Comorbidities in gout and hyperuricemia: causality or epiphenomena?

To review advances in the understanding of potentially causal relationships between gout, hyperuricemia and comorbidities. Observational studies reveal 4-5 comorbidity clusters in gout patients. There tend to be gout alone, gout with chronic kidney disease and gout with other metabolic comorbidities. However, heterogeneous study populations and confounding make inference difficult for causal relationships. Mendelian randomization leverages genetic information as an instrumental variable to indicate putatively causal relationships between traits of epidemiological interest. Thus far, Mendelian randomization has not indicated widespread causal relationships of serum urate for comorbid traits. However, BMI has a small causal effect on serum urate, which may partially explain the increased prevalence of metabolic syndrome and cardiovascular disease among those with gout and hyperuricemia. There is a lack of robust and sufficiently powered Mendelian randomization studies for many serum urate-associated traits, such as hypertension. No adequately powered studies have been completed for gout and its comorbidities. Although observational studies indicate putative causal effects of serum urate on comorbidities, Mendelian randomization studies suggest that serum urate does not have a causal role on the various tested comorbidities. There remains work to be done in clarifying the causal role of gout per se on the same traits.