Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women.

Received: 14 December 2015 Revised: 24 May 2016 Accepted: 5 June 2016 Published on: 5 July 2016 DOI: 10.1002/gepi.21991 RESEARCH ARTICLE Obesity and associated lifestyles modify the eﬀect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women Su Yon Jung 1 Eric M. Sobel 2 Jeanette C. Papp 2 Carolyn J. Crandall 3 Alan N. Fu 4 Zuo-Feng Zhang 4 1 Translational Sciences Section, Jonsson Com- prehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, California, United States of America 2 Department of Human Genetics, David Geﬀen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America 3 Division of General Internal Medicine, Depart- ment of Internal Medicine, David Geﬀen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America 4 Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, United States of America Correspondence Dr. Su Yon Jung, Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California Los Angeles, 700 Tiverton Ave, 3-264 Factor Building, Los Angeles, California 90095, United States of America. Email: sjung@sonnet.ucla.edu ABSTRACT Purpose: Impaired glucose metabolism-related genetic variants likely interact with obesity-modiﬁable factors in response to glucose intolerance, yet their interconnected pathways have not been fully charac- terized. Methods: With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP–glucose vari- ations. We used regression analysis plus stratiﬁcation and graphic approaches. Results: Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups diﬀerently demonstrated the direction and/or magnitude of the variants’ eﬀect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Conclusions: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism–relevant variants. These ﬁndings may inform research on the role of glucose home- ostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women. KEYWORDS glucose metabolism–related genetic variant, high-fat diet, obesity, physical activity, postmenopausal women INTRODUCT I O N Glucose intolerance is thought to be central in the develop- ment of chronic diseases such as type 2 diabetes mellitus (T2DM), metabolic syndrome, and cardiovascular disease (CVD) (Ainsworth, Haskell, & Whitt, 2000; Arcidiacono, Iiritano, & Nocera, 2012; Belkina & Denis, 2010; McCarthy, 2010). In particular, hyperinsulinemia and insulin resis- tance (IR) are key determinants of many obesity-relevant cancers, including reproductive (e.g. breast, endometrial, Genet. Epidemiol. 2016;40: 520–530 prostatic, ovarian) and nonreproductive (e.g. colorectal, kidney, esophageal, gastric, pancreatic, liver) cancers (Boesgaard et al., 2010; Bookman, Din-Lovinescu, & Worrall, 2013; Clayton et al., 2011). Besides its importance in glucose homeostasis, insulin is an essential hormone in anabolic processes in early cell growth and development, directly through the insulin receptor and indirectly through the insulin-like growth factor receptor (IGFR), and via their main downstream signaling pathways (Boesgaard et al., 2010; Clayton et al., 2011). Insulin receptors that are mainly found www.geneticepi.org © 2016 WILEY PERIODICALS, INC.