Paraoxonase 1 (PON1) is known for preventing atherosclerosis through lipid-modifying features, antioxidant activity, anti-inflammatory, anti-apoptosis, anti-thrombosis, and anti-adhesion properties. Uremic patients requiring haemodialysis (HD) are especially prone to atherosclerosis and its complications. We analysed the PON1 gene (PON1) polymorphisms and serum PON1 (paraoxonase) activity concerning dyslipidaemia and related cardiovascular diseases and mortality to show how they associate under uremic conditions modified by maintenance HD treatment. The rs662 AA + AG (OR 1.76, 95%CI 1.10–2.80, P = 0.018), rs854560 TT (OR 1.48, 95%CI 1.04–2.11, P = 0.031), and rs854560 AT + TT (OR 1.28, 95%CI 1.01–1.63, P = 0.040) contributed to the prevalence of atherogenic dyslipidaemia diagnosed by the triglyceride (TG)/HDL-cholesterol ratio ≥ 3.8. The normalized serum PON1 activity positively correlated with atherogenic dyslipidaemia (ẞ 0.67 ± 0.25, P = 0.008). The PON1 rs854560 allele T was involved in the higher prevalence of ischemic cerebral stroke (OR 1.38, 1.02–1.85, P = 0.034). The PON1 rs705379 TT genotype contributed to cardiovascular (HR 1.27, 95% CI 1.03–1.57, P = 0.025) and cardiac (HR 1.34, 95% CI 1.05–1.71, P = 0.018) mortality. All P-values were obtained in multiple regression analyses, including clinical variables. Multifaceted associations of PON1 with dyslipidaemia, ischemic cerebral stroke, and cardiovascular mortality in HD patients provide arguments for the consideration of PON1 and its protein product as therapeutic targets in the prevention of atherosclerosis and its complications in uremic patients.

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Cigarette smoking effects might correspond with paraoxonase 1 gene (PON1) single nucleotide variants (SNVs). We investigated the association of PON1 rs705379, rs854560, and rs662 with cardiovascular mortality in hemodialysis (HD) patients concerning conventional cigarette smoking. Cardiovascular, cardiac, coronary heart disease (CHD)- and non-CHD-related deaths were analyzed in 206 HD cigarette smokers and 659 HD non-smokers. P-values were adjusted for sex, age, and high-density lipoprotein cholesterol. Among all smokers, the rs705379 TT genotype was associated with cardiovascular (P = 0.028), cardiac (P = 0.046), and cardiac non-CHD-related (P = 0.001) mortality. Non-diabetic smokers showed similar qualitative significance to all smokers concerning mentioned death rates (P-values 0.011, 0.044, and 0.009, respectively). In diabetic non-smokers, the rs705379 T allele correlated with CHD-related deaths (P = 0.020). The rs854560 T allele was associated with lower cardiovascular mortality in non-diabetic smokers (P = 0.008). The rs854560 TT genotype showed a negative non-significant correlation with non-CHD-related cardiac death in all non-smokers (P = 0.079). In diabetic smokers, the rs662 G allele was associated with higher cardiac mortality (P = 0.005). In all non-smokers and non-diabetic non-smokers, the rs662 G correlated with cardiovascular deaths (P = 0.020 and P = 0.018, respectively). Genotyping PON1 SNVs may help argue HD smokers harboring the rs705379 TT genotype or T allele and non-smokers possessing the rs662 G allele for prevention against cardiovascular diseases. These groups are more burdened genetically for cardiovascular mortality.

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.