Are Abdominal Fat and Development of Type 2 Diabetes and CHD Causally Linked?

Increased waist-to-hip (WTH) ratio adjusted for body mass index (BMI) may be causally associated with higher risks for type 2 diabetes and coronary heart disease, according to a study published Feb. 14 in the Journal of the American Medical Association.

This mendelian randomization study used publicly available, summary-level data from four genome-wide association studies conducted from 2007 to 2015, including up to 322,154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111,986 individuals.

Results showed that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). In addition, a 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95 percent confidence interval (CI), 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95 percent CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40,530) and CHD (odds ratio, 1.46 [9 percent CI, 1.32-1.62]; absolute risk increase per 1,000 participant-years, 1.8 [95 percent CI, 1.3-2.4]; number of participants with CHD outcome, 66,440).

The authors conclude that genetic predisposition to higher WHR adjusted for BMI was associated with increased levels of quantitative risk factors (lipids, insulin, glucose and systolic blood pressure) as well as a higher risk for type 2 diabetes and CHD.

“These findings lend human genetic support to previous observations associating abdominal adiposity with cardiometabolic disease,” said lead author Connor A. Emdin, DPhil, et al. In addition, the results suggest that body fat distribution, beyond simple measurement of BMI, could explain part of the variation in risk of type 2 diabetes and CHD they found across individuals and subpopulations. Further, the authors explain, “WHR adjusted for BMI might prove useful as a biomarker for the development of therapies to prevent type 2 diabetes and CHD.”

In an accompanying editorial, George Davey Smith, MD, DSc, et al., comments on the study’s use of mendelian randomization for its “methodology that incorporates the natural randomization inherent in the generation of genetic individuality,” and suggests that the adoption of mendelian randomization may improve prediction of what randomized clinical trials will show.  

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Genetic Arrhythmic Conditions, Hypertriglyceridemia, Lipid Metabolism

Keywords: Abdominal Fat, Adiposity, Biological Specimen Banks, Biological Markers, Blood Pressure, Body Mass Index, Coronary Disease, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genetics, Medical, Genome-Wide Association Study, Glucose, Individuality, Insulins, Lipids, Obesity, Abdominal, Odds Ratio, Random Allocation, Randomized Controlled Trials as Topic, Risk Factors, Triglycerides, Waist-Hip Ratio

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