Abstract
Introduction Prospective studies suggest that high serum uric acid (UA) levels are associated with increased risk of myocardial infarction (MI), but causality of this association remains uncertain. Mendelian randomization studies assess causality by using genetic variants as unbiased proxies for circulating biomarkers. We tested the hypothesis that genetically raised UA levels are causally related to elevated MI risk. Methods All reported UA associated genetic variants were assessed for pleiotropy in public genome-wide association databases and in the Pakistan Risk of Myocardial Infarction Study (PROMIS), in which we measured >25 atherosclerosis-related biomarkers in >10,000 people. Genetic variants lacking pleiotropic associations (p<0.01) were evaluated for association with MI in 7031 cases and 6360 controls in PROMIS. Results Among the individuals studied (mean age 54 ± 10 years; 81% male), 1316 had UA measurements with mean UA 5.71 ± 1.54 mg/dl. Of the 36 genetic variants associated with UA at genome-wide significance (p <5x10-8), 5 were independent and not associated with any factors investigated. For each variant, genetically raised UA was not associated with MI risk in a concordant direction (Table). A score-based instrumental variable analysis found no causal relationship between UA levels and MI (OR 0.91, 95% CI 0.74 - 1.12, p = 0.39). This analysis will be repeated with CARDIoGRAM data in time for presentation. Conclusions (1) Genetically raised UA levels were not associated with elevated MI risk, and (2) the collection of UA genetic instruments did not reject the null hypothesis of no causal relationship. We suggest that UA levels are not causally related to MI risk.
Published Version
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