Open AccessGenome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans
Author(s) -
Jacob M. Keaton,
Jacklyn N. Hellwege,
Maggie C. Y. Ng,
Nicholette D. Palmer,
James S. Pankow,
Myriam Fornage,
James G. Wilson,
Adolfo Correa,
Laura J. RasmussenTorvik,
Jerome I. Rotter,
Yii Der I. Chen,
Kent D. Taylor,
Stephen S. Rich,
Lynne E. Wagenknecht,
Barry I. Freedman,
Donald W. Bowden
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0159977
Subject(s) - type 2 diabetes , single nucleotide polymorphism , genome wide association study , insulin resistance , insulin , biology , medicine , endocrinology , diabetes mellitus , genetics , gene , genotype
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 (AIR g ), 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 ( P interaction <5×10 −6 ) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIR g 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.