Background: Variation in body mass index (BMI) is associated with cardiovascular health outcomes, but the mechanisms leading from BMI to disease risk are still unclear. Aims: To use observational and genetically-informed methods to (1) explore the relationship between BMI and the plasma proteome and (2) identify potential drivers of obesity-related cardiovascular disease. Methods: This study used proteomic data measured by SomaLogic from 2,737 healthy adults from the INTERVAL study to explore the effect of self-reported BMI on 3,622 unique plasma proteins using observational and genetically-informed methods. Linear regression models were used, complemented by one-sample Mendelian randomization (MR) analyses using a genetic risk score (GRS) comprised of 654 single nucleotide polymorphisms (SNPs) from a recent genome-wide association study (GWAS) of adult BMI. Results: Observationally, BMI showed 1,576 protein associations at p < 1.4x10-5: the strongest being leptin and sex hormone binding globulin (SHBG). The GRS was positively associated with BMI but not with reported confounders. There was MR evidence that BMI (per standard deviation (SD) higher) had an effect on eight proteins, including leptin (0.63 SD, 95% CI 0.48-0.79, p = 1.6x10-15) and SHBG (-0.45 SD, 95% CI -0.65 to -0.25, p = 1.4x10-5). There was strong agreement in the direction and magnitude of observational and MR estimates. There was also evidence that proteins that are most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions: We here provide evidence for a profound impact of higher adiposity on the human proteome and suggests that such protein alterations could be important mechanistic drivers of obesity-related cardiovascular and metabolic diseases.
|Publication status||Published - 2020|