Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease
| Autor: | Peter W.F. Wilson, Scott M. Damrauer, Philip S. Tsao, Yan V. Sun, Kelly Cho, Zhuoran Ding, Christopher J. O'Donnell, Marijana Vujkovic, Kyung Min Lee, VA Million Veteran Program, Julie A. Lynch, Themistocles L. Assimes, Kyong-Mi Chang, Benjamin F. Voight, Christopher S. Thom, Michael G. Levin |
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| Rok vydání: | 2020 |
| Předmět: |
AcademicSubjects/SCI01140
medicine.medical_specialty Diabetes risk Coronary Artery Disease Type 2 diabetes Biology Polymorphism Single Nucleotide Body Mass Index Coronary artery disease 03 medical and health sciences 0302 clinical medicine Risk Factors Internal medicine Mendelian randomization Genetics medicine Humans Genetic Predisposition to Disease Obesity 030212 general & internal medicine Risk factor Association Studies Article Molecular Biology Genetics (clinical) 030304 developmental biology 0303 health sciences Smoking Mendelian Randomization Analysis General Medicine medicine.disease Diabetes Mellitus Type 2 Body mass index Genome-Wide Association Study |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa193 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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