A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study

Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1) activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization) the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF(2 alpha) (P = 0.03) and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 +/- 42.6 g/m(2); RQ: 147.7 +/- 51.1 g/m(2); RR: 167.3 +/- 41.9 g/m(2); P = 0.001) and in an inverse fashion to systolic function (LV Ejection Fraction) (QQ: 79 +/- 12%; RQ: 69 +/- 9%; RR: 65 +/- 10% P = 0.002). On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m(2) per risk allele, P = 0.005; LVEF: -2.96% per risk allele, P = 0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients.