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

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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
Issue number7
StatePublished - Jul 2016

Bibliographical note

Funding Information:
Genotyping services for the WFSM study were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University (contract HHSC268200782096C). The work at Wake Forest was supported by NIH grants K99-DK-081350 N.D.P.), R01-DK-066358 (D.W.B.), R01-DK-053591 (D.W.B.), R01-HL-56266 (B.I.F.), and R01-DK-070941 (B.I.F.), and in part by the General Clinical Research Center of the WFSM grant M01-RR-07122. This work was also supported by the NHLBI. The following four parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology-Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: ARIC, CARDIA, JHS, and MESA. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The authors thank the staff and participants of the ARIC study for their important contributions. The Coronary Artery Risk Development in Young Adults (CARDIA) Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Genotyping was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226) and the NHGRI Gene Environment Association Studies (GENEVA) (U01-HG004729, U01-HG04424, and U01-HG004446). This manuscript has been reviewed and approved by CARDIA for scientific content. The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The authors thank the participants and data collection staff of the Jackson Heart Study. Multi-Ethnic Study of Atherosclerosis (MESA), and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (CMP00068). Funding for CARe genotyping was provided by NHLBI contract N01-HC-65226. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Publisher Copyright:
© 2016 Keaton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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