TY - JOUR
T1 - Genetic evidence for a link between favorable adiposity and lower risk of type 2 diabetes, hypertension and heart disease
AU - Yaghootkar, Hanieh
AU - Lotta, Luca A.
AU - Tyrrell, Jessica
AU - Smit, Roelof A. J.
AU - Jones, Sam E.
AU - Donnelly, Louise
AU - Beaumont, Robin
AU - Campbell, Archie
AU - Tuke, Marcus A.
AU - Hayward, Caroline
AU - Ruth, Katherine S.
AU - Padmanabhan, Sandosh
AU - Jukema, J. Wouter
AU - Palmer, Colin C.
AU - Hattersley, Andrew
AU - Freathy, Rachel M.
AU - Langenberg, Claudia
AU - Wareham, Nicholas J.
AU - Wood, Andrew R.
AU - Murray, Anna
AU - Weedon, Michael N.
AU - Sattar, Naveed
AU - Pearson, Ewan
AU - Scott, Robert A.
AU - Frayling, Timothy M.
N1 - H.Y., A.R.W., and T.M.F. are supported by the European Research Council grants 323195 and SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. J.T. is funded by a Diabetes Research & Wellness Foundation fellowship. S.E.J. is funded by the Medical Research Council (MR/M005070/1). R.B. is also funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. M.A.T., A.M., and M.N.W. are supported by the Wellcome Trust Institutional Strategic Support Fund (WT097835MF). A.H. is a Wellcome Trust Senior Investigator and a National Institute of Health Research senior investigator. R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant 104150/Z/14/Z). E.P. holds a Wellcome Trust New Investigator Award (102820/Z/13/Z). The Wellcome Trust provides support for GoDARTS (awards 072960/z/03/z and 099177/z12/z). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (2001 D 032). Support for genotyping was provided by the 7th Framework Programme of the European Commission (223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Ageing grant 050-060-810). This work was performed as part of an ongoing collaboration of the PROSPER study group in the Universities of Leiden, Glasgow, and Cork. The research leading to these results has received funding from the Netherlands Consortium for Healthy Ageing and the European Commission Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PHASE. The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. GS:SFHS received core funding from the Chief Scientist Office of the Scottish Government Health Directorate CZD/16/6 and the Scottish Funding Council grant HR03006. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland, and was funded by the U.K.’s Medical Research Council and the Wellcome Trust. Ethics approval for the study was given by the National Health Service Tayside Research Ethics Committee (reference 05/S1401/89). EPIC-Norfolk was funded by the Medical Research Council Canada grants MC_UU_12015/1 and MC_PC_13048.
PY - 2016/8
Y1 - 2016/8
N2 - Recent genetic studies have identified some alleles 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, test for interactions between BMI and favorable adiposity genetics and 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/m(2) [0.066,0.174]; p=1E-5) and higher body fat percentage (0.301 % [0.230,0.372]; p=1E-16) compared to the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favourable adiposity alleles were at: 0.837 OR [0.784,0.894] lower risk of type 2 diabetes (p=1E-7), -0.859 mmHg [-1.099,-0.618] lower systolic (p=3E-12) and -0.394 mmHg [-0.534,-0.254] lower diastolic blood pressure (p=4E-8), 0.935 OR [0.911,0.958] lower risk of hypertension (p=1E-7) and 0.921 OR [0.872,0.973] lower risk of heart disease (p=3E-3). 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 favourable body fat distribution, with a lower waist-hip ratio (-0.004 [-0.005,-0.003] 50% vs 50%; p=3E-14) but in men, the favourable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267,0.641] 50% vs 50%; p=2E-6) and higher waist-hip ratio (0.0013 [0.0003,0.0024] 50% vs 50%; p=0.01). Results were strengthened when meta-analysing with five additional studies. 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. While higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.
AB - Recent genetic studies have identified some alleles 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, test for interactions between BMI and favorable adiposity genetics and 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/m(2) [0.066,0.174]; p=1E-5) and higher body fat percentage (0.301 % [0.230,0.372]; p=1E-16) compared to the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favourable adiposity alleles were at: 0.837 OR [0.784,0.894] lower risk of type 2 diabetes (p=1E-7), -0.859 mmHg [-1.099,-0.618] lower systolic (p=3E-12) and -0.394 mmHg [-0.534,-0.254] lower diastolic blood pressure (p=4E-8), 0.935 OR [0.911,0.958] lower risk of hypertension (p=1E-7) and 0.921 OR [0.872,0.973] lower risk of heart disease (p=3E-3). 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 favourable body fat distribution, with a lower waist-hip ratio (-0.004 [-0.005,-0.003] 50% vs 50%; p=3E-14) but in men, the favourable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267,0.641] 50% vs 50%; p=2E-6) and higher waist-hip ratio (0.0013 [0.0003,0.0024] 50% vs 50%; p=0.01). Results were strengthened when meta-analysing with five additional studies. 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. While higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.
U2 - 10.2337/db15-1671
DO - 10.2337/db15-1671
M3 - Article
C2 - 27207519
SN - 0012-1797
VL - 65
SP - 2448
EP - 2460
JO - Diabetes
JF - Diabetes
IS - 8
ER -
