A Mendelian randomization study of serum uric acid with the risk of venous thromboembolism

Abstract

Background: Observational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid levels and VTE and its subtypes, including deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE).

Methods: We utilized Mendelian randomization (MR) analysis to estimate the causal association in European individuals. We extracted two sets of polygenic instruments strongly associated (p < 5 × 10^-8) with uric acid from the CKDGen consortium and UK biobank, respectively. Genetic associations with the risk of VTE, DVT, and PE were obtained from the FinnGen biobank. We used the inverse-variance weighted method as the preliminary estimate. Additionally, we employed MR-Egger, weighted median, and Mendelian randomization pleiotropy residual sum and outlier method as complementary assessments. Sensitivity analyses were performed to test for pleiotropic bias.

Results: The genetically instrumented serum uric acid levels had no causal effects on VTE, DVT, and PE. Two sets of polygenic instruments used for exposure, along with three complementary MR methods, also yielded no significant association.

Conclusions: Our MR analysis provided no compelling evidence for a causal relationship of serum uric acid with the risk of VTE. This suggests that uric acid-lowering therapies in patients with hyperuricemia may not be effective in reducing the likelihood of developing VTE.

Keywords: Mendelian randomization; Uric acid; Venous thromboembolism.

Fig. 1

An overview of the study design

Fig. 2

The flowchart of instrumental variable selection. CKDGen, the Chronic Kidney Disease Genetics consortium; UKB, UK biobank. SNPs, single-nucleotide polymorphisms. LD, linkage disequilibrium. MAF, minor allele frequency

Fig. 3

Estimates for the causal effect of genetically predicted uric acid levels on venous thromboembolism. CKDGen, the Chronic Kidney Disease Genetics consortium; UKB, UK biobank; VTE, Venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism. IVW, inverse-variance weighted method