Serum Albumin and Circulating Metabolites and Risk of Venous Thromboembolism: A Two-Sample Mendelian Randomization Study

Abstract

Background and Aim: Previous observational studies indicated that the serum albumin levels and circulating metabolites are associated with a high risk of venous thromboembolism (VTE). However, whether these observations reflect causality remained unclear. Hence, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal associations of serum albumin and circulating metabolites with the risk of VTE. Methods and Results: Summary statistics of genetic instruments proxying serum albumin, total protein, and common circulating metabolites were extracted from genome-wide association studies in the European ancestry. Summary-level results of age- and sex-adjusted estimates for associations of the instruments with VTE were derived from the FinnGen consortium. We used the inverse-variance weighted (IVW) method as the primary analysis for univariable MR. Sensitivity analyses were performed to detect horizontal pleiotropy and outliers. Genetically proxied high-serum albumin and total protein levels were suggestive protective factor of VTE, with odds ratio (OR) = 0.69 (CI 0.54-0.89, p = 4.7 × 10^-3) and 0.76 (CI 0.61-0.95, p = 0.015), respectively. Genetically proxied low-monounsaturated fatty acids and the ratio of monounsaturated fatty acid to total fatty acid are causally associated with increased risk of VTE, with ORs = 0.89 (CI 0.80-0.99, p = 0.031) and 0.85 (CI 0.78-0.94, p = 9.92 × 10^-4), respectively. There is no indication of causal associations between other circulating metabolites and the risk of VTE. Conclusions: Genetically liability to low-serum albumin and total protein levels, low proxied monounsaturated fatty acids (MUFAs) and the ratio of MUFAs to total fatty acids are associated with the higher risk of VTE.

Keywords: mendelian randomization analysis; metabolic syndrome; monounsaturated fatty acid; serum albumin; venous thromboembolism.

Figure 1

The scheme of study design. SNP, single nucleotide polymorphism; UKBB, UK BioBank; BCAA, branched-chain amino acid; GWAS, genome-wide association study; VTE, venous thromboembolism.

Figure 2

Associations of genetically predicted serum albumin, total protein, MUFAs levels, and ratio of MUFAs to total fatty acids with VTE. MUFAs, monounsaturated fatty acids; VTE, venous thromboembolism; IVW, inverse-variance weighted; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; OR, odds ratio; CI, confidence interval. *No outliers detected. NA, no adjusted estimates is available.