Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease

• Type of Material: Article
• Authors: Christopher S. Thom, Childrens Hospital of Philadelphia; Zhuoran Ding, University of Pennsylvania; Michael G. Levin, Corporal Michael J Crescenz VA Medical Center; Scott M. Damrauer, University of Pennsylvania; Kyung Min Lee, VA Salt Lake City Health Care System; Julie Lynch, VA Salt Lake City Health Care System; Kyong-Mi Chang, Corporal Michael J Crescenz VA Medical Center; Philip S. Tsao, VA Palo Alto Health Care System; Kelly Cho, VA Boston Healthcare System; Peter Wilson, Emory University; Themistocles L. Assimes, VA Palo Alto Health Care System; Yan Sun, Emory University; Christopher J. O'Donnell, VA Boston Healthcare System; Marijana Vujkovic, Corporal Michael J Crescenz VA Medical Center; Benjamin F. Voight, University of Pennsylvania
• Language: English
• Date: 2020-10-01
• Publisher: OXFORD UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020. Published by Oxford University Press.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddaa193
• Title of Journal or Parent Work: HUMAN MOLECULAR GENETICS
• Volume: 29
• Issue: 19
• Start Page: 3327
• End Page: 3337
• Grant/Funding Information: The National Institutes of Health (DK101478 and HG010067 to B.F.V., HD043021 to C.S.T.); an American Academy of Pediatrics Marshall Klaus Neonatal-Perinatal Research Award (to C.S.T.); and a Linda Pechenik Montague Investigator Award (to B.F.V.). S.M.D. receives research support from ReanlytixAI and consulting fees from Calico Labs, outside the current work. This research is based on the data from the MVP, Office of Research and Development, Veterans Health Administration and was supported by awards IK2-CX001780 (to S.M.D.), I01-BX003362 (to P.S.T. and K.M.C.), I01-BX004821 and I01-BX003340 (to P.WF.W., K.C., Y.V.S.).; We gratefully acknowledge support from the Million Veteran Project-MVP000, VA Informatics and Computing Infrastructure (VINCI), Genomics Information System for Integrative Science (GenISIS) and the research program at the Corporal Michael J. Crescenz VA Medical Center. This publication does not represent the views of the Department of Veterans Affairs, the US Food and Drug Administration or the US Government. All authors confirm independence from funders and that all authors had full access to all of the statistics in the study. As such they can attest to the integrity of the data and the accuracy of the data analysis.
• Keywords: Genetics & Heredity; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; CARDIOVASCULAR RISK; OBESITY; MENDELIAN RANDOMIZATION; GENOME-WIDE ASSOCIATION; BIAS; HEALTH; Science & Technology
• Research Categories: Health Sciences, Public Health; Biology, Genetics

Abstract

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR 1.21, 95% CI: 1.15-1.27, P = 1 × 10-12) and coronary artery disease (CAD; OR 1.21, 95% CI: 1.16-1.26, P = 2 × 10-20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54-0.98 kg/m2, P = 1.8 × 10-11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01-1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08-1.17, P = 3 × 10-8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12-1.37, P = 2 × 10-5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89-1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity.