Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials.

Background Higher serum uric acid levels are associated with cardiovascular and neurovascular disease, but whether these relationships are causal is not known. We applied Mendelian randomization approaches to assess the association between genetically determined uric acid levels and outcomes under study in large clinical trials. Methods and Results We used 28 genetic variants related to serum uric acid as instruments to perform a range of 2-sample Mendelian randomization methods. Our analysis had statistical power to detect clinically relevant effects of genetically determined serum uric acid levels on the considered clinical outcomes; cognitive function, Alzheimer disease, coronary heart disease, myocardial infarction, systolic blood pressure, and stroke. There was some suggestive evidence for an association between higher genetically determined serum uric acid and cognitive function. There was also some suggestive evidence of a relationship between coronary heart disease, systolic blood pressure, and the serum uric acid genetic instruments, but likely related to genetic pleiotropy. Overall, there was no consistent evidence of a clinically relevant effect of genetically determined serum uric acid on any of the considered outcomes. Conclusions This Mendelian randomization study does not support a clinically relevant causal effect of genetically determined serum urate on a range of cardiovascular and neurovascular outcomes. The weak association of genetically determined serum urate with coronary heart disease and systolic blood pressure may be because of pleiotropic effects. If urate lowering drugs such as allopurinol are found to affect these outcomes in clinical trials, then the effects may be mediated through urate independent mechanisms.