GENETIC VARIATION IN KCNQ1 ASSOCIATES WITH FASTING GLUCOSE AND BETA-CELL FUNCTION: A STUDY OF 3734 SUBJECTS COMPRISING THREE ETHNICITIES LIVING IN SINGAPORE

Abstract

Objective: The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, β-cell function and other type 2 diabetes-related traits in a sample of Chinese, Malays and Asian-Indians living in Singapore.

Research Design and Methods: We examined the associations between 4 previously reported KCNQ1 SNPs with type 2 diabetes-related traits in 3734 participants from the population-based NHS98 cohort (2520 Chinese, 693 Malay, 521 Asian-Indians). Insulin resistance was calculated from fasting insulin and glucose using the Homeostasis model assessment method, while pancreatic β-cell function was assessed using the corrected insulin response at 120 minutes (CIR₁₂₀).

Results: SNPs rs2237897, rs2237892, rs2283228 were significantly associated with type 2 diabetes (OR= 1.48, p=3×10⁻⁴; OR=1.38, p=0.002; OR=1.31, p=0.012 respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, rs2283228 were significantly associated with higher fasting glucose levels (p=0.014, 0.011 and 0.034 respectively) and reduced CIR₁₂₀ (p=0.007, 0.013, 0.014 respectively). A similar trend was observed among the Malay and Asian-Indian minority groups although this did not reach statistical significance due to limited sample sizes.

Conclusions: The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.