Search

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. [ABSTRACT FROM AUTHOR]

Apolipoprotein H (apoH; also known as β2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys → Gly) and 316 (Trp → Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA. [ABSTRACT FROM PUBLISHER]

Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.Methods: We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.Results: Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)).Conclusions: We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region. [ABSTRACT FROM AUTHOR]