AbstractObjectiveLow 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).MethodsThe 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).ResultsCompared 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).ConclusionTo 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.