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-isoPGF2α (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.
Department of Nephrology, University Hospital of Ioannina, 45110 Ioannina, Greece.
E
0000-0002-1172-1829
E
Dounousi
Laboratory of Clinical Genetics and Human Reproduction, Medical School University of Ioannina, 45110 Ioannina, Greece.
I
I
Bouba
CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, 89124 Reggio Calabria, Italy.
B
B
Spoto
Department of Cardiology, University Hospital of Ioannina, 45110 Ioannina, Greece.
K
K
Pappas
CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, 89124 Reggio Calabria, Italy.
G
G
Tripepi
Laboratory of Clinical Genetics and Human Reproduction, Medical School University of Ioannina, 45110 Ioannina, Greece.
I
I
Georgiou
Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
A
A
Tselepis
Department of Internal Medicine, University Hospital of Ioannina, 45110 Ioannina, Greece.
M
M
Elisaf
Department of Nephrology, General Hospital "Papageorgiou" of Thessaloniki, 564 29 Thessaloniki, Greece.
D
D
Tsakiris
CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, 89124 Reggio Calabria, Italy.
C
C
Zoccali
Department of Nephrology, University Hospital of Ioannina, 45110 Ioannina, Greece.
K
K
Siamopoulos
D000368:Aged; D000483:Alleles; D043303:Aryldialkylphosphatase / Q000235:genetics*; D009202:Cardiomyopathies / Q000209:etiology*; D003430:Cross-Sectional Studies; D004452:Echocardiography; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics*; D016277:Ventricular Function, Left / Q000502:physiology
D043303:Aryldialkylphosphatase