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

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  • Hanieh Yaghootkar
  • Luca A Lotta
  • Jessica Tyrrell
  • Roelof A J Smit
  • Sam E Jones
  • Louise Donnelly
  • Robin Beaumont
  • Marcus A Tuke
  • Katherine S Ruth
  • Sandosh Padmanabhan
  • J Wouter Jukema
  • Colin C Palmer
  • Andrew Hattersley
  • Rachel M Freathy
  • Claudia Langenberg
  • Nicholas J Wareham
  • Andrew R Wood
  • Anna Murray
  • Michael N Weedon
  • Naveed Sattar
  • Ewan Pearson
  • Robert A Scott
  • Timothy M Frayling

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    Rights statement: This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Care Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at Diabetes URL: http://diabetes.diabetesjournals.org

    Accepted author manuscript, 3.88 MB, PDF document

Original languageEnglish
Pages (from-to)2448-2460
Number of pages13
JournalDiabetes
Volume65
Issue number8
DOIs
Publication statusPublished - 26 Apr 2016

Abstract

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.

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