Abstract
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
Highlights
Common variants examined in genome-wide association studies (GWAS) have identified ~80 loci associated with Type 2 diabetes (T2D) risk, these variants explain only about 15% of T2D heritability [1,2]
frequently sampled intravenous glucose tolerance test (FSIGT) was performed for all subjects without T2D (n = 492) to assess measures including insulin secretion (AIRg), insulin sensitivity index (SI), and disposition index (DI)
Genotyped single nucleotide polymorphisms (SNPs) from the exome chip were tested for association with insulin secretion (AIRg) in Insulin Resistance Atherosclerosis Family Study (IRASFS)
Summary
Common variants examined in genome-wide association studies (GWAS) have identified ~80 loci associated with T2D risk, these variants explain only about 15% of T2D heritability [1,2]. These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome.
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