Genetic Evidence for Different Adiposity Phenotypes and their Opposing Influence on Ectopic Fat and Risk of Cardiometabolic Disease
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posted on 2021-05-13, 09:23 authored by Susan Martin, Madeleine Cule, Nicolas Basty, Jessica Tyrrell, Robin N. Beaumont, Andrew R. Wood, Timothy M. Frayling, Elena Sorokin, Brandon Whitcher, Yi Liu, Jimmy D. Bell, E. Louise Thomas, Hanieh YaghootkarTo understand the causal role of adiposity and ectopic fat in type 2
diabetes and cardiometabolic diseases, we aimed to identify two clusters of
adiposity genetic variants, one with ‘adverse’ metabolic effects (UFA) and the
other with, paradoxically, ‘favourable’ metabolic effects (FA). We performed a
multivariate genome-wide association study using body fat percentage and
metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing
alleles were associated with an adverse metabolic profile, higher risk of
disease, higher CRP, higher fat in subcutaneous and visceral adipose tissue,
liver and pancreas for UFA; and a favourable metabolic profile, lower risk of
disease, higher CRP, higher subcutaneous adipose tissue but lower liver fat for
FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for risk-increasing
effect of UFA and protective effect of FA on type 2 diabetes, heart disease,
hypertension, stroke, non-alcoholic
fatty liver disease and polycystic ovary syndrome. FA is distinct from
UFA by its association with
lower liver fat, and protection from cardiometabolic diseases;
it was not associated with visceral or
pancreatic fat. Understanding the difference in FA and UFA may lead to new
insights in preventing, predicting and treating of cardiometabolic diseases.
