Serum Urate Does Not Have a Causal Effect on Gout Comorbidity Risk, According to Mendelian Randomization Studies

Gout inflammation on foot
Man on bed with pillow embrace foot with painful swollen gout inflammation
Researchers reviewed the causal relationships between gout, hyperuricemia, and associated comorbidities.

Although observational studies have reported a causal relationship between gout and comorbidities, mendelian randomization studies have suggested that serum urate does not have a causal effect on the risk for gout comorbidities, according to findings from a literature review published in Current Opinion in Rheumatology.

Investigators assessed studies of gout and hyperuricemia and comorbidities published 18 months before March 2020, in which prevalence rates of gout comorbidities were compared between patients with and without hyperuricemia. Comorbidities of interest included hypertension, chronic kidney disease, obesity, diabetes, nephrolithiasis, myocardial infarction, heart failure, and stroke. Findings from observational studies were compared with findings from mendelian randomization studies, considering the strengths and limitations of each study design.

Observational studies identified “clustering” of comorbidities in patients with gout, with some comorbidities more likely to occur in the presence of other comorbidities. Most studies reported 4 to 5 clusters: diabetes and liver disease tended to co-occur, and metabolic syndrome and cardiovascular disease (CVD) were often reported together. Specific cluster components varied across studies, though many researchers agreed that comorbidity clusters in patients with gout significantly differed from comorbidity clusters in the general population. Mendelian randomization studies tended to show no causal association between serum urate and certain gout comorbidities. A study indicated that serum urate may have a protective effect on kidney function in men, though investigators hypothesized that pleiotropic effects from a single locus could have obfuscated study findings. Another study found a causal role of genetically defined serum urate on sudden cardiac death, but the same cohort displayed no causal association with prevalent CVD.

Compared with observational studies, mendelian randomization studies avoid the limitations of cohort heterogeneity and confounding. By using genetic data, mendelian randomization can directly identify “putative causal relationships;” however, these studies are less commonly conducted. In addition, no adequately powered study has yet been conducted on the effect of hyperuricemia.

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The current landscape of gout research presents conflicting evidence for the role of hyperuricemia in comorbidity risk. Further research is necessary to clarify the role of serum urate in gout comorbidities.


Sumpter NA, Saag KG, Reynolds RJ, Merriman TR. Comorbidities in gout and hyperuricemia: causality or epiphenomena? Curr Opin Rheumatol. 2020;32(2):126-133.