Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

eLife

Matthew J Bown¹  Lam C Tsoi²  Philip E Stuart²  James T Elder³  Christopher Kabrhel⁴  Ian PM Tomlinson⁵  Andrew R Wood⁶  Jessica Tyrrell⁶  Susan Martin⁶  Robin N Beaumont⁶  Timothy M Frayling⁶  Hanieh Yaghootkar⁷  Naveed Sattar⁸  Joshua A Bell⁹  Emma E Vincent^1,10  Caroline J Bull^1,10  Marc J Gunter^1,11  Nikos Papadimitriou^1,11  E Louise Thomas^1,12  Jimmy D Bell^1,12  Philip Law^1,13  Richard Houlston^1,13  Malcolm G Dunlop^1,14 

[1] Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom;Department of Dermatology, University of Michigan, Ann Arbor, United States;Department of Dermatology, University of Michigan, Ann Arbor, United States;Ann Arbor Veterans Affairs Hospital, Ann Arbor, United States;Department of Emergency Medicine, Massachusetts General Hospital, Boston, United States;Department of Emergency Medicine, Harvard Medical School, Boston, United States;Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, United Kingdom;Institute of Biomedical and Clinical Science, University of Exeter Medical School, Research, Innovation, Learning and Development building, Royal Devon & Exeter Hospital, Exeter, United Kingdom;Institute of Biomedical and Clinical Science, University of Exeter Medical School, Research, Innovation, Learning and Development building, Royal Devon & Exeter Hospital, Exeter, United Kingdom;Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom;Centre for Inflammation Research and Translational Medicine (CIRTM), Department of Life Sciences, Brunel University London, Uxbridge, United Kingdom;Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom;Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom;MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom;Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom;School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom;Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France;Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom;The Institute of Cancer Research, London, United Kingdom;University of Edinburgh, Edinburgh, United Kingdom;Western General Hospital, Edinburgh, United Kingdom;

关键词: Mendelian randomisation;    obesity;    favourable adiposity;    cardiovascular disease;    cancer;    Human;   

DOI  :  10.7554/eLife.72452

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Background:Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases.Methods:We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically ‘favourable adiposity’ (FA) and ‘unfavourable adiposity’ (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases.Results:MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism.Conclusions:Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy.Funding:Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.

【 授权许可】

CC BY