Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans

• Published in: PloS one Vol. 11; no. 7; p. e0159977
• Main Authors: Keaton, Jacob M., Hellwege, Jacklyn N., Ng, Maggie C. Y., Palmer, Nicholette D., Pankow, James S., Fornage, Myriam, Wilson, James G., Correa, Adolfo, Rasmussen-Torvik, Laura J., Rotter, Jerome I., Chen, Yii-Der I., Taylor, Kent D., Rich, Stephen S., Wagenknecht, Lynne E., Freedman, Barry I., Bowden, Donald W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.07.2016; Public Library of Science (PLoS)
• Subjects: Adult; African Americans; Analysis; Arteriosclerosis; Atherosclerosis; Biochemistry; Biology and Life Sciences; Biomedical research; Black or African American - genetics; Blood Glucose; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Epistasis, Genetic; Family studies; Female; Genetic factors; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Glucose; Health care; Humans; Hypotheses; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Insulin Secretion; Loci; Male; Medicine and Health Sciences; Metabolism; Middle Aged; Minority & ethnic groups; People and places; Polymorphism, Single Nucleotide; Precision medicine; Preventive medicine; Public health; Quantitative Trait Loci; Reproducibility of Results; Risk Assessment; Risk Factors; Secretion; Sensitivity; Single-nucleotide polymorphism; Studies; Type 2 diabetes; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0159977

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.