Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease

Yaghootkar, H. et al. (2016) Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension, and heart disease. Diabetes, 65(8), pp. 2448-2460. (doi:10.2337/db15-1671) (PMID:27207519)

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Abstract

Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These “favorable adiposity” alleles are collectively associated with lower insulin levels and higher subcutaneous–to–visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m2 [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic −0.859 mmHg [−1.099, −0.618]; P = 3E-12 and diastolic −0.394 mmHg [−0.534, −0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (−0.004 cm [95% CI −0.005, −0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Sattar, Professor Naveed
Authors: Yaghootkar, H., Lotta, L. A., Tyrrell, J., Smit, R. A.J., Jones, S. E., Donnelly, L., Beaumont, R., Campbell, A., Tuke, M. A., Hayward, C., Ruth, K. S., Padmanabhan, S., Jukema, J. W., Palmer, C. C., Hattersley, A., Freathy, R. M., Langenberg, C., Wareham, N. J., Wood, A. R., Murray, A., Weedon, M. N., Sattar, N., Pearson, E., Scott, R. A., and Frayling, T. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Diabetes
Publisher:American Diabetes Association
ISSN:0012-1797
ISSN (Online):1939-327X
Copyright Holders:Copyright © 2016 American Diabetes Association
First Published:First published in Diabetes 65(8):2448-2460
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
472322PHASE: A Pharmacogenomic Study of Statins in the Elderly at Risk for Cardiovascular DiseaseMuriel CaslakeEuropean Commission (EC)223004RI CARDIOVASCULAR & MEDICAL SCIENCES
381721Generation ScotlandAnna DominiczakScottish Executive Health Department (SEHHD-CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES