KR102565803B1 - Method for providing information for hypertension and kits using the same - Google Patents

Abstract

In the present specification, between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2, and Detecting a single nucleotide polymorphism (SNP) genotype for at least one gene region of JAG1, and determining a risk of developing hypertension for an individual based on the detected genotype Provides a method for providing information on hypertension do.

Description

Method for providing information on hypertension and kit using the same {METHOD FOR PROVIDING INFORMATION FOR HYPERTENSION AND KITS USING THE SAME}

The present invention relates to a biomarker capable of predicting and diagnosing the risk of developing hypertension according to sodium intake from a biological sample isolated from a subject.

Hypertension is a high-ranking risk factor in the world as a cause of death, and is the most common and difficult to treat disease known to be a fundamental cause of circulatory system diseases such as cerebrovascular disease and cardiovascular disease among all adult diseases. Such high blood pressure may be divided into essential hypertension and secondary hypertension depending on the cause, and essential hypertension accounts for most of the high blood pressure. Unlike secondary hypertension, in which the cause of essential hypertension has been identified, the cause is not clearly identified, but lifestyle factors such as old age, obesity, lack of exercise, diabetes, hyperlipidemia, smoking, stress, genetic factors, and salt intake, calcium, potassium It can be caused by dietary factors such as , magnesium and the like.

Among the above-mentioned causes, salt intake may be the main cause in the prevalence of hypertension in Korea. More specifically, the current US FDA recommends 2,400 mg of sodium per day, and the daily sodium intake of US adults is 3,900 mg.

On the other hand, the sodium intake of Korean adults appears to be 6,000 to 8,000 mg, more than twice that of US adults, due to eating habits such as soup, stew, kimchi, salted seafood, and sauces with high salt content. Accordingly, as Korean adults appear to have a high incidence of hypertension due to the above-mentioned high-salt eating habits, a more systematic management of salt intake is required.

The background description of the invention has been prepared to facilitate understanding of the present invention. It should not be construed as an admission that matters described in the background art of the invention exist as prior art.

Meanwhile, the inventors of the present invention paid attention to salt (sodium) sensitivity, in which blood pressure response to salt intake is different for each individual.

Salt sensitivity may refer to a case where the average blood pressure increased by 10% or more by the high-salt diet (Na = 240 mmol) compared to the blood pressure at the time of the low-salt diet (Na = 100 mmol). Furthermore, salt-sensitive people require higher blood pressure than normal people even with a small amount of salt intake, which may increase the incidence of hypertension, and it is estimated that about 50% of hypertensive patients have salt-sensitive hypertension. More specifically, salt sensitivity appears specifically in primary aldosteronism, renal artery stenosis, renal disease, and low renin essential hypertension, and can cause left ventricular hypertrophy, loss of nighttime blood pressure, and lipid metabolism disorders, leading to cardiovascular disease. It is highly probable that it can increase the mortality rate.

As a result, as there is a risk of mortality in case of salt sensitivity even in normal blood pressure, restriction of salt, that is, sodium intake, can lower blood pressure and reduce the occurrence of cardiovascular disease in salt-sensitive hypertensive patients.

Furthermore, since this sensitivity to salt is related to genetic susceptibility, sensitivity to sodium intake may vary depending on race and region.

Accordingly, the inventors of the present invention paid attention to genetic mutations related to salt sensitivity in order to prevent and treat hypertension in Korean adults who require more salt intake management.

Furthermore, the inventors of the present invention paid more attention to single nucleotide polymorphism (SNP), which is a single nucleotide substitution in a DNA sequence, among genetic variations affecting disease. More specifically, human genes are 99% identical to each other, and individual differences are shown by the remaining 1% of genes. SNPs account for most of the genetic variation included in this 1% portion. On average, about 100 to 300 nucleotide sequence mutations are observed in SNPs in genome sequences, and are known as highly reliable genetic mutations due to their high frequency of occurrence.

Accordingly, the inventors of the present invention performed SNP analysis in order to accurately identify the location of genes contributing to the susceptibility to hypertension onset due to salt sensitivity, and thus found base mutations for hypertension according to specific sodium intake in Koreans. .

That is, the inventors of the present invention select a risk group for hypertension according to salt sensitivity by detecting and confirming genetic mutations that can induce hypertension even with the same amount of sodium intake, and thus nutritional management and treatment such as a low-salt diet for blood pressure control wanted to provide.

After all, the problem to be solved by the inventors of the present invention is to predict, diagnose, and provide the risk of hypertension due to sodium intake through genetic mutations that are statistically significant and highly correlated in Koreans.

The tasks of the present invention are not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those skilled in the art from the following description.

In order to solve the above problems, the present invention, from a biological sample isolated from the subject, EML6, FGF5, NT5C2, between ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, GML and CYP11B1 , detecting a single nucleotide polymorphism (SNP) genotype for at least one gene region of between CNNM2 and NT5C2, between MYL2 and CUX2, and JAG1, and determining the risk of developing hypertension for the individual based on the detected genotype. To provide information on hypertension.

According to a feature of the present invention, detecting the genotype may include detecting a base for rs67617923 in the EML6 gene, and detecting a base for rs16998073 in the FGF5 gene.

According to another feature of the present invention, the step of determining the risk of developing hypertension may include determining the individual as a high risk group for developing hypertension when the base for rs67617923 is A and the base for rs16998073 is T. .

According to another feature of the present invention, detecting the genotype may include detecting a base for rs11191582 in the NT5C2 gene, and detecting a base for rs11105378 in a gene region between ATP2B1 and LINC00936.

According to another feature of the present invention, the step of determining the risk of developing hypertension, when the base for rs11191582 is A and the base for rs11105378 is T, determining the individual as a low-risk group for developing hypertension.

According to another feature of the present invention, the step of detecting the genotype includes detecting a base for rs12509595 in the gene region between PRDM8 and FGF5, detecting a base for rs6913309 in the gene region between C6orf10 and HLA-DQB1, and detecting a base for rs112735431 in the RNF213 gene. According to another feature of the present invention, the step of determining the risk of developing high blood pressure is, when the base for rs12509595 is C, the base for rs6913309 is A, and the base for rs112735431 is A, the individual has a sodium intake of 2 g / day or more case, a step of determining a high-risk group for developing hypertension may be included.

According to another feature of the present invention, the step of detecting the genotype includes detecting a base for rs3819496 in the gene region between GML and CYP11B1, detecting a base for rs140473396 in the gene region between CNNM2 and NT5C2, MYL2 and The method may include detecting a base for rs12229654 in the gene region between CUX2 and detecting a base for rs1887320 in the JAG1 gene.

According to another feature of the present invention, the step of determining the risk of developing high blood pressure, the base for rs3819496 is G, the base for rs140473396 is AC, the base for rs12229654 is G, and the base for rs1887320 is G, the subject If the sodium intake is 2 g / day or more, it may include determining a low-risk group for developing hypertension.

According to another feature of the present invention, the step of detecting the genotype may include sequencing analysis, hybridization by microarray, allele specific PCR, and dynamic allele-specific hybridization. , DASH), PCR extension analysis, PCR-SSCP (PCR-single strand conformation polymorphism), PCR-RFLP (PCR-resctriction fragment length polymorphism), and at least one of TaqMan techniques.

On the other hand, in order to solve the above problems, the present invention is between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, C6orf10 and HLA in the method for providing information on hypertension according to an embodiment of the present invention -A probe configured to amplify or detect a polynucleotide containing a single nucleotide polymorphism (SNP) site for at least one gene region of DQB1, RNF213, GML and CYP11B1, CNNM2 and NT5C2, MYL2 and CUX2, and JAG1 ( A composition for providing information on hypertension, including a probe or primer formulation, may be provided.

According to the features of the present invention, the probe or primer is G or A, the base for rs67617923 in the EML6 gene, A or T, the base for rs16998073 in the FGF5 gene, and G or A, the base for rs11191582 in the NT5C2 gene. , C or T, the base for rs11105378 in the gene between ATP2B1 and LINC00936, T or C, the base for rs12509595 in the gene region between PRDM8 and FGF5, and T, the base for rs6913309 in the gene region between C6orf10 and HLA-DQB1 or A, G, the base for rs112735431 in the gene of RNF213, or A or G, the base for rs3819496 in the gene region between GML and CYP11B1, ACACACAC or AC, the base for rs140473396 in the gene region between CNNM2 and NT5C2; T or G, the base for rs12229654 in the gene region between MYL2 and CUX2, and A or G, the base for rs1887320 in the gene of JAG1, can be amplified or detected.

On the other hand, in order to solve the above problems, the present invention may provide a kit for providing information on hypertension, including a composition for providing information on hypertension according to an embodiment of the present invention.

According to the features of the present invention, the kit may be at least one of RT-PCR, ddPCR, microarray chip and DNA chip kits.

According to another feature of the present invention, the kit may further include a display means configured to indicate an individual's susceptibility to hypertension according to sodium intake, according to the genotype of the SNP for the measured gene region. In this case, the display unit may display at least one of susceptibility to hypertension when the sodium intake is less than 2 g/day and susceptibility to hypertension when the sodium intake is 2 g/day or more.

Hereinafter, the present invention will be described in more detail through examples. However, since these examples are merely intended to illustrate the present invention by way of example, the scope of the present invention should not be construed as being limited by these examples.

In the present invention, between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2, from biological samples isolated from the subject. and JAG1, a single nucleotide polymorphism (SNP) genotype for at least one gene region may be detected, and thus information on the risk of developing hypertension for the individual may be provided.

Furthermore, the present invention not only predicts and diagnoses the onset of hypertension in an individual, but also provides information on the risk of developing hypertension according to sodium intake, thereby promoting the individual's nutritional management to prevent and treat hypertension can promote

Furthermore, unlike conventional markers of salt sensitivity and high blood pressure, the present invention provides markers with high correlation in a domestic population with a high-salt specific eating habit, thereby providing higher predictive and diagnostic power for the domestic population than conventional markers. can

Furthermore, since the present invention is a genotype that appears specifically in hypertensive patients and rarely appears in normal people, it is possible to effectively diagnose the presence or risk of hypertension at an early stage, thereby enhancing the effectiveness of treatment.

Accordingly, the present invention can effectively predict the susceptibility of disease onset due to sodium intake, prevent disease at an early stage, and thereby reduce the burden of the patient's psychological and medical expenses.

Effects according to the present invention are not limited by the contents exemplified above, and more various effects are included in the present specification.

1 is a flowchart of a method for providing information on hypertension according to an embodiment of the present invention.
2 is a schematic diagram illustrating a selection process for an analysis group in a method for providing information on hypertension according to an embodiment of the present invention by way of example.
3 is a general characteristic result for an analysis group in a method for providing information on hypertension according to an embodiment of the present invention.
4a and 4b are the results of hypertension susceptibility genes according to Koreans in the method for providing information on hypertension according to an embodiment of the present invention.
5 is a SNP result related to hypertension susceptibility gene loci according to sodium intake in a method for providing information on hypertension according to an embodiment of the present invention.
6a and 6b are results of SNPs in a method for providing information on hypertension according to an embodiment of the present invention.
7 is a Miami plot result for gene regions including SNPs in a method for providing information on hypertension according to an embodiment of the present invention.

Advantages and features of the present invention, and methods of achieving them, will become clear with reference to the detailed description of the following embodiments taken in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and will be implemented in various forms different from each other, only these embodiments make the disclosure of the present invention complete, and common knowledge in the art to which the present invention pertains. It is provided to completely inform the person who has the scope of the invention, and the present invention is only defined by the scope of the claims.

As used herein, the term "prediction or diagnosis" includes all types of assays used to determine or elicit prediction of disease occurrence, risk of disease occurrence, and susceptibility to disease, and preferably It may include, but is not limited to, diagnosing or predicting the risk of developing by determining whether or not hypertension is present.

As used herein, the term "allele" refers to several types of a gene present in the same locus of a homologous chromosome, for example, an SNP has two types of alleles. Allele frequencies can be used to represent genetic polymorphisms within a particular population.

The term "rs_id" used in this specification may refer to an independent marker assigned to all SNPs initially registered by NCBI, which began accumulating SNP information in 1998. In the present specification, it is described in the form of rs (number), which may mean an SNP that is a polymorphic marker in the method for providing information on hypertension according to an embodiment of the present invention, and those skilled in the art can use rs-id The location and sequence of the SNP can be easily confirmed through NCBI. Furthermore, the specific sequence corresponding to NCBI's dbSNP (The Single Nucleotide Polymorphism Database) number rs_id and information about it may change little by little over time (according to the Genome Reference Consortium human genome build version), but It will be apparent to those skilled in the art that the scope extends to altered sequences.

As used herein, the term “polynucleotide or nucleic acid” may refer to DNA or RNA in single or double stranded form. DNA is composed of four bases: adenine (A), guanine (G), cytosine (C), and thymine (T), and RNA has uracil (U) instead of thymine. . In the nucleic acid double strand, A forms a hydrogen bond with T or U, and C with G base, and the relationship between these bases is called complementary. Furthermore, the term "genomic DNA" used in the present specification is the total nucleotide sequence of a gene of an individual, and may refer to DNA containing almost complete genetic information. Further, as used herein, the term “protein” refers to a polymer of amino acid residues, and may be used interchangeably with polypeptide or peptide.

As used herein, "one letter (three letters) of amino acid" may refer to the following amino acids according to standard abbreviation conventions in the field of biochemistry. A (Ala): alanine, C (Cys): cysteine, D (Asp): aspartic acid, E (Glu): glutamic acid, F (Phe): phenylalanine, G (Gly): glycine, H (His): histidine, I (IIe): isoleucine, K (Lys): lysine, L (Leu): leucine, M (Met): methionine, N (Asn): asparagine, O (Ply): pyrrolysine, P (Pro): Proline, Q (Gln): glutamine, R (Arg): arginine, S (Ser): serine, T (Thr): threonine, U (Sec): selenocysteine, V (Val): valine, W (Trp): Tryptophan and Y (Tyr): Tyrosine.

As used herein, "genome wide association study (GWAS)" is an analysis method for discovering genetic variations associated with a specific trait (disease), and SNPs or SNPs for the entire genome or a specific genome region Association studies with specific traits (diseases) are conducted using markers that can represent genetic variations, and the results of association studies show that specific genetic mutations are frequent in specific trait groups (disease groups) and normal groups. If it appears, it can be said that there is a correlation.

As used herein, the term "subject" may refer to a subject for prediction or diagnosis of a specific trait, that is, a salt sensitivity or hypertensive disease. Thus, by obtaining DNA from a biological sample isolated from an individual, the above-described specific trait of the individual can be predicted or diagnosed. At this time, the biological sample may include, but is not limited to, hair, urine, blood, various bodily fluids, separated tissues, isolated cells, and saliva, and may include any material from an object that can be extracted by DNA. there is.

Method for providing information on hypertension and kit accordingly

Hereinafter, a method for providing information on hypertension according to an embodiment of the present invention and a kit according to the method will be described in detail with reference to FIG. 1 .

Referring to FIG. 1 , a flowchart of a method for providing information on hypertension according to an embodiment of the present invention is shown. A method for providing information on hypertension according to an embodiment of the present invention provides information between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, RNF213, GML and CYP11B1 from a biological sample isolated from a subject. Detecting a single nucleotide polymorphism (SNP) genotype for at least one gene region among, between CNNM2 and NT5C2, between MYL2 and CUX2, and JAG1 (S110) and determining the risk of developing hypertension for the individual based on the detected genotype It may include the step (S120) of doing.

At this time, SNP (single nucleotide polymorphism), that is, single nucleotide polymorphism means that only a single base differs among polymorphic sites in which two or more alleles exist in one locus. SNPs are relatively frequent and stable, and are distributed throughout the genome, so they can generate genetic diversity of individuals. In addition, SNPs may generally include phenotypic changes associated with single nucleotide polymorphisms, and the SNPs of the present invention may indicate retrospective susceptibility and consequently differences in the incidence of hypertension. Furthermore, in the present specification, "SNP" may be used interchangeably with "mutation" and "SNP marker".

First, between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2, from DNA of biological samples isolated from individuals and rs67617923, rs16998073, rs11191582, rs11105378, rs12509595, rs6913309, rs112735431, rs381949 in the step of detecting a single nucleotide polymorphism (SNP) genotype for at least one gene region of JAG1 (S110). 6, at least one of rs140473396, rs12229654 and rs1887320 SNPs can be detected.

More specifically, first, the SNP rs67617923 may be all or part of a polynucleotide including the 101st base of the polynucleotide of SEQ ID NO: 1 for the EML6 gene region. Furthermore, the 101st base corresponding to the polynucleotide of SEQ ID NO: 1 is G or A, and rs67617923 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs16998073 may be all or part of the polynucleotide including the 101st base in the polynucleotide of SEQ ID NO: 2 for the FGF5 gene region. Furthermore, the 101st corresponding base in the polynucleotide of SEQ ID NO: 2 is A or T, and rs16998073 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs11191582 may be all or part of a polynucleotide including the 101st base of the polynucleotide of SEQ ID NO: 3 for the NT5C2 gene region. Furthermore, the 101st corresponding base in the polynucleotide of SEQ ID NO: 3 is G or A, and rs11191582 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs11105378 may be all or part of a polynucleotide including the 101st base in the polynucleotide of SEQ ID NO: 4 for the gene region between ATP2B1 and LINC00936. Furthermore, the 101st corresponding base in the polynucleotide of SEQ ID NO: 4 is C or T, and rs11105378 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs12509595 may be all or part of a polynucleotide including the 101st base in the polynucleotide of SEQ ID NO: 5 for the gene region between PRDM8 and FGF5. Furthermore, the 101st corresponding base in the polynucleotide of SEQ ID NO: 5 is T or C, and rs12509595 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs6913309 may be all or part of a polynucleotide including the 81st base in the polynucleotide of SEQ ID NO: 6 for the gene region between C6orf10 and HLA-DQB1. Furthermore, the base corresponding to the 81st position in the polynucleotide of SEQ ID NO: 6 is T or A, and rs6913309 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs112735431 may be all or part of a polynucleotide including the 100th base corresponding to the polynucleotide of SEQ ID NO: 7 for the RNF213 gene region. Furthermore, the 100th base in the polynucleotide of SEQ ID NO: 7 is G or A, and rs112735431 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs3819496 may be all or part of a polynucleotide including the 91st base in the polynucleotide of SEQ ID NO: 8 for the gene region between GML and CYP11B1. Furthermore, the base corresponding to the 91st position in the polynucleotide of SEQ ID NO: 8 is A or G, and rs3819496 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Next, the SNP rs140473396 may be all or part of a polynucleotide including the 51st base in the polynucleotide of SEQ ID NO: 9 for the gene region between CNNM2 and NT5C2. Furthermore, the 51st base corresponding to the polynucleotide of SEQ ID NO: 9 is ACACACAC or AC, and rs140473396 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not. More specifically, as the SNP rs140473396 is a section in which insertion and/or deletion are repeated in various types of SNPs, the base corresponding to the 51st in the polynucleotide of SEQ ID NO: 9 is ACACACAC or AC as well as , a more diverse sequence of bases may be included.

Next, the SNP rs12229654 may be all or part of a polynucleotide including the 101st base in the polynucleotide of SEQ ID NO: 10 for the gene region between MYL2 and CUX2. Furthermore, the 101st corresponding base in the polynucleotide of SEQ ID NO: 10 is T or G, and rs140473396 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

Finally, the SNP rs1887320 may be all or part of a polynucleotide including the 101st base in the polynucleotide of SEQ ID NO: 11 for the JAG1 gene region. Furthermore, the 101st base corresponding to the polynucleotide of SEQ ID NO: 11 is A or G, and rs1887320 may be a polynucleotide consisting of 5 to 300 consecutive bases including this or a polynucleotide complementary thereto, but is limited thereto It is not.

In addition, the nucleotide sequences for SNPs, that is, SEQ ID NOs: 1 to 11 used in the method for providing information on hypertension according to an embodiment of the present invention, considering mutations having biological equivalent activity, are substantially similar to the sequences described in the sequence listing. Sequences showing substantial identity may also be included. At this time, the substantial identity is to align the sequence in the method for providing information on hypertension according to an embodiment of the present invention and any other sequence so as to correspond as much as possible, and an algorithm commonly used in the art. When the aligned sequence is analyzed using , it may mean a sequence showing homology of at least 60%, preferably 70%, more preferably 80%, and still more preferably 90%. Therefore, the SNP used in the method for providing information on hypertension according to an embodiment of the present invention is a base sequence having high homology with the base sequence represented by SEQ ID NOs: 1 to 11 including the above-described SNP, for example, It may include all base sequences having a high homology of 70% or more, preferably 80% or more, and most preferably 90% or more.

Furthermore, from the DNA of the biological sample isolated from the subject, between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2 and JAG1, in the step of detecting a single nucleotide polymorphism (SNP) genotype for at least one gene region (S110), sequencing analysis, hybridization by microarray, allele specific PCR (allele specific PCR), dynamic allele By at least one method of dynamic allele-specific hybridization (DASH), PCR extension analysis, PCR-single strand conformation polymorphism (PCR-SSCP), PCR-resctriction fragment length polymorphism (PCR-RFLP), and TaqMan technique It may be performed, but is not limited thereto, and may include all of various methods that can be used for nucleotide sequence confirmation by those skilled in the art to which the present invention belongs.

More specifically, the detection of the SNP genotype can be performed by a PCR method that amplifies the DNA fragment where the above-described SNP is located using a primer set including a primer designed with the base where the SNP is located as the 3' end.

For example, to detect the case where a specific base is substituted from A to G, a PCR reaction can be performed by designing a primer containing A as the 3' terminal base and an opposite primer capable of amplifying a DNA fragment of an appropriate size. there is. Accordingly, when the base at the SNP position described above is A, the amplification reaction is normally performed and a band at the desired position is observed. When the above-mentioned base is substituted with G, the primer can complementarily bind to the template DNA, but the 3' A band may not be observed because the amplification reaction is not performed properly because the end side is not able to form a complementary bond.

Furthermore, PCR extension analysis first amplifies a DNA fragment containing the base where the single nucleotide polymorphism is located with a primer pair, and then inactivates it by dephosphorylating all nucleotides added to the reaction, whereby a SNP-specific extension primer, This may be achieved by performing a primer extension reaction by adding a dNTP mixture, dideoxynucleotide, reaction buffer, and DNA polymerase.

At this time, the extension primer takes the base immediately adjacent to the 5' direction of the base where the SNP is located as the 3' end, nucleic acids having the same base as dideoxynucleotide are excluded from the dNTP mixture, and dideoxynucleotide is SNP. It is selected from one of the base types shown. For example, in the case of an A to G substitution, when a mixture of dGTP, dCTP and TTP and ddATP are added, the primers are extended by DNA polymerase, and after a few bases, the first occurrence of the A base is cleaved by ddATP. The primer extension reaction may be terminated. At this time, if the substitution of the base does not occur, the extension reaction is terminated at that position, so the type of base representing the SNP can be determined by comparing the lengths of the extended primers.

Furthermore, the detection method can detect SNPs by detecting the fluorescence of a genetic analyzer used for general sequencing when the extended primer or dideoxynucleotide is fluorescently labeled, and the non-labeled extended primer and dideoxynucleotide In case of using MALDITOF (matrix assisted laser desorption ionization-time of flight) technique, SNP can be detected by measuring molecular weight. However, the above method is an exemplary SNP detection method, and is not limited thereto, and the SNP detection method may be performed using various methods.

Next, in the step of determining the risk of developing hypertension for the individual based on the detected genotype (S120), the risk of developing hypertension according to the salt intake of the individual can be determined through the specific base of the SNP detected by the above method. . More specifically, between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, between RNF213, between GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2, and for the JAG1 gene region, respectively. According to one of the bases corresponding to the 51st to 101st polynucleotides of SEQ ID NOs: 1 to 11 of , it can be determined as a high-risk group and a low-risk group for developing hypertension according to a predetermined level of sodium intake.

For example, first, the 101st corresponding base in the polynucleotide of SEQ ID NO: 1 for the EML6 gene region may include G or A, and in this case, if the base is A, determining the risk of developing hypertension (S120 ), the individual can be determined as a high-risk group for developing hypertension.

Next, the 101st corresponding base in the polynucleotide of SEQ ID NO: 2 for the FGF5 gene region may include A or T. In this case, if the base is T, in the step of determining the risk of developing hypertension (S120), the individual can be determined as a high-risk group for developing hypertension.

Next, the 101st corresponding base in the polynucleotide of SEQ ID NO: 3 for the NT5C2 gene region may include G or A. In this case, if the base is A, in the step of determining the risk of developing hypertension (S120), the individual can be determined as a low-risk group for developing hypertension.

Next, the 101st corresponding base in the polynucleotide of SEQ ID NO: 4 for the gene region between ATP2B1 and LINC00936 may include C or T, and in this case, if the base is T, determining the risk of developing hypertension (S120 ), the individual can be determined as a low-risk group for developing hypertension.

Next, the 101st corresponding base in the polynucleotide of SEQ ID NO: 5 for the gene region between PRDM8 and FGF5 may include T or C, and in this case, if the base is C, determining the risk of developing hypertension (S120 ), if the salt intake is 2 g / day or more, it can be determined as a high-risk group for hypertension.

Then, the 81st corresponding base in the polynucleotide of SEQ ID NO: 6 for the gene region between C6orf10 and HLA-DQB1 may include T or A, wherein, if the base is A, determining the risk of developing hypertension In (S120), if the salt intake is 2g/day or more, the individual may be determined as a high-risk group for developing hypertension.

Then, the 100th corresponding base in the polynucleotide of SEQ ID NO: 7 for the RNF213 gene region may include G or A. In this case, if the base is A, in the step of determining the risk of developing hypertension (S120), the individual If salt intake is 2 g/day or more, it can be determined as a high-risk group for hypertension.

Next, the 91st corresponding base in the polynucleotide of SEQ ID NO: 8 for the gene region between GML and CYP11B1 may include A or G, and in this case, if the base is G, determining the risk of developing hypertension (S120 ), if the salt intake is 2 g / day or more, it can be determined as a low-risk group for developing hypertension.

Then, the 51st corresponding base in the polynucleotide of SEQ ID NO: 9 for the gene region between CNNM2 and NT5C2 may include ACACACAC or AC, and in this case, if the base is AC, determining the risk of developing hypertension (S120 ), if the salt intake is 2 g / day or more, it can be determined as a low-risk group for developing hypertension. At this time, rs140473396, which is the 51st base in the polynucleotide of SEQ ID NO: 9 for the gene region between CNNM2 and NT5C2, is a section in which insertion and / or deletion of various types of SNPs are repeated. The base corresponding to the 51st position in the polynucleotide of No. 9 may include not only ACACACAC or AC, but also a variety of base sequences.

Then, the 101st corresponding base in the polynucleotide of SEQ ID NO: 10 for the gene region between MYL2 and CUX2 may include T or G, and in this case, if the base is G, determining the risk of developing hypertension (S120 ), if the salt intake is 2 g / day or more, it can be determined as a low-risk group for developing hypertension.

Finally, the 101st corresponding base in the polynucleotide of SEQ ID NO: 11 for the JAG1 gene region may include A or G. In this case, if the base is G, in the step of determining the risk of developing hypertension (S120), the individual If salt intake is 2g/day or more, it can be determined as a low-risk group for developing hypertension.

Accordingly, the method for providing information on hypertension according to an embodiment of the present invention can predict and diagnose the risk and susceptibility of developing hypertension of an individual according to salt intake by the method described above.

Furthermore, the present invention may provide a composition based on the method for providing information on hypertension described above and a kit including the same.

First, the composition for providing information on hypertension according to an embodiment of the present invention is between EML6, FGF5, NT5C2, ATP2B1 and LINC00936, between PRDM8 and FGF5, between C6orf10 and HLA-DQB1, A probe or primer configured to amplify or detect a polynucleotide comprising a single nucleotide polymorphism (SNP) site for at least one gene region of RNF213, between GML and CYP11B1, between CNNM2 and NT5C2, between MYL2 and CUX2, and JAG1 (primer) may be included.

At this time, the probe may mean a polynucleotide fragment such as RNA or DNA having a length of several to hundreds of base pairs that can specifically bind to mRNA, cDNA (complementary DNA), DNA, etc. of a specific gene, As a labeling factor such as fluorescence or radiation is additionally attached to the 5' or 3' end of the probe so that it can be recognized with the naked eye, the presence or absence of the target mRNA or cDNA to be bound and the amount of expression can be confirmed. there is. For example, a probe may include a sequence capable of binding to or recognizing a SNP, i.e., complementary to a polynucleotide sequence comprising the SNP. Furthermore, the probe may be in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, or an RNA probe,

At this time, selection of such a probe and hybridization conditions may be appropriately selected according to techniques known in the art. Furthermore, the probe can be used in diagnostic methods for detecting alleles (or alleles). At this time, the diagnosis method includes detection methods based on nucleic acid hybridization such as Southern blot, etc., and in a method using a DNA chip, it may be provided in a form pre-bound to a substrate of a DNA chip, but is not limited thereto.

Furthermore, a primer may refer to a short single-stranded oligonucleotide that serves as a starting point for DNA synthesis. The primer specifically binds to a polynucleotide as a template under suitable buffer and temperature conditions, and DNA polymerase adds a nucleoside triphosphate having a base complementary to the template DNA to the primer. DNA is synthesized by linking them together. Primers generally consist of 15 to 30 nucleotide sequences, and the melting temperature (Tm) of binding to the template strand may vary depending on the base composition and length. The sequence of the primer does not have to have a sequence completely complementary to a part of the base sequence of the template, and it is sufficient to have sufficient complementarity within a range capable of hybridizing with the template and performing the specific function of the primer. Primers for the polymerase chain reaction (PCR) are the template (or sense) and the opposite side (antisense, antisense) of both ends (5' end or 3' end) of a specific section of the polynucleotide to be amplified. ) It may consist of a pair (set) that binds complementary to each. Furthermore, those skilled in the art can easily design a primer pair by referring to the nucleotide sequence of the cDNA or genetic DNA for the SNP site of SEQ ID NOs: 1 to 11 described above.

In addition, the probe or primer of the composition based on the method for providing information on hypertension according to the present invention can be chemically synthesized using a phosphoramidite solid support method or other well-known methods. Such nucleic acid sequences can also be modified using a number of means known in the art. Here, non-limiting examples of modifications include methylation, "capping", substitution of one or more homologs of a natural nucleotide, and modifications between nucleotides, such as uncharged linkages (e.g., methyl phosphonates, phosphotriesters). , phosphoroamidates, carbamates, etc.), or transformation into charged linkages (eg, phosphorothioates, phosphorodithioates, etc.); and the like.

Therefore, in the present invention, the probe or primer of the composition based on the method for providing information on hypertension is G or A, which is the 101st base in SEQ ID NO: 1 for the gene region of EML6, and the 101st base in SEQ ID NO: 2 for the gene region of FGF5. A or T, G or A, the 101st base in SEQ ID NO: 3 for the gene region of NT5C2, C or T, the 101st base in SEQ ID NO: 4 for the gene region between ATP2B1 and LINC00936, and the gene between PRDM8 and FGF5 T or C, the 101st base in SEQ ID NO: 5 for the region, T or A, the 81st base in SEQ ID NO: 6 for the genomic region between C6orf10 and HLA-DQB1, 100th base in SEQ ID NO: 7 for the gene region of RNF213 ACACACAC or AC, MYL2, which is the 51st base in SEQ ID NO: 9 for the gene region between A or G, CNNM2 and NT5C2, which is the 91st base in SEQ ID NO: 8 for the gene region between bases G or A, GML and CYP11B1, and T or G, the 101st base in SEQ ID NO: 10 for the gene region between CUX2 and A or G, the 101st base in SEQ ID NO: 11 for the gene region of JAG1, can be amplified or detected.

Next, in the present invention, the kit including the composition based on the method for providing information on hypertension may be at least one of RT-PCR, ddPCR, microarray chip and DNA chip kits, and the above-described SNPs of SEQ ID NOs: 1 to 11 Information on hypertension according to the individual's salt intake can be determined by detection through amplification or by detecting the expression level of the SNP.

For example, when a kit containing a composition based on the method for providing information on hypertension according to an embodiment of the present invention is a kit necessary for performing RT-PCR or dd-PCR, each probe specific for SNP Alternatively, in addition to primer pairs, a test tube or other suitable container, reaction buffer, deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile It may include a number and the like, but is not limited thereto. In addition, a primer pair specific to a gene used as a control may be included.

Furthermore, a kit including a composition based on the method for providing information on hypertension according to an embodiment of the present invention may be a kit for performing a DNA chip. A DNA chip generally has nucleic acid species attached to the surface of a flat solid support plate in a gridded array. It is an analysis tool that enables mass parallel analysis by multiple hybridization reactions between hostile nucleic acids.

Furthermore, a kit including a composition based on the method for providing information on hypertension according to an embodiment of the present invention may be a kit for performing a microarray chip. In the case of a kit for performing a microarray chip, a kit including a composition based on a method for providing information on hypertension according to an embodiment of the present invention is immobilized with a nucleic acid including at least one SNP of SEQ ID NOs: 1 to 11. It may include a microarray having a substrate with The microarray may be composed of a conventional microarray except for including the polynucleotide, primer or probe of the present invention. Hybridization of nucleic acids on microarrays and detection of hybridization results are well known in the art. At this time, the detection is, for example, labeling the nucleic acid sample with a labeling factor capable of generating a detectable signal including a fluorescent material such as Cy3 and Cy5, hybridization on a microarray, and the signal generated from the labeling material. The hybridization result can be detected by detection.

Furthermore, a kit containing a composition based on the method for providing information on hypertension according to an embodiment of the present invention exhibits an individual's susceptibility to hypertension according to salt intake according to the genotype of the SNP for the measured gene region. It may further include a display means configured to. More specifically, the display means, according to the SNPs of SEQ ID NOs: 1 to 11, that is, one of the 51st to 101st bases, when the salt intake is less than 2g / day, the susceptibility to hypertension and when the salt intake is 2g / day or more At least one of the onset susceptibility to high blood pressure may be displayed, but is not limited thereto, and all of various information that may be derived through the method for providing information on high blood pressure according to an embodiment of the present invention may be displayed.

Through the above process, the method for providing information on hypertension according to an embodiment of the present invention, the composition based thereon, and the kit including the same can predict and diagnose a disease for an individual, that is, hypertension, through gene detection and confirmation, In addition, by predicting and diagnosing the onset susceptibility of hypertension due to salt intake, which may be a major cause of hypertension, it is possible to reduce the incidence of hypertension in individuals through nutritional management.

Hereinafter, SNPs of a method for providing information on hypertension according to an embodiment of the present invention will be described with reference to FIGS. 2 to 7 .

2 is a schematic diagram illustrating a selection process for an analysis group in a method for providing information on hypertension according to an embodiment of the present invention by way of example.

In order to select genetic mutations optimized for the Korean genome, the inventors of the present invention first collected samples of men and women aged 40 or older who had undergone health examinations at medical institutions and medical-related centers, and among them, blood pressure, waist circumference, body mass, alcohol Cases with missing values for data such as , smoking and exercise were excluded.

Then, among the selected group, patients with a systolic blood pressure of 140 mmHg or higher (SBP≥140 mmHg), a diastolic blood pressure of 90 mmHg or higher (DBP≥90 mmHg), and a history of hypertension in the past were defined as hypertensive patients, and groups were classified according to sodium intake. Divided. More specifically, the inventors of the present invention divided the group to which the above exclusion criteria were applied into a control group without hypertension and cardiovascular disease and a patient group with hypertension and cardiovascular disease, that is, a case group, and then each again. Within the group for , group 1 with sodium intake of 2 g/day or more and group 2 with sodium intake of less than 2 g/day were compared.

At this time, for comparison of each group, blood was extracted into a blood tube containing EDTA, and then SNP genotypes of each group were extracted using an array (KoreanChip) of the National Biobank of Korea. Furthermore, in order to confirm the association between SNP and salt intake with hypertension, logistic regression analysis was used to calculate and show odds ratios (ORs) and 95% confidence intervals (CIs).

Accordingly, the finally obtained population data has the effect of easily identifying genes that can cause salt intake and consequently high blood pressure by applying the above-mentioned exclusion criteria, and further selecting genes optimized for Koreans. .

Furthermore, referring to FIG. 3 , general characteristic results for the analysis group selected through the above-described process are shown. First, regardless of hypertension, the group with sodium intake of 2g/day or more showed significantly higher waist circumferences and diastolic blood pressure (DBP) than the group with sodium intake of less than 2g/day (P-value ¹ <0.0001).

Furthermore, the group with no hypertension and sodium intake of 2 g/day or more showed significantly higher average waist circumferences, systolic blood pressure (SBP) and diastolic blood pressure (DBP) than the group with sodium intake of less than 2 g/day ( P-value ² <0.0001).

Furthermore, the group with hypertension and sodium intake of 2g/day or more showed significantly higher body mass index (BMI) and waist circumferences than the group with sodium intake of less than 2g/day (P-value ³ < 0.0001).

As a result, body mass index (BMI), waist circumferences, systolic blood pressure (SBP) and diastolic blood pressure (DBP) may vary according to sodium intake.

4a and 4b are the results of hypertension susceptibility genes according to Koreans in the method for providing information on hypertension according to an embodiment of the present invention.

First, referring to FIG. 4A , genetic loci for hypertension susceptibility found in a conventional genome-wide association study (GWAS), that is, SNPs are shown. SNPs for hypertension susceptibility previously identified may include rs12037987, rs13394970, rs72806698, rs73029563, rs388224, rs16998073, rs6590816, rs11105365 and rs167479, and their odds ratios (Odds Ratio, OR) is found to be between 0.899 and 1.240. That is, when an object includes at least one of conventional rs12037987, rs13394970, rs72806698, rs73029563, rs388224, rs16998073, rs6590816, rs11105365, and rs167479, it is 0.899 to 1. As shown to be 240 times more susceptible to hypertension, , may increase the incidence of hypertension.

Next, referring to FIG. 4B , loci for hypertension susceptibility selected through the determined population of FIG. 2 described above, that is, SNPs are shown. A total of 1,278 SNPs for hypertension susceptibility were selected through the determined group of FIG. 2, among which SNPs highly associated with hypertension were rs3821843, rs6831174, rs112590692, rs2472928, rs3819305, rs7812039, rs4527847, rs4948645 , rs140473396, rs7938342, rs7485618, rs112735431 and rs913220 (P<1X10 ^-8 ), and their odds ratio is 0.848 to 1.651. That is, if the object is rs3821843, rs6831174, rs112590692, rs2472928, rs3819305, rs7812039, rs4527847, rs4948645, rs140473396, rs7938342, rs7485618, rs11 When at least one of 2735431 and rs913220 was included, it was 0.848 to 1.651 times higher for hypertension than subjects without it. It appears to be highly sensitive, which appears to be at a similar level to the conventional SNPs described above.

Furthermore, the SNP shown in FIG. 4b appears to be a completely different SNP from the aforementioned conventional SNP of FIG. 4a. That is, the results of these many SNPs may mean that there is a gene that gives sensitivity to hypertension specifically according to the group.

5 is a SNP result related to hypertension susceptibility gene loci according to sodium intake in a method for providing information on hypertension according to an embodiment of the present invention.

First, when sodium intake is less than 2 g / day, SNPs statistically significantly associated with hypertension appear to be rs67617923, rs16998073, rs11191582 and rs11105378 (P=5X10 ^-6 to P=5X10 ^-9 ).

Among them, rs67617923 and rs16998073 have odds ratios of 1.294 and 1.245, respectively. When an individual includes rs67617923 and rs16998073, the incidence of hypertension is 1.294 and 1.245 times higher than that of individuals without rs67617923 and rs16998073, respectively. Accordingly, in the method for providing information on hypertension according to an embodiment of the present invention, when the individual has at least one of rs67617923 and rs16998073, the individual may be determined as a high-risk group for developing hypertension. That is, an individual containing at least one of rs67617923 and rs16998073 may have a higher sensitivity to sodium than an individual not containing the same, and thus may have a higher incidence of hypertension.

In this case, rs67617923 is a SNP included in the EML6 gene, and may be the A genotype (base) of 54968517 bp of chromosome 2. In addition, rs16998073 is a SNP included in the FGF5 gene, and may be a T genotype (base) at 81184341 bp of chromosome 4.

Then, the odds ratios of rs11191582 and rs11105378 are 0.849 and 0.874, respectively, and when the individual includes rs67617923 and rs16998073, the incidence of hypertension is 0.849 and 0.874 times lower than that of the individual not including rs16998073, respectively. Accordingly, in the method for providing information on hypertension according to an embodiment of the present invention, when the individual has at least one of rs11191582 and rs11105378, the individual may be determined as a low-risk group for developing hypertension.

In this case, rs11191582 is a SNP included in the NT5C2 gene, and may be the A genotype (base) of 104913653 bp of chromosome 10. In addition, rs11105378 is a SNP included in the gene region between ATP2B1 and LINC00936, and may be a T genotype (base) located at 90090741 bp of chromosome 12.

Furthermore, when sodium intake was 2 g/day or more, SNPs statistically significantly associated with hypertension were rs12509595, rs6913309, rs112735431, rs3819496, rs140473396, rs12229654, rs112735431 and rs1887320 (P=5X 10 ^-6 to P=5X10 ^{- 9} ).

Among them, rs12509595, rs6913309, and rs112735431 have odds ratios of 1.228, 1.145, and 1.706, respectively. It appears that the incidence of hypertension is 1.706 times higher . Accordingly, in the method for providing information on hypertension according to an embodiment of the present invention, when the individual has at least one of rs12509595, rs6913309, and rs112735431, and the individual has a sodium intake of 2 g/day or more, the high-risk group for developing hypertension can be determined. That is, an individual containing at least one of rs12509595, rs6913309, and rs112735431 has a higher sensitivity to sodium than an individual not containing the same, and thus may have a higher incidence of hypertension.

In this case, rs12509595 is a SNP included in the gene region between PRDM8 and FGF5, and may be a C genotype (base) at 81182554 bp of chromosome 4. In addition, rs6913309 is a SNP included in the gene region between C6orf10 and HLA-DQB1, and may be an A genotype (base) at 32339840 bp of chromosome 6. In addition, rs112735431 is a SNP included in the RNF213 gene, and may be the A genotype (base) of 78358945 bp of chromosome 17.

Then, rs3819496, rs140473396, rs12229654, and rs1887320 have odds ratios of 0.892, 0.836, 0.834, and 0.892, respectively, so that the objects are rs3819496, rs140473396, rs12229654, and rs188732 Inclusion of 0 was 0.892, 0.836, 0.834, and 0.892, respectively, than subjects without it. It appears to be twice as low in the incidence of hypertension. Accordingly, in the method for providing information on hypertension according to an embodiment of the present invention, when the subject includes at least one of rs3819496, rs140473396, rs12229654, and rs1887320, the subject has a sodium intake of 2 g / day or more. there is. That is, an individual containing at least one of rs3819496, rs140473396, rs12229654, and rs1887320 may have a lower sensitivity to sodium than an individual not containing the same, and thus may have a lower incidence of hypertension.

In this case, rs3819496 is a SNP included in the gene region between GML and CYP11B1, and may be a G genotype (base) located at 143923891 bp of chromosome 8. In addition, rs140473396 is a SNP included in the gene region between CNNM2 and NT5C2, and may be the AC genotype (base) of 104795885 bp position of chromosome 10. In addition, rs12229654 is a SNP included in the gene region between MYL2 and CUX2, and may be a G genotype (base) located at 111414461 bp of chromosome 12. In addition, rs1887320 is a SNP included in the JAG1 gene, and may be a G genotype (base) located at 10965998 bp of chromosome 20.

Accordingly, a method for providing information on hypertension according to an embodiment of the present invention is rs67617923, rs16998073, rs11191582, rs11105378, rs12509595, rs6913309, rs112735431, rs3819496, rs140473396, rs1222 Through at least one of 9654 and rs1887320, to the sodium intake for the subject It is possible to predict and diagnose the risk of developing hypertension according to

Furthermore, referring to FIGS. 6A and 6B , results of SNPs in the method for providing information on hypertension according to an embodiment of the present invention described above are shown.

First, referring to FIG. 6A , when sodium intake is less than 2 g/day, SNPs capable of predicting and diagnosing the risk of developing hypertension are shown.

SNPs that may increase the incidence of hypertension when sodium intake is less than 2 g/day appear to include rs67617923 and rs16998073.

At this time, rs67617923 is the 101st base in SEQ ID NO: 1 for the EML6 gene region is A, and by detecting this, the individual is highly sensitive to sodium, and thus a high-risk group for developing hypertension, which can develop hypertension even with a small amount of sodium intake can decide Furthermore, when the 101st base in SEQ ID NO: 1 for the EML6 gene region is G, the individual can be determined as a normal or low-risk group for developing hypertension.

In addition, rs16998073 is the 101st base in SEQ ID NO: 2 for the FGF5 gene region is T, and by detecting this, the individual is highly sensitive to sodium, making it a high-risk group for developing hypertension, which can cause hypertension even with a small amount of sodium intake can decide Furthermore, when the 101st base in SEQ ID NO: 2 for the FGF5 gene region is A, the individual may be determined as a normal or low-risk group for developing hypertension.

SNPs that can reduce the incidence of hypertension when sodium intake is less than 2 g/day appear to include rs11191582 or rs11105378.

At this time, rs11191582 is the 101st base in SEQ ID NO: 3 for the NT5C2 gene region is A, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 101st base in SEQ ID NO: 3 for the NT5C2 gene region is G, the individual can be determined to be normal.

In addition, rs11105378 is T at the 101st base in SEQ ID NO: 4 for the gene region between ATP2B1 and LINC00936, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 101st base in SEQ ID NO: 4 for the gene region between ATP2B1 and LINC00936 is C, the individual can be determined to be normal.

Next, referring to FIG. 6B , SNPs capable of predicting and diagnosing the risk of developing hypertension when sodium intake is 2 g/day or more are shown.

SNPs that can increase the incidence of hypertension when sodium intake is 2 g/day or more appear to include rs12509595, rs6913309 and rs112735431.

At this time, rs12509595 is the 101st base in SEQ ID NO: 5 for the gene region between PRDM8 and FGF5 is C, and by detecting this, according to the high sensitivity of the individual to sodium, when the sodium intake is 2 g / day or more, hypertension develops It can be determined as a high-risk group for developing hypertension. Furthermore, when the 101st base in SEQ ID NO: 5 for the gene region between PRDM8 and FGF5 is T, the individual may be determined as a normal or low-risk group for developing hypertension.

In addition, rs6913309 is the 81st base in SEQ ID NO: 6 for the gene region between C6orf10 and HLA-DQB1 is A, and by detecting this, according to the high sensitivity to sodium, when the sodium intake is 2 g / day or more, hypertension It can be determined as a high-risk group for developing hypertension. Furthermore, when the 81st base in SEQ ID NO: 6 for the gene region between C6orf10 and HLA-DQB1 is T, the individual may be determined as a normal or low-risk group for developing hypertension.

In addition, in rs112735431, the 100th base in SEQ ID NO: 7 for the RNF213 gene region is A, and by detecting this, according to the high sensitivity of the individual to sodium, when the sodium intake is 2 g / day or more, hypertension can develop It can be determined as a high-risk group for developing hypertension. Furthermore, when the 100th base in SEQ ID NO: 7 for the RNF213 gene region is G, the individual may be determined as a normal or low-risk group for developing hypertension.

SNPs that may increase the incidence of hypertension when sodium intake is 2 g/day or more appear to include rs3819496, rs140473396, rs12229654 and rs1887320.

In this case, rs3819496 is G at the 91st base in SEQ ID NO: 8 for the gene region between GML and CYP11B1, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 91st base in SEQ ID NO: 8 for the gene region between GML and CYP11B1 is A, the individual can be determined to be normal.

In addition, rs140473396 is AC at 51st base in SEQ ID NO: 9 for the gene region between CNNM2 and NT5C2, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 51st base in SEQ ID NO: 9 for the gene region between CNNM2 and NT5C2 is AC, the individual can be determined to be normal.

In addition, rs12229654 is G at the 101st base in SEQ ID NO: 10 for the gene region between MYL2 and CUX2, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 101st base in SEQ ID NO: 10 for the gene region between MYL2 and CUX2 is T, the individual can be determined to be normal.

In addition, rs1887320 is G at the 101st base in SEQ ID NO: 11 for the JAG1 gene region, and by detecting this, the individual can be determined as a low-risk group for developing hypertension. Furthermore, when the 101st base in SEQ ID NO: 11 for the JAG1 gene region is A, the individual can be determined to be normal.

Relatedly, referring to FIG. 7 , a Miami plot result for a gene region including SNPs in a method for providing information on hypertension according to an embodiment of the present invention is shown. At this time, the Miami plot is a chart visualized by displaying the statistical value, that is, the p-value, in each SNP in a scatter plot according to the location in the genome of the SNP, and through this, if the association with the phenotype is shown, SNPs showing significance above or near the threshold at the locus may appear in clusters.

In the case of sodium intake of 2g/day or more, genes containing statistically significant SNPs with a p value of 5x10 ^-8 or less include FGF5, HLA-DQ5, CYP17A1, CNNM2, NT5C2, ATP2B1, MYL2, RNF213, and JAG1. appears as That is, the above-mentioned SNPs for the FGF5, HLA-DQ5, CYP17A1, CNNM2, NT5C2, ATP2B1, MYL2, RNF213, and JAG1 gene regions were significantly associated with hypertension when consuming more than 2g/day of sodium than other SNPs. can mean

Accordingly, in the method for providing information on hypertension according to an embodiment of the present invention, when the sodium intake is 2 g/day or more, the SNP genes associated with hypertension are PRDM8-FGF5, C6orf10-HLA-DQB1, RNF213, GML-CYP11B1, It may include at least one of CNNM2-NT5C2, MYL2-CUX2, and JAG1, and since SNPs other than GML-CYP11B1 show high significance in the above-described Miami plot, they may be markers with higher predictive and diagnostic power. Therefore, preferably, in the method for providing information on hypertension according to an embodiment of the present invention, when sodium intake is 2g/day or more, genes of SNPs associated with hypertension are PRDM8-FGF5, C6orf10-HLA-DQB1, RNF213, It may be at least one of CNNM2-NT5C2, MYL2-CUX2, and JAG1.

Furthermore, when sodium intake is less than 2 g / day, genes containing significant SNPs with a p value of 5x10 ^-8 or less appear to include SPTBN1, FGF5, CYP17A1, CNNM2, NT5C2 and ATP2B1. That is, it may mean that the above-mentioned SNPs for the SPTBN1, FGF5, CYP17A1, CNNM2, NT5C2, and ATP2B1 gene regions are significantly associated with hypertension when consuming less than 2 g/day of sodium than other SNPs.

Therefore, in the method for providing information on hypertension according to an embodiment of the present invention, when the sodium intake is less than 2 g / day, the gene of the SNP associated with hypertension may include at least one of EML6, FGF5, NT5C2 and ATP2B1 - LINC00936 And, as SNPs other than EML6 show high significance in the above-described Miami plot, they may be markers with higher predictive and diagnostic power. Therefore, preferably, in the method for providing information on hypertension according to an embodiment of the present invention, when the sodium intake is less than 2 g / day, the SNP gene associated with hypertension is FGF5, NT5C2 and ATP2B1 - At least one of LINC00936. there is.

According to the above results, the method for providing information on hypertension according to an embodiment of the present invention can more accurately predict and diagnose hypertension by providing markers with high statistical significance and correlation according to sodium intake, and furthermore, By predicting and diagnosing hypertension at an early stage, the individual can perform nutritional management for the prevention and treatment of hypertension on their own, so that the therapeutic effect on hypertension can be enhanced.

Although the embodiments of the present invention have been described in more detail with reference to the accompanying drawings, the present invention is not necessarily limited to these embodiments, and may be variously modified and implemented without departing from the technical spirit of the present invention. Therefore, the embodiments disclosed in the present invention are not intended to limit the technical idea of the present invention, but to explain, and the scope of the technical idea of the present invention is not limited by these embodiments. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting. The protection scope of the present invention should be construed according to the claims below, and all technical ideas within the equivalent range should be construed as being included in the scope of the present invention.

<110> Industry-Academic Cooperation Foundation, Yonsei University <120> METHOD FOR PROVIDING INFORMATION FOR HYPERTENSION AND KITS USING THE SAME <130> DP-2020-0801 <160> 11 <170> KoPatentIn 3.0 <210> 1 <211> 211 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = G or A <400> 1 cccctagccc atcctctgct caagaacctg gtgaacttaa acaaaaaaat tcagatttaa 60 tgaccccact cctaaggatt ctgattcagt aggtataggt ntgaggcccc aaaatctgca 120 tttaaaaagt tgccatagaa atatatatat aggtgtatat aaataagtac acatgcacac 180 acacacacac ttccttgctc tttctgttaa g 211 <210> 2 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = A or T <400> 2 tgtccgtcct tccaacccag catgagacat tgtaggatga acagtcttgc cttcaggacc 60 cttgcctcag tgaggcctgg cctcagttta aacccagggg natgttgtaa atattgagac 120 ggtctctaga gtgaaggaaa tattgggctc tgacttgact tatacaccct gacttctctt 180 ttcttaggct tctgggttcc a 201 <210> 3 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = G or A <400> 3 tgtagttat tcctccctca gaaaataaac aatgtgaatt acaagagaag gaagtatgtg 60 cagatcatat tacaggagga acctaaagta tttccacagc naggtatttt tttttctgac 120 ttcattaact gcttttaaac aaaacatctg cgttcacaaa tatttcactt aatcgcctga 180 aaatttcagc tcatgtgaaa a 201 <210> 4 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = C or T <400> 4 ggtagaaggc agctacacag gtgttcattt tattcaataa tcatacattc cctttagtca 60 aagtaactag tgtgttttgg agctagtctg tttttcatgg natgttaaca aaagaacatt 120 agttttgttt tttttttcac cctctaaatt ctaacatctc ttaagaaatg actgctgttt 180 tcccgagatt ctacttcctt c 201 <210> 5 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = T or C <400> 5 agccaggtgt ggtggtgcgt gcctgtagtt acagctactc agcaggctaa agtgcgaaga 60 tcacttgagc ataggagatg gaagctgcag tgaaccctga ntgtgccact gcactctagc 120 ctgggagaca gaattagacc ctgtttcata aaaaaaaaaa aaaaaaaaaa aaagactgga 180 agtactgcac ccctccacat a 201 <210> 6 <211> 161 <212> DNA <213> Homo sapiens <220> <221> variation <222> (81) <223> n = T or A <400> 6 aggatcaaaa ggctaggaag atttaataat gctttggagg accttgaact tgtataggat 60 actggaaggg aactcactct ntctgggctt tagaattatt tctagttttt cagagatttt 120 taaggccaga gattgtatat cattaatctt tgtaactctt t 161 <210> 7 <211> 200 <212> DNA <213> Homo sapiens <220> <221> variation <222> (100) <223> n = G or A <400> 7 agctgaggct ggtaaagttc ctgcctgaga ttttggcctt gcaaagggat ctagtgaagc 60 agttccagaa cgtccagcaa gttgaataca gctccatcan aggcttcctc agcaagcaca 120 gctcaggtgt ggctctgctc tgacaggacc aggactgtcc cgcatttggc ggttcgaaag 180 gatcactgca taggggaaca 200 <210> 8 <211> 181 <212> DNA <213> Homo sapiens <220> <221> variation <222> (91) <223> n = A or G <400> 8 gaggctgaga atctgggctt tgtctccaca gtggccactg ctggggacct tgatggcatg 60 gttttgtcat gttgggatta ctgcctctaa ntgaggctga gaactatctt tcccataact 120 ccctcgtggg gtaatagttg gcaaaaagag gaacttgagt gagattcgca aggtatgggt 180 g 181 <210> 9 <211> 101 <212> DNA <213> Homo sapiens <220> <221> variation <222> (51) <223> n = - or AC <400> 9 gatcctgagt ctatcagtca ggatccaacc agagaaacaa aaccaatagg nacacacaca 60 cacacacaca ctctttcatc aagggattta ttataagact c 101 <210> 10 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = T or G <400> 10 acccatgttt gaacagtcaa ctgtacaagg aaactttaaa acatgttgtg atgtccccca 60 catcccaata ctgttttgga gaaaggtact tgcatttgca ntatggaaat tatttgtatt 120 atttcaaaca tttggagcat ctgcttgcct ggtaccctat gcataattga atattttctc 180 aatggttgga agagtgttct g 201 <210> 11 <211> 201 <212> DNA <213> Homo sapiens <220> <221> variation <222> (101) <223> n = A or G <400> 11 acccatgttt gaacagtcaa ctgtacaagg aaactttaaa acatgttgtg atgtccccca 60 catcccaata ctgttttgga gaaaggtact tgcatttgca ntatggaaat tatttgtatt 120 atttcaaaca tttggagcat ctgcttgcct ggtaccctat gcataattga atattttctc 180 aatggttgga agagtgttct g 201

Claims (16)

obtaining the individual's sodium intake;
Detecting a single nucleotide polymorphism (SNP) genotype for a gene region between ATP2B1 and LINC00936 from a biological sample isolated from the subject, and
Determining the risk of developing hypertension for the individual based on the detected genotype and the sodium intake,
The step of detecting the genotype,
A method for providing information on hypertension comprising detecting a base for rs11105378 in the gene region between the ATP2B1 and LINC00936. delete delete delete According to claim 1,
The step of determining the risk of developing hypertension,
The base for rs11105378 is T,
If the sodium intake of the individual is less than 2 g / day,
A method for providing information on hypertension, comprising determining the subject as a low-risk group for developing hypertension. delete delete delete delete According to claim 1,
The step of detecting the genotype,
Sequencing analysis, hybridization by microarray, allele specific PCR (allele specific PCR), dynamic allele-specific hybridization (DASH), PCR extension analysis, PCR-SSCP (PCR-single strand conformation polymorphism), PCR-RFLP (PCR-resctriction fragment length polymorphism), and TaqMan technique, performed by at least one method, a method for providing information on hypertension. Contains a probe or primer preparation configured to amplify or detect a polynucleotide containing a single nucleotide polymorphism (SNP) site for a gene region between ATP2B1 and LINC00936 from a biological sample isolated from an individual whose sodium intake was obtained do,
The probe or primer,
A composition for providing information on hypertension configured to amplify or detect C or T, which is a base for rs11105378 in the gene region between the ATP2B1 and LINC00936. delete A kit for providing information on hypertension, comprising the composition of claim 11. According to claim 13,
The kit,
A kit for providing information on hypertension, which is at least one of RT-PCR, ddPCR, microarray chip and DNA chip kits. According to claim 13,
The kit,
The kit for providing information on hypertension, further comprising a display means configured to indicate the susceptibility to hypertension of the individual according to the sodium intake according to the genotype of the SNP for the measured gene region. According to claim 15,
The display means,
Susceptibility to hypertension when the sodium intake is less than 2 g/day, and
A kit for providing information on hypertension, which displays at least one of the onset susceptibility to hypertension when the sodium intake is 2 g / day or more.

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