title: Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.
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/m(2) [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.
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Roelof A J
authors.initials: RA
authors.lastname: Smit
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Sam E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, U.K.
authors.forename: Louise
authors.initials: L
authors.lastname: Donnelly
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Robin
authors.initials: R
authors.lastname: Beaumont
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
authors.forename: Archie
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Tuke
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ruth
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.affiliation: Department of Cardiology and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands Interuniversity Cardiology Institute of the Netherlands, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, U.K.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Palmer
authors.affiliation: Genetics of Diabetes, University of Exeter Medical School, Exeter, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hattersley
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Faculty of Medicine, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, U.K.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, U.K.
authors.forename: Ewan
authors.initials: E
authors.lastname: Pearson
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Genetics of Human Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, U.K. t.m.frayling@exeter.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D050154:Adiposity / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006331:Heart Diseases / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D016017:Odds Ratio; D012307:Risk Factors; D012737:Sex Factors; D055105:Waist Circumference; D049629:Waist-Hip Ratio