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 2 737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3 622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomization (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 1 576 proteins (P<1.4x10-5), 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=1.6x10-15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P=6.7x10-12) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4x10-5). There was agreement in the magnitude of observational and MR estimates (R2 = 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2221-2229 |
| Number of pages | 9 |
| Journal | International Journal of Obesity |
| Volume | 45 |
| Early online date | 5 Jul 2021 |
| DOIs | |
| Publication status | Published - 1 Oct 2021 |
Bibliographical note
Funding Information:Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]*. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. A complete list of the investigators and contributors to the INTERVAL trial is provided in this reference [24]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. This work was also supported by the Wellcome Trust grant number 206194. *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Funding Information:
This publication is the work of the authors who are guarantors for its contents. LJG is funded by the University of Bristol alumni on the 4-year BHF Integrative Cardiovascular Science PhD programme. JAB is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). DAH and LJC are funded by the Wellcome Trust (202802/Z/16/Z). KW is supported by the Wellcome Trust. GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). NS is supported by the Wellcome Trust, British Heart Foundation and NIHR funding to the Cambridge Bioresource. JD is funded by the National Institute for Health Research (Senior Investigator Award). IH is supported by the EPSRC Prostanoid programme (EP/ M012530/1) and BHF (PG/16/3/31833). NJT is a Wellcome Trust Investigator (202802/ Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_12013/3) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/ A19169). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. This research was funded in whole, or in part, by the Wellcome Trust (202802/Z/16/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted paper version arising from this submission.
Publisher Copyright:
© 2021, The Author(s).
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