Abstract
Background and Aims
Paraoxonase 1 gene (PON1) single nucleotide variants (SNVs), known as associated with lipoprotein peroxidation, are related to atherosclerotic diseases, including coronary heart disease (CHD). Cigarette smoking, causing increased susceptibility to lipoprotein oxidation, contributes to cardiovascular events, and its effects are linked with PON1 SNVs. We investigated the association of PON1 rs705379 (-108C>T), rs854560 (163A>T), and rs662 (575A>G) SNVs with cardiovascular mortality in maintenance hemodialysis (HD) patients concerning cigarette smoking status.
Method
In the HD group, there were 206 smokers and 659 non-smokers. Among all patients who died (n = 542), cardiovascular mortality was similar in smokers and non-smokers (59.0% vs. 59.3%, respectively). Deceased smokers were burning 20 (5 - 25) cigarettes daily. We obtained PON1 polymorphisms by HRM analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379). All cardiovascular, cardiac, CHD- and non-CHD-related deaths were analyzed in smokers and non-smokers concerning PON1 SNVs and DM status. The Kaplan-Meier method with the log-rank test and the Cox regression analyses were applied for the estimation of survival. If computed P-values were below 0.05, the adjustment for sex, age, and HDL-cholesterol was applied. We have shown only adjusted P-values for survival analyses.
Results
HD cigarette smokers, who died from cardiovascular diseases, were younger (63.5, 31.1 – 86.3 vs. 74.0, 26.8 – 95.9 years, P = 2.992e-10), predominantly men (70, 85.3% vs. 91, 38.1%, P = 1.5e-13), had more atherogenic serum lipid profile (atherogenic index estimated as the TG/HDL cholesterol ratio 4.90, 0.72 – 25.6 vs. 3.79, 0.66 – 49.7, P = 0.003; HDL-cholesterol level 34.8, 17.3 – 103 vs. 40.0, 7 – 103 mg/dL, P = 0.0004; TG 167.0, 48.8 – 652 vs. 149.8, 40.0 – 856 mg/dL, P = 0.034), but similar RRT duration compared to deceased HD non-smokers. Cigarette smoking status did not influence cardiovascular mortality either in DM or non-DM group. DM smokers showed similar cardiovascular mortality to non-DM smokers, but among HD non-smokers, DM patients demonstrated higher cardiovascular mortality than non-DM subjects (P = 0.029). Among all smokers, the rs705379 TT genotype was associated with all cardiovascular (P = 0.028), all cardiac (P = 0.046), and cardiac non-related with CHD (P = 0.001) mortality. The rs705379 TT genotype smokers, who died from cardiac reasons, showed a higher frequency of myocardial infarction than CC+CT bearers (66.7% vs. 29.2%, P = 0.047). Non-DM smokers showed similar qualitative significance to all smokers concerning all cardiovascular, all cardiac, and cardiac non-related with CHD death rates (P-values 0.011, 0.044, and 0.009, respectively). In DM non-smokers, the rs705379 T allele correlated with CHD related deaths (P = 0.020). The rs854560 T allele, compared to the AA genotype, was associated with lower cardiovascular mortality in non-DM smokers (P = 0.008). The rs854560 TT genotype showed a negative correlation with cardiac death non-related to CHD in all non-smokers (P = 0.079). In DM smokers, the rs662 G allele was associated with a higher risk of cardiac mortality (P = 0.005). In all non-smokers and non-DM non-smokers, the rs662 G allele correlated with cardiovascular deaths (P = 0.020 and P = 0.018, respectively).
Conclusion
The variant alleles of PON1 rs705379 (T) and rs662 (G) are associated with cardiac mortality in HD patients. The rs854560 variant allele (T) possessors present better cardiovascular survival than the AA genotype subjects. Cardiovascular mortality is not merely related to polymorphic variants known as associated with lower serum activity or concentration of paraoxonase, a PON1 protein product. Assessing PON1 SNVs enables the prediction of cardiovascular mortality risk in HD smokers and non-smokers and may help select patients for advanced prevention against cardiovascular diseases.
SMOKING
