KR20240061944A - KCNQ1 SNP markers for diabetes and use thereof) - Google Patents

Abstract

The present invention relates to a SNP (single nucleotide polymorphism) marker for diabetes prediction or diagnosis. More specifically, a biomarker composition for diabetes prediction or diagnosis for KCNQ1 SNP, a diabetes prediction or diagnosis comprising an agent capable of amplifying or detecting the SNP. It relates to a composition, a kit containing the composition, and a method of providing information for predicting or diagnosing diabetes.

Description

KCNQ1 SNP markers for diabetes prediction or diagnosis and use thereof {KCNQ1 SNP markers for diabetes and use thereof)}

The present invention relates to a SNP (single nucleotide polymorphism) marker for diabetes prediction or diagnosis. More specifically, a biomarker composition for diabetes prediction or diagnosis for KCNQ1 SNP, a diabetes prediction or diagnosis comprising an agent capable of amplifying or detecting the SNP. It relates to a composition, a kit containing the composition, and a method of providing information for predicting or diagnosing diabetes.

Type 2 diabetes mellitus (T2DM) is a global chronic metabolic disease that occurs when pancreatic β-cell function is impaired and insulin cannot be produced, causing hyperglycemia (1, 2). T2DM is a multifactorial disease affected by a combination of genetic and environmental factors.

One of these environmental factors is alcohol consumption, which causes many problems in all aspects of human life. In particular, chronic alcohol consumption increases the risk of T2DM, leading to disruption of glucose homeostasis and pancreatic β-cell function, including impaired insulin secretion and β-cell death (3, 4). Although the impact of alcohol consumption on the risk of type 2 diabetes has been reported in many studies, further research is needed to investigate the interaction between genetic variants and environmental factors leading to the development of diabetes.

Various susceptibility genes for T2DM have been identified by meta-analysis of genome-wide association studies (GWAS). Among these genes, variants in voltage-gated potassium channel subfamily Q member 1 (KCNQ1), a novel diabetes susceptibility gene, have been associated with diabetes in many studies in various ethnic groups (5-7). . KCNQ1 encodes a pore-forming alpha subunit consisting of the KvLQT1 (or Kv7.1) voltage-gated potassium channel and the potassium voltage-gated channel subfamily E member (KCNE) (8, 9). KvLQT1 channels are essential for controlling cellular repolarization processes, including regulation of insulin secretion after electrical depolarization of pancreatic β cells. Numerous KCNQ1 variants are correlated with the prevalence of T2DM and insulin responsiveness, with increased fasting blood glucose levels due to impaired insulin secretion (10). Although various KCNQ1 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to T2DM, data on the association between KCNQ1 haplotypes and T2DM are limited. Additionally, few studies have evaluated the interaction between genetic susceptibility and environmental risk factors in terms of T2DM risk. Here, we evaluated the multifactorial interaction between alcohol consumption and KCNQ1 variants on the risk of developing T2DM in two independent Korean cohort studies: the Health Examinees study (HEXA) and the Anseong-Ansan community-based Korean cohort study.

Chronic drinking is well known as one of the causes of type 2 diabetes, and is known to be associated with changes in glucose homeostasis and the development of insulin resistance due to impaired insulin secretion. In the present invention, the correlation between insulin secretion ability and drinking according to KCNQ1 mutation, which is well known to have a high correlation with diabetes, was analyzed using Anseong-Ansan community and urban cohort data. The three risk mutations of KCNQ1 were grouped together to form a haplotype and analyzed. It was confirmed that those with the haplotype had an increased fasting blood sugar level and a higher prevalence of diabetes compared to the control group. In drinkers with the KCNQ1 haplotype, insulin secretion capacity and blood insulin levels were decreased compared to non-drinkers, and an accompanying increase in blood sugar levels was observed. Through the results of this analysis, it was confirmed that the risk of pancreatic beta cell damage increases when KCNQ1 gene mutation and alcohol consumption are combined, and that it can affect the development of diabetes by reducing insulin secretion ability.

In the present invention, it was confirmed that when drinking and KCNQ1 mutation were accompanied, the insulin secretion capacity was significantly lower than that of the control group. Based on these results, we aim to provide a scientific basis for establishing future drinking and diabetes-related policies and promoting them to the public.

Korean Patent No. 1788117 Korean Patent No. 1722107 Korean Patent Publication No. 1979633

Ackermann, A. M. & Gannon, M. J. Mol. Endocrinol. 38, 193-206. Cnop, M. et al. Diabetes 54(Suppl 2), S97-S107. Kim, J. Y. et al. World J. Biol. Chem. 6, 1-15. Dembele, K. et al. Cell Biol. Toxicol. 25, 141-152. Unoki, H. et al. Nat. Genet. 40, 1098-1102. Saif-Ali, R. et al. Int. J. Mol. Sci. 12, 5705-5718. Tan, J. T. et al. Diabetes 58, 1445-1449. Smith, J. A. et al. Biochemistry 46, 14141-14152. Vanoye, C. G. et al. J.Gen. Physiol. 134, 207-217. van Vliet-Ostaptchouk, J. V. et al. PLoS ONE 7, e32148. Tan, J. T. et al. J. Clin. Endocrinol. Metab. 95, 390-397. Ao, D. et al. PLoS ONE 10, e0128901. Lee, D. Y. et al. Sci. Rep. 7, 7322. Jang, H. B. et al. Sci. Rep. 9, 20029. Baliunas, D. O. et al. Diabetes Care 32, 2123-2132. Li, X. H. et al. Am. J. Clin. Nutr. 103, 818-829. Ullrich, S. et al. Pflugers Arch. 451, 428-436. Liu, L. et al. Islets 6, e962386. Barro-Soria, R. et al. Proc. Natl. Acad. Sci. U.S.A. 114, E7367-E7376. Wang, X. et al. J. Diabetes Res. 2020, 8278574. Tsuji-Wakisaka, K. et al. Biochim. Biophys. Acta 1452-1459, 2011. Hiramoto, M. et al. Int. J. Mol. Med. 41, 717-728. Ou, K. et al. J. Clin. Investig. 129, 209-214. Kanduri, C. Semin. Cell Dev. Biol. 22, 343-350. Asahara, S. et al. Proc. Natl. Acad. Sci. U.S.A. 112, 8332-8337. Yu, X. X. & Liao, M. Q. J diabetes Res. 2020, 7145139. Kim, Y. & Han, B. G. Int. J. Epidemiol. 46, e20. Yoo, M. G. et al. Int. J.Environ. Res. Public Health 13, 1133. Moon, S. et al. Sci. Rep. 9, 1382. Cho, Y. S. et al. Nat. Genet. 41, 527-534. Matthews, D. R. et al. Diabetologia 28, 412-419.

An object of the present invention is a biomarker composition for predicting or diagnosing diabetes for KCNQ1 SNP, a composition for predicting or diagnosing diabetes containing an agent capable of amplifying or detecting the SNP, a kit containing the composition, and a composition for predicting or diagnosing diabetes. It is intended to provide a method of providing information.

The present invention provides a biomarker composition for predicting or diagnosing diabetes, including two or more KCNQ1 single nucleotide polymorphisms (SNPs) selected from the group consisting of rs3852528, rs2237892, and rs11024175.

According to one embodiment of the present invention, the present invention provides a method for predicting or diagnosing diabetes, comprising an agent capable of amplifying or detecting two or more selected from the group consisting of KCNQ1 single nucleotide polymorphism (SNP) rs3852528, rs2237892, and rs11024175. A composition is provided.

Preferably, the single nucleotide polymorphism may include rs3852528, rs2237892, and rs11024175.

In the present invention, the term "SNP (single nucleotide polymorphism)" refers to polymorphic sites where two or more alleles exist at one genetic locus, differing only by a single base. says that

The agent may be a primer pair or probe capable of amplifying or detecting a single nucleotide polymorphism.

In the present invention, the term "primer" refers to a base sequence having a short free 3' terminal hydroxyl group, which can form a base pair with a complementary template and serves as a starting point for copying the template strand. It refers to a short sequence that functions as a The appropriate length of the primer may vary depending on the purpose of use, but generally consists of 15 to 30 bases. The primer sequence need not be completely complementary to the template, but should be sufficiently complementary to hybridize to the template.

In the present invention, the term “probe” refers to a hybridization probe, which is an oligonucleotide capable of sequence-specific binding to the complementary strand of a nucleic acid. The probe of the present invention is an allele-specific probe, in which a polymorphic site is present among nucleic acid fragments derived from two members of the same species, and hybridizes to the DNA fragment derived from one member, but hybridizes to the DNA fragment derived from the other member. There is no hybridization in one fragment. In this case, hybridization conditions must be sufficiently stringent to ensure that only one of the alleles hybridizes, showing a significant difference in hybridization intensity between alleles. Preferably, the probe may be single stranded for maximum efficiency in hybridization, more preferably a deoxyribonucleotide, but is not limited thereto.

The probe may be a sequence that is perfectly complementary to the sequence containing the SNP, but may also be a substantially complementary sequence to the extent that it does not interfere with specific hybridization. Suitable conditions for hybridization can be determined by referring to information commonly known in the art. The stringent conditions used for hybridization must be sufficiently stringent to ensure hybridization to only one of the alleles, and can be determined by controlling temperature, ionic strength (buffer concentration), and the presence of compounds such as organic solvents. These stringent conditions may vary depending on the sequence being hybridized.

The diabetes may be alcohol-drinking diabetes, and the diabetes may be type 2 diabetes.

According to another embodiment of the present invention, the composition; and providing a kit for predicting or diagnosing diabetes, including a user manual.

The kit can predict or diagnose diabetes by confirming the SNP marker, which is a marker for diabetes prediction or diagnosis, through amplification, or by checking the expression level of the mRNA for the expression level of the SNP marker.

Specifically, the kit may be an RT-PCR kit or a microarray chip kit.

The RT-PCR kit may include each primer pair capable of amplifying a nucleic acid containing the SNP site, as well as a test tube or other suitable container, reaction buffer, deoxynucleotides (dNTPs), and Taq-polymerization. It may include enzymes such as enzymes and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterilized water, etc. It may also include a pair of primers specific to the gene used as a quantitative control.

The microarray chip kit may include a microarray having a substrate on which nucleic acid containing the SNP site is immobilized. The microarray may be a conventional microarray except that it contains the polynucleotide, primer, or probe of the present invention. Hybridization of nucleic acids and detection of hybridization results on microarrays are well known in the art. The detection may be performed, for example, by labeling a nucleic acid sample with a labeling material capable of generating a detectable signal including a fluorescent substance, such as Cy3 and Cy5, and then hybridizing the labeling material on a microarray. The hybridization result can be detected by detecting the signal generated from.

According to another embodiment of the present invention, reacting the composition with a separated sample; and confirming a single nucleotide polymorphism for KCNQ1. To provide a method of providing information for predicting or diagnosing diabetes, including a step.

The separated sample may be DNA obtained from samples such as hair, urine, blood, various body fluids, separated tissues, separated cells, or saliva, but is not limited thereto.

The confirmation is performed by sequence analysis, hybridization by microarray, allele-specific PCR (allele-specific PCR), dynamic allele-specific hybridization (DASH), PCR extension analysis, and PCR-SSCP (PCR-single strand). conformation polymorphism), PCR-RFLP (PCR-restriction fragment length polymorphism), and TaqMan technology. It may be performed by one or more methods selected from the group consisting of, but is not limited to, this.

It was confirmed that the SNP marker of the present invention increases the risk of pancreatic beta cell damage when KCNQ1 gene mutation and alcohol consumption are combined, and it was confirmed that it can affect the development of diabetes by reducing insulin secretion ability, predicting the risk of diabetes or It can be useful for objective diagnosis.

In addition, the present invention seeks to provide a scientific basis for establishing future drinking and diabetes-related policies and promoting them to the public by confirming that the insulin secretion ability is significantly lower than that in the control group when drinking and KCNQ1 mutations are accompanied.

Hereinafter, the present invention will be described in more detail through examples. Since these examples are merely for illustrating the present invention, the scope of the present invention is not to be construed as limited to these examples.

KCNQ1 (Potassium voltage-gated channel subfamily Q member 1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). An association study between KCNQ1 gene variants and T2DM has been reported. T2DM, a multifactorial disease, is caused by the interaction between genetic susceptibility and environmental factors. In the present invention, the association between the KCNQ1 haplotype, which consists of the major alleles rs3852528, rs11024175, and rs2237892 (ht: ACC), and environmental factors such as alcohol consumption associated with the risk of T2DM was investigated in two independent Korean populations. We analyzed data from health screening studies, namely HEXA (n = 50,357 subjects) and the Anseong-Ansan Community-Based Korean Cohort Study (n = 7603). In both cohorts, fasting blood glucose levels were significantly increased in moderate-to-heavy drinkers and homozygous ACC haplotype carriers. A significant association between KCNQ1 haplotype and alcohol consumption was observed in diabetes risk in the HEXA (OR 1.587; 95% CI 1.128-2.234) and Ansung-Ansan (OR 2.165; 95% CI 1.175-3.989) cohorts. Does not have KCNQ1 haplotype. In the Anseong-Ansan cohort, an association between alcohol consumption and KCNQ1 haplotype with β-cell function was observed. Moderate-to-heavy drinkers with the ACC haplotype showed lower fasting insulin levels and an average 60-minute insulin production index (IGI ₆₀ ) compared to light drinkers and abstainers without the ACC haplotype. These findings indicate that KCNQ1 variants play a synergistic role with alcohol consumption in the development of T2DM and impaired β-cell function.

<Example 1> Study population

Data were obtained from two cohort studies conducted at the National Institutes of Health as part of the Korean Genome and Epidemiology Study (27). Written consent was obtained from all subjects, and the present invention was approved by the National Biobank and the Korea Centers for Disease Control and Prevention. This study protocol was approved by the National Institutes of Health Review Board (2019-03-01-PE-A). All study protocols were performed according to approved guidelines.

Participants in HEXA were enrolled from 38 health examination centers and hospitals located in eight regions (metropolitan area or major cities) in Korea from 2004 to 2013. The present invention used baseline data from HEXA (n = 53,754). Subjects with missing data on alcohol consumption (n = 2924) or KCNQ1 haplotype (n = 473) were excluded. A total of 50,357 subjects were included in the study. The community-based Ansung-Ansan cohort study has been described in detail previously (28). The present invention used data from 8840 subjects living in rural Anseong or urban Ansan. Individuals with missing data on alcohol consumption (n = 828) or type 2 diabetes (n = 409) were excluded, leaving 7603 subjects included in this study.

<Example 2> Anthropometric and biochemical analyzes

Information on age, family history of diabetes, physical activity and smoking (pack-years) was obtained using an interview-based questionnaire. Body mass index (BMI) was calculated by dividing weight (kg) by the square of height (m). Fasting blood glucose levels and lipid profiles (total cholesterol, triglycerides, and HDL-cholesterol) were measured using a Hitachi 747 chemistry analyzer (Hitachi Ltd., Tokyo, Japan) according to the manufacturer's recommendations. In the Ansan-Ansung cohort, insulin levels were measured using the INS-IRMA kit (Biosource, Nivelles, Belgium) and a gamma counter (Packard Instrument Co., Meriden, CT, USA), whereas insulin levels were not measured in the HEXA cohort.

<Example 3> Genotyping

All genotyping data were provided with approval from the National Biobank and the Korea Centers for Disease Control and Prevention (no. 2019-022). In the Ansung-Ansan cohort study, genotyping was performed using Affymetrix genome-wide human SNP Array 5.0 and genotype imputation was performed using IMPUTE2. The 1000 Genomes Project of East Asian Ancestry Samples was used as a reference panel. In the HEXA study, genotyping was performed using the Korean Chip designed by the National Institute of Genome Science of the National Institutes of Health. Expected genotyping and quality control information have been described in detail previously (29, 30).

<Example 4> T2DM and pancreatic β-cell function

T2DM was defined as a fasting blood glucose level >126 mg/dL. Additionally, subjects who reported currently taking antidiabetic drugs and insulin were considered to have T2DM. Subjects were followed until the occurrence of T2DM or last examination. In the Ansung-Ansan cohort, pancreatic β-cell function was estimated using an oral glucose tolerance test (75 g). The average 60-minute insulinogenic index (IGI ₆₀ ) was calculated as follows (13).

(insulin level [μU/mL]) at 60 min-insulin level at 0 min) ÷ (glucose level [mmol/L] at 60 min-glucose level at 0 min)

<Example 5> Measurement of alcohol consumption

Information on alcohol consumption was collected in both cohorts using an interview-based questionnaire. Subjects were asked whether they consumed at least one alcoholic beverage per month; If yes, they are asked about previous or current drinking. In the present invention, former drinkers were excluded because the drinking period was unclear. Because women were not in the heavy drinking group, baseline alcohol consumption information was used to divide subjects into three groups: abstainers, light drinkers, and moderate-to-heavy drinkers. Sorted.

<Example 6> Statistical analysis

Statistical analyzes were performed using the SAS software package (ver. 9.4; SAS Institute, Cary, NC, USA). Data are expressed as mean ± standard deviation, number (%), or odds ratio (OR) with 95% confidence interval (CI). Logarithmic transformation was applied to variables that were not Gaussian distributed. Student's t-test and one-way ANOVA analysis were performed to compare clinical characteristics according to drinking status. The chi-square test was used to compare categorical variables (drinking status and KCNQ1 haplotype). Multivariate logistic regression analysis was performed to detect the association between T2DM and KCNQ1 haplotype according to the Ansan-Anseong cohort after adjusting for alcohol consumption and age, gender, smoking, BMI, family history of diabetes, physical activity, and income in HEXA. All reported p-values are two-tailed and p-values <0.05 were considered significant.

<Test Example 1> General characteristics of the study population

The number of subjects with KCNQ1 variants was similarly distributed between the two cohorts (results omitted). Baseline characteristics of subjects according to KCNQ1 haplotype, including major alleles of three SNPs (ht:ACC/ACC), are shown in Table 1. Blood pressure, triglycerides, cholesterol (HDL and total), and levels of liver enzymes alanine aminotransferase and aspartate aminotransferase did not differ according to KCNQ1 haplotype in the two cohorts. The average 60-minute insulin production index (IGI 60) value was 13.7 ± 29.6 in non-carriers, 12.4 ± 26.7 in ACC/- carriers, and 11.5 ± 19.3 in ACC/ACC carriers, in those with homozygous ACC haplotype (ACC/ACC carrier). Subjects showed a tendency for decreased β-cell function in the Anseong-Ansan cohort (p < 0.0651). Fasting blood glucose levels and prevalence of T2DM were significantly higher in subjects with KCNQ1 homozygous ACC haplotype than non-carriers in both cohorts.

Table 1. General characteristics of the subjects ( KCNQ1 haplotype) in the HEXA and Ansung-Ansan cohorts All data except type 2 diabetes and alcohol consumption are presented as the mean ± standard deviation. Student's t -test was used for comparisons of continuous variables and the chi-square test for comparisons of categorical variables according to KCNQ1 haplotype.

After confirming the baseline characteristics of subjects according to alcohol consumption status (27,024 abstainers and 23,333 drinkers in the HEXA cohort and 3826 abstainers and 3777 drinkers in the Anseong-Ansan cohort) (results omitted), all drinkers were categorized as abstainers. In comparison, levels of alcohol markers including diastolic blood pressure, fasting blood sugar, HDL-cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase were higher. Systolic blood pressure and total cholesterol levels differed significantly according to alcohol consumption only in the HEXA cohort (p < 0.001). IGI 60 values and fasting insulin levels were lower in drinkers in the Anseong-Ansan cohort. Type 2 diabetes prevalence was not affected by alcohol consumption in either cohort. The prevalence of T2DM was 9.9% in abstainers and 10.1% in drinkers in the HEXA cohort, and 11.8% in abstainers and 12.5% in drinkers in the Anseong-Ansan cohort.

<Test Example 2> Effect of the association between the KCNQ1 haplotype and alcohol consumption on fasting blood glucose

Fasting blood glucose levels were increased in subjects carrying the KCNQ1 haplotype compared with non-carriers, regardless of alcohol consumption in both cohorts (Table 1). Additionally, fasting blood sugar levels were significantly higher in alcohol drinkers (results omitted). We evaluated the synergistic effect between alcohol consumption and KCNQ1 haplotype on fasting blood glucose levels (Table 2). In both cohorts, moderate-to-heavy drinkers and subjects with the ACC haplotype had higher fasting blood glucose levels than abstainers without the ACC haplotype, and light alcohol consumption was associated with increased fasting blood glucose levels regardless of ACC haplotype. Moderate-to-heavy drinkers with the ACC haplotype showed significantly higher fasting blood sugar levels compared to abstainers with the ACC haplotype.

Table 2. Effect of the KCNQ1 haplotype on the fasting glucose level according to alcohol consumption in the HEXA and Ansung-Ansan cohorts Data are expressed as the mean ± standard deviation fasting glucose level. ¹⁾ One-way ANOVA was used to assess the relationships with the KCNQ1 haplotype. ²⁾ Student's t -test was used to assess the relationship between alcohol consumption and the KCNQ1 haplotype.

<Test Example 3> The effects of the KCNQ1 haplotype and alcohol consumption on T2DM risk

Multivariate logistic regression analysis was performed to evaluate the association between KCNQ1 haplotype and alcohol consumption on T2DM risk (Table 3).

Table 3. Association between type 2 diabetes and the KCNQ1 haplotype according to alcohol consumption in the HEXA and Ansung-Ansan cohorts The p -values were calculated by multivariate logistic regression models adjusted for age, sex, smoking, body mass index, family history of diabetes, physical activity, and income level.

In the HEXA cohort, light drinkers with the ACC haplotype had a higher risk of developing T2DM (odds ratio [OR] 1.530; 95% confidential interval [CI] 1.008-2.323), and the risk of T2DM was significantly correlated with the ACC haplotype (OR 1.587; 95% CI 1.128-2.323). 2.234) was significantly increased compared to the abstainer ACC haplotype that does not have KCNQ1. Here, the risk of T2DM was not higher in abstainers carrying the ACC haplotype (OR 1.334, 95% CI 0.888-2.003) compared to non-carriers. Additionally, ACC haplotype heterozygous and light drinking had a risky effect on T2DM in the HEXA population. In Anseong-Ansan, subjects with the homozygous ACC haplotype showed an increased risk of T2DM (OR 2.588; 95% CI 1.498-4.469 in abstainers; OR 2.165; 95% CI 1.175-3.989 in moderate-to-heavy drinkers). . In both cohorts, the risk of T2DM was increased in moderate-to-heavy drinkers homozygous for the ACC haplotype compared to abstainers without the ACC haplotype. The risk of T2DM showed a similar pattern among subjects carrying the major KCNQ1 SNP allele and ACC haplotype (results omitted). According to KCNQ1 genetic factors, which have a greater impact on the risk of type 2 diabetes than environmental factors, subjects with each of the three SNPs and the major allele of the ACC haplotype had a higher risk of type 2 diabetes compared to subjects without the major allele or haplotype. The risk of type 2 diabetes was higher. These results indicate that the risk of T2DM is significantly increased by KCNQ1 haplotype and alcohol consumption in HEXA, but ACC haplotype was a slightly more influential factor in the Anseong-Ansan cohort.

<Test Example 4> Effect of the association between the KCNQ1 haplotype and alcohol consumption on β-cell function

As shown in Table 4, fasting insulin levels consistently decreased along with fasting blood sugar levels in the ACC haplotype and alcohol consumption groups in the Anseong-Ansan cohort.

Table 4. Changes in β-cell function and the fasting insulin level according to the KCNQ1 haplotype and alcohol consumption in the Ansung-Ansan cohort. Data are expressed as the mean ± standard deviation. IGI ₆₀ : insulinogenic index at 1 h after the oral glucose tolerance test. Differences in the association between the KCNQ1 haplotype and alcohol consumption were assessed by one-way ANOVA.

To understand the impact of increased fasting blood glucose levels, fasting blood sugar levels, fasting insulin levels, IGI ₆₀ according to KCNQ1 haplotype and alcohol consumption, homeostasis model evaluation for insulin resistance and insulin index in subjects excluding T2DM patients related to insulin sensitivity. decided. Compared to abstainers, fasting insulin levels were significantly lower depending on the amount of alcohol exposure. Additionally, subjects with the ACC haplotype tended to have decreased fasting insulin levels. We found an association effect between alcohol consumption and KCNQ1 haplotype possession on the reduction of fasting insulin levels. IGI ₆₀ values tended to be lower in people with the ACC haplotype than in non-carriers. Additionally, drinkers were found to have lower IGI ₆₀ values compared to abstainers, regardless of the amount of alcohol consumed. The IGI ₆₀ value increased in light drinkers compared to moderate-to-heavy drinkers and abstainers with the ACC haplotype, but it was not significant. In addition, many studies have reported the importance of insulin sensitivity over insulin secretion, but in the present study, there was no significant difference in the homeostasis model evaluation for insulin resistance or insulin sensitivity index (results omitted). Previous studies have consistently reported that alcohol consumption contributes to impaired insulin secretion, as found in the current study (results omitted). Our results suggest that the interaction between KCNQ1, ACC haplotype, and alcohol consumption increases the risk of T2DM due to pancreatic β-cell dysfunction rather than insulin resistance and/or changes in insulin sensitivity.

To summarize the above results, we determined the nature of the KCNQ1 ACC haplotype and the synergistic effect between KCNQ1 haplotype and alcohol consumption on the risk of T2DM with elevated fasting blood glucose levels and beta-cell dysfunction. This is the first study to investigate the association between KCNQ1 and alcohol consumption on the risk of developing T2DM.

Additionally, the present invention has several advantages, such as the use of a large sample size and replicated results using clinical indicators (glucose and insulin) to identify T2DM in two independent cohorts. These findings potentially suggest that the interaction between KCNQ1 variants and alcohol consumption contributes to the pathogenesis of T2DM through pancreatic β-cell dysfunction.

Claims (12)

KCNQ1 single nucleotide polymorphism (SNP) A biomarker composition for predicting or diagnosing diabetes containing two or more selected from the group consisting of rs3852528, rs2237892, and rs11024175 The biomarker composition for predicting or diagnosing diabetes according to claim 1, wherein the single nucleotide polymorphism includes rs3852528, rs2237892, and rs11024175. The biomarker composition for predicting or diagnosing diabetes according to claim 1, wherein the diabetes is alcohol-related diabetes. The biomarker composition for predicting or diagnosing diabetes according to claim 1, wherein the diabetes is type 2 diabetes. A composition for predicting or diagnosing diabetes containing an agent capable of amplifying or detecting two or more KCNQ1 single nucleotide polymorphisms (SNPs) selected from the group consisting of rs3852528, rs2237892, and rs11024175. The composition for predicting or diagnosing diabetes according to claim 5, wherein the single nucleotide polymorphism includes rs3852528, rs2237892, and rs11024175. The composition for predicting or diagnosing diabetes according to claim 5, wherein the agent is a primer pair or probe capable of amplifying or detecting a single nucleotide polymorphism. The composition for predicting or diagnosing diabetes according to claim 5, wherein the diabetes is alcohol-related diabetes. The composition for predicting or diagnosing diabetes according to claim 5, wherein the diabetes is type 2 diabetes. The composition of any one of claims 5 to 9; and a kit for predicting or diagnosing diabetes, including instructions for use. The kit for predicting or diagnosing diabetes according to claim 10, wherein the kit is an RT-PCR kit or a microarray chip kit. Reacting the composition of any one of claims 5 to 8 with a separated sample; A method of providing information for predicting or diagnosing diabetes, including the step of confirming a single nucleotide polymorphism for KCNQ1.