PON-1 haplotype (-108C>T, L55M, and Q192R) modulates the serum levels and activity PONase promoting an atherogenic lipid profile in rheumatoid arthritis patients.

Abstract

Paraoxonase 1 (PON1) promotes antioxidant and antiatherogenic activity related to the hydrolysis of oxidized lipids of low-density lipoproteins. In rheumatoid arthritis (RA) patients, it has been reported that low PON1 activity is related to an impaired lipid profile, increasing cardiovascular risk (CVR). The goal of this study was to analyze the effect of common PON1 polymorphisms and haplotypes on enzymatic activity, PON1 serum levels (PON1s), and lipid parameters related to atherogenic profile in RA patients. A cross-sectional study was carried out on 250 Mexican patients with RA. The lipid profile was determined by colorimetric tests. The PON1 activity (CMPAase) was measured by spectrophotometry. The levels of PON1s were determined by ELISA, and the polymorphisms in the PON-1 gene (-108C>T, L55M, and Q192R) were genotyped by the PCR-RFLP method. The haplotypes were estimated and statistical analysis was performed. The median of the CMPAase activity and PON1 levels was 13.91U/mL and 24.75ng/mL, respectively. The CMPAase activity was significantly lower in carriers of -108TT and 192QQ genotypes (β = - 4.09, P = 0.001 and β = - 3.73, P = 0.002, respectively); moreover, the PON1 levels were lower in 192Q allele carriers (P < 0.01). The TLQ haplotype was associated with CMPAase activity < 13.91U/mL (OR = 2.29, P < 0.001), as well as with levels of PON1s < 24.75ng/mL (OR = 1.65, P = 0.017). In this study, the CMPAase activity (< 13.91U/mL) showed a positive association with lower levels of high-density lipoprotein cholesterol (HDL-c; < 40/50mg/dL), and with a triglycerides/HDL-c ratio > 3%, and a total cholesterol/HDL-c ratio > 4.5/5%, all representatives of an atherogenic risk lipid profile. PON1 polymorphisms modulate the CMPAase activity and PON1 levels in Mexican patients with RA. The CMPAase activity < 13.91U/mL is associated with an atherogenic lipid profile, independently of inflammation markers and treatment with anti-rheumatic drugs. Key Points •The haplotype TLQ is a marker for low PONase activity in rheumatoid arthritis. •The haplotype TLQ is a marker for low PON1 serum levels in rheumatoid arthritis. •The enzymatic PON1 activity represents the best marker for an atherogenic lipid profile in rheumatoid arthritis, in comparison with PON1 levels. •The haplotype TLQ is a marker of low PON1 activity, levels of PON1s, and atherogenic lipid profile, independent of treatment therapy in rheumatoid arthritis.