Genome‐wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans |
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| Authors: | 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 |
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| Institution: | 1. Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;2. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;3. Center for Diabetes Research, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;4. Department of Biochemistry, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;5. Center for Public Health Genomics, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;6. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America;7. Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America;8. Department of Medicine, University of Mississippi Medical Center, Jackson, Mississipi, United States of America;9. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America;10. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor‐UCLA Medical Center, Torrance, California, United States of America;11. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America;12. Division of Public Health Sciences, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America;13. Department of Internal Medicine – Section on Nephrology, Wake Forest School of Medicine, Winston‐Salem, North Carolina, United States of America |
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| 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. |
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| Keywords: | gene– gene interactions insulin resistance insulin sensitivity |
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