step c) between 0.60 and 0.99, and / or d) And a family history of hypercholesterolemia when the single nucleotide polymorphism value is 0.40 to 0.99. However, the present invention is not limited to this, as it can be arbitrarily specified by the experience of the diagnostic person.
In another embodiment of the present invention, the diagnosis is preferably for Koreans. However, the present invention is not limited to this, as long as familial hypercholesterolemia can be diagnosed using the single base polymorphism combination
In another embodiment of the present invention, the biological sample is preferably not limited to blood, plasma or serum, as long as it can identify genetic information.
In another embodiment of the present invention, the method may further comprise a method for diagnosing existing familial hypercholesterolemia. The conventional diagnostic method is preferably a measurement of the concentration of low-density lipoprotein (LDL-C) in the blood, but is not limited thereto as long as it is a method used for diagnosing familial hypercholesterolemia.
The invention also encompasses a method for identifying a family of probes or primers comprising a set of complementary probes or primers for one or more single base polymorphisms selected from the group consisting of the single nucleotide polymorphisms rs629301, rs1367117, rs6544713, rs6511720, rs429358, and rs7412. A kit for diagnosing hypercholesterolemia is provided.
The present invention also relates to the use of the single base polymorphism rs651007. rs599839. wherein the kit comprises a complementary probe or primer set for at least one single base polymorphism selected from the group consisting of rs12654264, and rs2738446.
In one embodiment of the present invention, the diagnostic kit comprises a probe or a primer set capable of confirming gene mutations of LDLR (low density lipoprotein receptor), APOB (apolipoprotein B), and / or PCSK9 (proprotein convertase subtilisin / kexin type 9) May be further included.
Also, the present invention provides a method for detecting a protein comprising the steps of: a) inputting a gene sequence of low density lipoprotein receptor (LDLR), apopiprotein B (APLOB) and proprotein convertase subtilisin / kexin type 9 (PCSK9) of a biological sample isolated from a human; b) a detector for analyzing the gene sequence to select a sample for which no mutation has been observed; c) a calculator for identifying single nucleotide polymorphisms (SNPs) rs629301, rs1367117, rs6544713, rs6511720, rs429358, and rs7412 of the selected sample and calculating a weighted mean SNP score; And d) an output indicating the presence of familial hypercholesterolemia at the weighted average single nucleotide polymorphism value.
Also, the present invention provides a method for detecting a protein comprising the steps of: a) inputting a gene sequence of low density lipoprotein receptor (LDLR), apopiprotein B (APLOB) and proprotein convertase subtilisin / kexin type 9 (PCSK9) of a biological sample isolated from a human; b) a detector for analyzing the gene sequence to select a sample for which no mutation has been observed; c) single nucleotide polymorphism (SNP) of the selected sample. rs599839. rs12654264, and rs2738446 and calculating a weighted mean SNP score; And d) an output indicating the presence of familial hypercholesterolemia at the weighted average single nucleotide polymorphism value.
The combination of single nucleotide polymorphic markers according to the present invention not only can diagnose familial hypercholesterolemia in patients not diagnosed by the conventional diagnosis of familial hypercholesterolemia, And to increase the accuracy and sensitivity of this study. Therefore, it is expected that it will play an important role in prevention of various complications by enabling early diagnosis of familial hypercholesterolemia in Koreans.
FIG. 1 is a graph showing a result of analyzing a relationship between familial hypercholesterolemia and SNP set 1 according to an embodiment of the present invention.
FIG. 2 is a graph showing the results of analysis of the association with familial hypercholesterolemia using SNP set 2 according to an embodiment of the present invention.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Example 1: Identification of family-associated hypercholesterolemia-associated genes
To identify the genes of Koreans associated with familial hypercholesterolemia (FH), 96 experimental groups and 2 274 control subjects, who were diagnosed with familial hypercholesterolemia according to the Simon Broome diagnostic criteria, Were used for the experiment. In the experimental group, patients who did not have familial combined hyperlipidemia or familial dysbetalipoproteinemia were included. Low density lipoprotein receptor (LDLR) (NC_000019.9 and NM_000527.4), which is known to have a high association with familial hypercholesterolemia, apolipoprotein B, APOB (NC_000002 (SEQ ID NO: 11) and NM_000384.2), and PCSK9 (proprotein convertase subtilisin / kexin type 9 (NC_000001.10 and NM_174936.3)) were mutagenized by whole exome sequencing Respectively. Genomic DNA was extracted from patients blood according to protocol using DNeasy Blood & Tissue Kit (Qiagen), and the extracted DNA was extracted with Agilent SureSelect Human All Exome 50Mb kit (Agilent Technologies) and the Illumina HiSeq2000 platform. The results of the total exon sequence analysis showed that there were no mutations in the three genes in 65 patients with more than half of the 96 experimental groups, although 31 genes were known to have a high association with familial hypercholesterolemia Mutations were observed in one or more of the three genes. The mutation included a mutation that occurred if at least one mutation occurred in any of the three genes. As a result, the diagnosis of familial hypercholesterolemia using LDLR, APOB, or PCSK9 was less accurate than that of familial hypercholesterolemia. A method for diagnosing cholesterolemia patients is necessary.
Therefore, 65 patients who had no mutation in the three genes and 31 patients who had mutations were divided into two experimental groups to perform the second analysis. A total of 16 single nucleotide polymorphisms (SNPs) listed in Table 1 below were used for the secondary analysis. Each SNP of the experimental group was analyzed using SNaPshot or Taqman SNP genotyping, and the Affymetrix SNP assay (ver. 6.0) was used for the control group (HEXA). Weighted average low density-lipid protein increase For the measurement of genetic risk values (weighted mean SNP score). We calculated the weighted sum of the risk allele for each individual in the experimental and control groups and found that the allele and beta coefficients of the low-density lipoprotein (LDL-C) The correlation between the LDL-C level of the control group and the SNP score of each of the other SNP sets was calculated using linear regression (Nature (2010) 466 (7307): 707-713) Respectively. In addition, Welch's two-sample t-test was used to compare SNP scores between groups, and all statistical analyzes were analyzed using R 3.1.2 (http://www.r-project.org) .
[Table 1]
As a result of statistical analysis using a different SNP set, six SNP sets (set 1) of rs629301, rs1367117, rs6544713, rs6511720, rs429358 and rs7412 among a total of 16 SNPs, rs651007 (SEQ ID NO: 1), rs599839 C value in the case of using four sets of SNPs (set 2) of SEQ ID NO: 2, rs12654264 (SEQ ID NO: 3) and rs2738446 (SEQ ID NO: 4) In addition, in the case of rs429358 and rs7412, it was confirmed that the combination of haplotype is highly related to the patients with familial hypercholesterolemia.
The weighted average SNP value was 0.67 [SD = 0.07] when six SNP sets (set 1) were used, and the correlation with the LDL-C value of the control group was p = 2.1X10 -4 and R 2 = 0.01 Respectively. In the untreated group, the weighted mean SNP score was significantly higher than that of the control group (0.72 [SD = 0.07], p = 1.8X10 - 8 ) (Fig. 1). On the other hand, the weighted average SNP values of the control group and the experimental group were not significantly different in the experimental group in which the mutation was observed. In addition, we found that the weighted mean SNP score was significantly higher in the experimental group without mutation (p = 5.0X10 -3 ) than the experimental group in which the mutation was observed. From the above results, it was confirmed that high-risk familial hypercholesterolemia or low-risk group can be diagnosed by using the weighted average SNP value measured using six sets of SNPs. In addition, the weighted average SNP values of the samples to be analyzed were measured using the combination of 6 SNPs, and it was confirmed that the SNPs can be diagnosed at high risk when the SNPs were 0.60 to 0.99.
When four SNP sets (set 2) were used, it was confirmed that the relationship between the weighted average SNP value and the LDL-C value of the control group was p = 5.0 × 10 -12 and R 2 = 0.02. In the untreated group, the weighted mean SNP score was significantly higher than that of the control group (0.49 [SD = 0.08], p = 3.6 × 10 -3 ) (FIG. 2). From the above results, it was confirmed that the SNPs of the samples to be analyzed using the four sets of SNPs were measured, and that the SNPs of the samples could be diagnosed as high risk when the SNPs were 0.40 to 0.99.
Through the above results, it is possible to diagnose or predict Korean familial hypercholesterolemia using SNP set 1 and / or SNP set 2 of the present invention, as well as to diagnose or predict familial hypercholesterolemia using conventional LDLR, APOB, or PCSK9 In addition to the method for diagnosing cholesterolemia, if a patient diagnosed with familial hypercholesterolemia using the SNP set 1 and / or the SNP set 2 of the present invention is diagnosed as a patient whose mutation is not observed in the above three genes, , It was confirmed that the diagnosis could be made for patients who were not diagnosed as having hypercholesterolemia, thereby confirming that the diagnostic accuracy of familial hypercholesterolemia can be increased.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
<110> Medizen Humancare Inc. <120> Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia <130> DPB150038 <160> 4 <170> KoPatentin 3.0 <210> 1 <211> 51 <212> DNA <213> Homo sapiens <400> 1 tggctgcttt cagggaagaa gttcaaggca gtggcaggga gctccttgca c 51 <210> 2 <211> 51 <212> DNA <213> Homo sapiens <400> 2 aagagaaaga aataggagca ggatcaactt ccagatatac agagaatata a 51 <210> 3 <211> 51 <212> DNA <213> Homo sapiens <400> 3 gtaacctttc ttttctgaag catccattat atagagactg tgcattttta a 51 <210> 4 <211> 51 <212> DNA <213> Homo sapiens <400> 4 cgtacccagc ctccttgaag tttttgtgac ctgcaactcc cctacctgcc c 51
Claims (13)
b) selecting a sample in which no mutation has been observed in said step; And
c) single nucleotide polymorphism (SNP) of the selected sample. rs599839. identifying rs12654264, and rs2738446, and determining a weighted mean SNP score. < Desc / Clms Page number 17 >
Wherein said diagnosis is intended for a Korean person.
Wherein the biological sample is blood, plasma, or serum.
b) a detector for analyzing the gene sequence to select a sample for which no mutation has been observed;
c) a calculator for identifying single nucleotide polymorphism (SNP) rs651007, rs599839, rs12654264, and rs2738446 of the selected sample and calculating a weighted mean SNP score; And
d) a device for the diagnosis of familial hypercholesterolemia comprising an output showing the family weighted average single nucleotide polymorphism value as a family hypercholesterolemia.
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| KR102511160B1 (en) * | 2021-07-28 | 2023-03-17 | 대한민국 | Methods for predicting the high risk group of hypercholesterolemia by using total cholesterol associated genetic variants |
| CN114410769A (en) * | 2021-12-14 | 2022-04-29 | 上海大格生物科技有限公司 | SNP marker related to hypercholesterolemia based on SOD3 gene, kit and application |
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Non-Patent Citations (4)
| Title |
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| Futema M et al., Clin Chem. Vol.61(1), pp.231-238 (2015. 1. 공개)* |
| Go MJ et al., Genomics Inform. Vol.10(2), pp.99-105. doi: 10.5808/GI.2012.10.2.99. (Epub 2012. 6. 30.)* |
| Nature.vol.466(7307), pp.707-713. doi:10.1038/nature09270, (2010. 8. 5.) |
| Talmud P et al., Lancet. Vol.381, pp.1293-1301 (2013. 4. 13. 공개) |
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