Genome-wide interaction with insulin secretion loci reveals novel loci for type 2 diabetes in African Americans

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. Rasmussen-Torvik, Jerome I. Rotter, Yii Der I. Chen, Kent D. Taylor, Stephen S. Rich, Lynne E. Wagenknecht, Barry I. Freedman, Donald W. Bowden

Research output: Contribution to journalArticle

3 Scopus citations

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 (Pnoitcaretni<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.

Original languageEnglish (US)
Article numbere0159977
JournalPloS one
Volume11
Issue number7
DOIs
StatePublished - Jul 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Keaton, J. M., Hellwege, J. N., Ng, M. C. Y., Palmer, N. D., Pankow, J. S., Fornage, M., Wilson, J. G., Correa, A., Rasmussen-Torvik, L. J., Rotter, J. I., Chen, Y. D. I., Taylor, K. D., Rich, S. S., Wagenknecht, L. E., Freedman, B. I., & Bowden, D. W. (2016). Genome-wide interaction with insulin secretion loci reveals novel loci for type 2 diabetes in African Americans. PloS one, 11(7), [e0159977]. https://doi.org/10.1371/journal.pone.0159977