A genetic marker of hyperuricemia predicts cardiovascular events in a meta-analysis of three cohort studies in high risk patients

Introduction: The strongest genetic marker of uric acid levels, the rs734553 SNP in the GLUT9 urate transporter gene, predicts progression to kidney failure in CKD patients and associates with systolic BP and carotid intima media thickness in family-based studies. Methods: Since genes are transmitted randomly (Mendelian randomization) we used this gene polymorphism as an unconfounded research instrument to further explore the link between uric acid and cardiovascular disease (cardiovascular death, and non-fatal myocardial infarction and stroke) in a meta-analysis of three cohort studies formed by high risk patients (MAURO: 755 CKD patients; GHS: 353 type 2 diabetics and coronary artery disease and the TVAS: 119 patients with myocardial infarction). Results: In separate analyses of the three cohorts, the incidence rate of CV events was higher in patients with the rs734553 risk (T) allele (TT/GT) than in those without (GG patients) and the HR in TT/GT patients in the three cohorts (range 1.72-2.14) coherently signaled an excessive cardiovascular risk with no heterogeneity (I2 = 0.01). The meta-analytical estimate (total number of patients, n = 1227; total CV events, n = 222) of the HR for the combined end-point in TT/GT patients was twice higher (pooled HR: 2.04, 95% CI: 1.11-3.75, P = 0.02) than in GG homozygotes. Conclusions: The T allele of the rs734553 polymorphism in the GLUT9 gene predicts a doubling in the risk for incident cardiovascular events in patients at high cardiovascular risk. Findings in this study are compatible with the hypothesis of a causal role of hyperuricemia in cardiovascular disease in high risk conditions.