Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study

Abstract

Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Delta insulin). After Bonferroni correction, rs505922 (beta: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 x 10(-8)]) located in the ABO gene reached genome-wide significant level (P < 5 x 10(-8)) and was also replicated successfully (beta: -7.8% [MAF 0.32, P = 7.2 x 10(-5)]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic beta-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic beta-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.