Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians

Abstract

Variants in genes involved in pancreatic β-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes (ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1, ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR) = 1.37 (95% Confidence Interval (CI) 1.19–1.57), P = 9.4 × 10⁻⁶ for rs1884613 and OR = 1.37 (95% CI 1.20–1.57), P = 6.0 × 10⁻⁶ for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1, ABCC8, ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR = 1.68 (95% CI 1.25–2.24), P = 4.9 × 10⁻⁴). Thus, pancreatic β-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians.