Synergistic effect between the KCNQ1 haplotype and alcohol consumption on the development of type 2 diabetes mellitus in Korean cohorts

Ji Young Park,Sang Ick Park,Hye-Ja Lee,Min-Gyu Yoo,Ji Ho Yun

doi:10.1038/s41598-021-01399-9

Abstract

Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). Association studies between KCNQ1 genetic variants and T2DM have been reported. The multifactorial disease T2DM is caused by interactions between genetic susceptibility and environmental factors. In this study, we examined the associations between the KCNQ1 haplotype, which consists of the major alleles rs3852528, rs11024175, and rs2237892 (ht: ACC), and environmental factors such as alcohol consumption, which are related to the risk of T2DM, in two independent Korean populations. Data from health examination studies, i.e., HEXA (n = 50,357 subjects) and the Ansung–Ansan community-based Korean cohort study (n = 7603), were analyzed. In both cohorts, fasting blood glucose levels were significantly increased in moderate-to-heavy drinkers and carriers of the homozygous ACC haplotype. A significant association between the KCNQ1 haplotype and alcohol consumption in the risk of diabetes was observed 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 compared with abstainers not carrying the KCNQ1 haplotype. Associations of the KCNQ1 haplotype with alcohol consumption and β-cell function were observed in the Ansung–Ansan cohort. Moderate-to-heavy drinkers with the ACC haplotype had lower fasting insulin levels and mean 60 min insulinogenic index (IGI60) compared with light drinkers and abstainers not carrying 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.

Highlights

Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM)
The effects of alcohol consumption on the risk of T2DM have been reported by many studies, additional studies investigating the interplay between genetic variants and environmental factors leading to the onset of diabetes are needed
Our results suggest that the interplay between the KCNQ1 ACC haplotype and alcohol consumption increases the risk of T2DM resulting from pancreatic β-cell dysfunction, rather than a change in insulin resistance and/or insulin sensitivity

Summary

Introduction

Potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the strongest susceptibility genes for type 2 diabetes mellitus (T2DM). Moderate-to-heavy drinkers with the ACC haplotype had lower fasting insulin levels and mean 60 min insulinogenic index (IGI60) compared with light drinkers and abstainers not carrying 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. Various susceptibility genes for T2DM have been identified by meta-analyses of genome-wide association studies (GWAS) Among these genes, the variants of voltage-gated potassium channel subfamily Q member 1 (KCNQ1), a novel diabetes susceptibility gene, have been implicated in diabetes in many studies in various ethnic groups[5,6,7]. We evaluated the multifactorial interplay between alcohol consumption and KCNQ1 variants on the risk of developing T2DM in two independent Korean cohort studies: the HEXA (Health Examinees study) and Ansung–Ansan community-based Korean cohort study

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