Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus

Abstract

Objective. Low serum paraoxonase 1 (PON1) activity determined with paraoxon as substrate has been found to be associated with coronary artery disease. This study was undertaken to examine the relationship of PON1 activity and genotype to risk of systemic lupus erythematosus (SLE).Methods. The impact of 7 PON1 single-nucleotide polymorphisms (SNPs) was analyzed in relation to PON1 activity, SLE risk, lupus nephritis, antiphospholipid antibody (aPL) positivity, and carotid vascular disease in 380 SLE patients (334 white, 46 black) and 497 controls (455 white, 42 black).Results. Compared with findings in controls, PON1 activity with paraoxon substrate was reduced both in white lupus patients (mean ؎ SEM 618.9 ؎ 24.0 units/liter versus 719.6 ؎ 24.6 units/liter; P ‫؍‬ 0.007) and in black lupus patients (991.1 ؎ 82.7 units/liter versus 1,164.3 ؎ 101.4 units/liter; P ‫؍‬ 0.2711). Low PON1 activity in SLE was not associated with the occurrence of aPL, carotid vascular disease, or the use of immunosuppressive drugs. In multiple regression analyses, the Q192R SNP was found to be independently associated with PON1 activity and explained 28% and 41% of the variation in PON1 activity in white patients and black patients, respectively. Stratification of the lupus sample by presence (n ‫؍‬ 81) or absence (n ‫؍‬ 247) of renal disease revealed significant associations with 3 promoter SNPs, with odds ratios of 3.82 (95% confidence interval [95% CI] 1.49-9.82, P ‫؍‬ 0.005), 3.41 (95% CI 1.35-8.61, P ‫؍‬ 0.009), and 2.17 (95% CI 1.01-4.68, P ‫؍‬ 0.049).Conclusion. To our knowledge, this is the first study to assess the role of PON1 activity in SLE risk in a large biracial sample from the US. Our data indicate that low PON1 activity determined with paraoxon substrate is independently associated with SLE and that certain PON1 SNPs are associated with lupus nephritis.

Novel common and rare genetic determinants of paraoxonase activity: FTO, SERPINA12, and ITGAL

“…Given that SNPs in PON2 have been previously reported in this cohort to predict PON1 enzyme activity, the failure of additional PON2 SNPs to predict PON1 activity in SKAT analyses may and the quorum-sensing factor of pseudomonas aeruginosa ( 35,36 ). Perhaps due to this extensive substrate specifi city, PON1 also has been implicated in numerous human diseases in addition to vascular disease, such as Parkinson's disease (37)(38)(39)(40)(41), systemic lupus erythematosus (42)(43)(44), breast cancer ( 45,46 ), age-related macular degeneration (47)(48)(49), and diabetes ( 50 ), among other disorders ( 51 ). Given the recent failures of HDL-C to prevent atherosclerotic outcomes in recent trials and the varied effects of PON1 on numerous important human diseases, a fuller understanding of PON1 activity may shed light on the cardioprotective role of HDL.…”

Effect of efavirenz on high‐density lipoprotein antioxidant properties in HIV‐infected patients

“…It has been known that the distribution of PON-1 polymorphisms differs with ethnicity [27][28][29].The focal approach of the association of different end-points of cardiovascular problems and PON-1 arrived from genotype studies [30]. However, some authors have highlighted the role of PON-1 activity determinations [30,31], safeguarding the necessity to perform functional studies.…”

Paraoxonase (PON1) Gene Polymorphisms in Fabry Disease: Correlation with Renal Disease

“…Moreover, PON1 levels are sensitive to the specific (functional) polymorphic variants of Leu55Met and/or Gln192Arg. Thus, polymorphic phenotypes (PON55 and PON192) of PON1 have been correlated with cardiovascular risk [12] including that induced by macrovascular pathogenesis [19], and with developing acute ischemic stroke [20,21] as well as renal disease [22]. …”