Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates
Year: 2021
Type: article
Study design: Observational Study
Abstract: Background Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. Methods We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. Results Observationally, BMI was associated with 1576 proteins ( P < 1.4 × 10 −5 ), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48–0.79, P = 1.6 × 10 −15 ), FABP4 (0.64 SD per SD BMI, 95% CI 0.46–0.83, P = 6.7 × 10 −12 ) and SHBG (−0.45 SD per SD BMI, 95% CI −0.65 to −0.25, P = 1.4 × 10 −5 ). There was agreement in the magnitude of observational and MR estimates ( R 2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
Source: International Journal of Obesity
Institutions: University of Bristol, MRC Integrative Epidemiology Unit, Medical Research Council, Wellcome Sanger Institute, University of Cambridge, National Institute for Health and Care Research, Health Data Research UK, NIHR Cambridge Biomedical Research Centre, NHS Blood and Transplant, John Radcliffe Hospital, University of Oxford
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: Sanofi, NHS Blood and Transplant, Wellcome Trust, Scottish Government, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, University of Cambridge, University of Bristol, Public Health Agency, Cambridge University Hospitals, Chief Scientist Office, Scottish Government Health and Social Care Directorate, NIHR BioResource, Elizabeth Blackwell Institute for Health Research, University of Bristol, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Health and Social Care Research and Development Division, NIHR Cambridge Biomedical Research Centre, Health Data Research UK
Awards: G1131969086, G1182606701, G1192034430, G1605161196, Institutional Strategic Support Fund, G1653514516, G1671907826, G173885373, NIHR Senior Investigator Award, G1953244154, G1987169411, G2266788633, G235045266, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G2438974996, G2466259667, G2538597952, G2642749895, G2797452859, G2804450655, G2809956348, G2957837340, Glycogen-synthase kinase-3α and glycogen synthase kinase-3β: yin and yang in platelet function and thrombus formation?, G3217060148, G3288322216, G3344456887, G3600350110, G3609641447, G3831911591, G3986547339, G4075560779, G4194769985, The Avon Longitudinal Study for Parents and Children: An international resource for population genomic and lifecourse epidemiology. Core programme support 2014-2019., G4584873075, G4603568690, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., G481861851, G4926237837, G5036201495, G5117680084, G5329469444, G5383869258, Institutional Strategic Support Fund, G5562631338, G5663387099, G5857625837, G587296758, G612368666, G624298721, G6423108142, G6467398148, G6506225041, G6550979745, G6682065591, G6787924332, Mendelian randomization to hypothesis-free causal inference, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers., Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), G762219591, G7939076303, G8131818847, G8201869620, G8205009473, G8221014710, G824700880, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., G8346449347, G8502142660, Synthesis and Biology of Prostanoids, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W3173171825