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

Ruifang Li-Gao, Françoise Carlotti, Renée de Mutsert, Astrid van Hylckama Vlieg, Eelco J P de Koning, J Wouter Jukema, Frits R Rosendaal, Ko Willems van Dijk, Dennis O Mook-Kanamori

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 5 × 10-8) and was also replicated successfully (β: -7.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-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.

Original languageEnglish
Pages (from-to)2327-2336
Number of pages10
JournalDiabetes
Volume68
Issue number12
DOIs
Publication statusPublished - Dec 2019

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