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dc.contributor.authorBown, Matthew
dc.date.accessioned2022-03-09T16:17:38Z
dc.date.available2022-03-09T16:17:38Z
dc.date.issued2022
dc.identifier.citationMartin, S., Tyrrell, J., Thomas, E. L., Bown, M. J., Wood, A. R., Beaumont, R. N., Tsoi, L. C., Stuart, P. E., Elder, J. T., Law, P., Houlston, R., Kabrhel, C., Papadimitriou, N., Gunter, M. J., Bull, C. J., Bell, J. A., Vincent, E. E., Sattar, N., Dunlop, M. G., Tomlinson, I. P., … Yaghootkar, H. (2022). Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation. eLife, 11, e72452. https://doi.org/10.7554/eLife.72452en_US
dc.identifier.urihttp://hdl.handle.net/20.500.12904/15228
dc.description.abstractBackground: 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.
dc.description.urihttps://elifesciences.org/articles/72452en_US
dc.subjectMendelian randomisationen_US
dc.subjectcanceren_US
dc.subjectcardiovascular diseaseen_US
dc.subjectepidemiologyen_US
dc.subjectfavourable adiposityen_US
dc.subjectgeneticsen_US
dc.subjectgenomicsen_US
dc.subjectglobal healthen_US
dc.subjectobesityen_US
dc.titleDisease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisationen_US
dc.typeArticleen_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
rioxxterms.versionNAen_US
rioxxterms.versionofrecordhttps://doi.org/10.7554/eLife.72452en_US
rioxxterms.typeJournal Article/Reviewen_US
refterms.panelUnspecifieden_US
refterms.dateFirstOnline2022
html.description.abstractBackground: 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.en_US
rioxxterms.funder.project94a427429a5bcfef7dd04c33360d80cden_US


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