Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans

Jacob M. Keaton, Chuan Gao, Meijian Guan, Jacklyn N. Hellwege, 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, Maggie C.Y. Ng, Donald W. Bowden

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10−8) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (Pinteraction= 1.43 × 10−8; Pjoint= 4.70 × 10−8). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.

Original languageEnglish (US)
Pages (from-to)559-570
Number of pages12
JournalGenetic epidemiology
Volume42
Issue number6
DOIs
StatePublished - Sep 2018

Bibliographical note

Funding Information:
The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN26820110 0005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN26 8201100010C, HHSN268201100011C, and HHSN2682011 00012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

Funding Information:
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), North-western 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. Geno-typing 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.

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., M.C.Y.N.), R01-DK-053591 (D.W.B.), R01-DK-087914 (M.C.Y.N), U01-DK-105556 (M.C.Y.N.), 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 authors would like to acknowledge the contributions of the involved research institutions, study investigators, field staff, and study participants of ARIC, CARDIA, JHS, MESA, and WFSM. J.M.K. wrote the manuscript and researched and analyzed the data. J.N.H., C.G., M.G., and N.D.P. researched data, contributed to data analysis, and reviewed and edited the manuscript. J.S.P., M.F., J.G.W., A.C., L.J.R.T., J.I.R., S.S.R., L.E.W., and B.I.F. reviewed and edited the manuscript. B.I.F. recruited and phenotyped WFSM participants. M.C.Y.N. assisted with data analysis, designed the study, and reviewed and edited the manuscript. D.W.B. contributed to manuscript writing and study design, contributed to the discussion, and reviewed and edited the manuscript. D.W.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
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.

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., M.C.Y.N.), R01-DK-053591 (D.W.B.), R01-DK-087914 (M.C.Y.N), U01-DK-105556 (M.C.Y.N.), 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.

Publisher Copyright:
© 2018 WILEY PERIODICALS, INC.

Keywords

  • gene–gene interactions
  • insulin resistance
  • insulin sensitivity

Fingerprint

Dive into the research topics of 'Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans'. Together they form a unique fingerprint.

Cite this