The Association of Hyperuricemia and Gout With the Risk of Cardiovascular Diseases: A Cohort and Mendelian Randomization Study in UK Biobank

Background: The association between hyperuricemia/gout with cardiovascular diseases (CVD) have been investigated. However, whether the magnitude of associations differs between hyperuricemia and gout, and the causality of these associations, remains inconclusive. Methods: Based on UK Biobank, we conducted a cohort analysis including 431,967 participants, who were categorized as gout, hyperuricemia, and normal groups at recruitment, and followed up for CVD until December 2019. The phenotypic association of hyperuricemia/gout with CVD was estimated by Cox regression, adjusting for multiple confounders. Further exploration on the causality of such links was performed using Mendelian Randomization (MR) analysis, where we selected exclusive genetic variants for hyperuricemia and for gout based on summary GWAS data from independent populations. Results: During mean 10.20 years of follow-up, hyperuricemia patients were associated with increased CVD (HR = 1.33, 95% CI: 1.29-1.36), compared to individuals who were free of hyperuricemia/gout. The risk elevation was even higher for gout patients (HR = 1.54, 95% CI: 1.48-1.62). Furthermore, we found significantly positive association between genetic liability for hyperuricemia and CVD in both one-sample (OR = 1.06, 95% CI: 1.02-1.11) and two-sample (OR = 1.09, 95% CI: 1.03-1.16) MR analysis. However, genetic liability for gout was not associated with CVD (OR = 0.89, 95% CI: 0.79-1.01 in one-sample, and OR = 0.92, 95% CI: 0.82-1.21 in two-sample MR analysis). Conclusion: Individuals with hyperuricemia/gout were at increased risk of various types of CVD. As the MR analyses suggest a causal effect of hyperuricemia, but not gout, on CVD, these results indicate the possible effects of other gout-associated factors on the development of CVD, in addition to the uric acid pathway.