Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression.

BACKGROUND & AIMS: We have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2-5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort. METHODS & RESULTS: Over a 29 ± 11 months follow-up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25-4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06-1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels. CONCLUSIONS: The rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage.

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.