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Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates

Authors :
Nicholas J. Timpson
David J. Roberts
Nicholas A. Watkins
George Davey Smith
Nicole Soranzo
Joshua A. Bell
Lucy J Goudswaard
Adam S. Butterworth
Ingeborg Hers
Willem H. Ouwehand
Klaudia Walter
Laura J Corbin
David A. Hughes
John Danesh
Emanuele Di Angelantonio
Source :
Goudswaard, L J, Bell, J A, Hughes, D A, Corbin, L J, Walter, K, Davey Smith, G, Soranzo, N, Danesh, J, Di Angelantonio, E, Ouwehand, W H, Watkins, N A, Roberts, D, Butterworth, A S, Hers, I & Timpson, N J 2021, ' Effects of adiposity on the human plasma proteome : observational and Mendelian randomisation estimates ', International Journal of Obesity, vol. 45, pp. 2221-2229 . https://doi.org/10.1038/s41366-021-00896-1
Publication Year :
2021

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 −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 (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.

Details

ISSN :
14765497
Volume :
45
Issue :
10
Database :
OpenAIRE
Journal :
International journal of obesity (2005)
Accession number :
edsair.doi.dedup.....432993e5629952ada53f97690a515509