A Single-Nucleotide Polymorphism in a Methylatable Foxa2 Binding Site of the G6PC2 Promoter Is Associated With Insulin Secretion In Vivo and Increased Promoter Activity In Vitro

OBJECTIVE—The G6PC2 gene encoding islet-specific glucose-6-phosphatase related protein (IGRP) has a common promoter variant, rs573225 (−231G/A), located within a Foxa binding site. We tested the cis-regulatory effects of rs573225 on promoter activity and its association with insulin response to oral glucose. RESEARCH DESIGN AND METHODS—Functional effects of rs573225 were explored in transfected INS-1 and HIT-T β-cell lines. A total of 734 young obese subjects of European ancestry were genotyped for rs573225. Insulin and glucose levels were measured in response to oral glucose, and the insulinogenic index (IGI) of insulin secretion was calculated. RESULTS—In vitro, the G allele showed a higher affinity for binding Foxa2 transcription factor and increased G6PC2 promoter activity. Foxa2 binding is modified if the C adjacent to the G allele is methylated. IGI was associated with rs573225 by linear regression analysis and was 30% greater in AA or AG than in GG obese children. rs573225 was also associated with fasting glucose. CONCLUSIONS—rs573225 is a functional cis-regulatory (epi)-single-nucleotide polymorphism (SNP) of G6PC2 associated with glucose-insulin homeostasis in obese children, likely to explain the results of recent genome-wide association studies in nondiabetic adults.