Paraoxonase 1 Activity and Pon 1 Gene Polymorphisms As a Potential Prognostic Biomarker in Sickle Cell Disease

Background: Sickle cell disease (SCD) has a clinical heterogeneity and vasoocclusive events are an important clinical characteristic among patients. The paraoxonase 1 (PON 1) is a serum glycoprotein associated with the high-density lipoproteins cholesterol (HDL-C) and the variability of the PON1 activity has been associated with the PON1 genotypes. We tested a possible relevance of the PON1 in SCD patients in steady and crisis state, studying its activity and genotype, investigating M55L (rs854560) and R192Q (rs662) polymorphisms, and their association with markers of hemolysis, inflammation and organ dysfunction.

Methods: The casuistic of the study was compound by 373 individuals, 154 SCD patients in steady state, 23 SCD patients in crisis, and 196 healthy controls. Chemistry, inflammatory and hematological biomarkers were investigated by chemiluminescence, immunoassay and electronic cell counter respectively. Molecular biology analyses were performed by PCR and PCR-RFLP techniques.

Results: The allelic frequency of PON1192R among SCD patients group was 0.38 and of PON1192Q was 0.62. The allelic frequency of the control group individuals was 0.45 to the PON1192R and 0.55 to PON1192Q. The allelic frequency of PON1M55L gene polymorphism was 0.91 to the PON155L and 0.09 to the PON155M among the SCD patients group. The allelic frequency of the PON155L was 0.85 and for the PON155M was 0.15 among individuals of the control group. PON1 gene polymorphisms allelic frequencies were in Hardy-Weinberg equilibrium. Patients with genotype RR of PON1192 (p=0.0015) and MM of PON155 (p=0.0013) showed less PON1 activity than others genotypes. PON1 activity was higher among SCD patients in crisis and steady states than in control group individuals (p<0.0001). The PON1 activity was higher among SCD patients with higher concentrations of high density lipoprotein cholesterol (HDL-C) (p-0.03), higher iron serum levels (p=0.007), and lower ferritin levels (p<0.0001). SCD patients with the PON1c.55M allele had lower platelet count (p=0.011), creatinine (p=0.033), and C Reactive Protein (p=0.014), and patients with the PON1192R alleles had higher triglycerides (p=0.013) and very low lipoprotein cholesterol (VLDL-C). Related to clinical characteristics SCD patients that experienced stroke (p=0.045) had lower PON1 activity and patients that made splenectomy (0.011) had highest PON1 activity.

Conclusion: The PON1 activity and genetic alteration were not explored among SCD patients and may represent a new insight to explain endothelial dysfunction and oxidative stress reaction among these patients. Also, PON1 may represent an important molecule in SCD pathogenesis and the associated mechanisms need to be evaluated once it seems to be delivery from the HDL-C structure under a very intense hemolytic and inflammatory environment as happened in SCD, and may be explore as a further therapeutic strategy in disease.