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Poster presentation Background Single nucleotide polymorphisms (SNPs) of the TNF gene at positions -238 and -308 have earlier been associated with psoriasis vulgaris and psoriatic arthritis (PsA). However, a strong linkage disequilibrium at the chromosomal region 6p21 renders the interpretation of these findings difficult since also other risk factors for psoriasis (PSORS1) than SNPs of the TNF gene have bee mapped to that particular region. Therefore, in this study several SNPs of the TNF gene and of its neighbouring lymphotoxin alpha (LTA) gene were analysed independently and dependently on carrying the PSORS1 risk allele. Methods SNPs in the promoter of the TNF gene (-238G/A, -308G/A, -857C/T, -1031T/C), and one SNP of the LTA gene (+252A/G), of the TNLFRSF1A gene (+36A/G) and of the TNLFRSF1B gene (+676T/G), respectively, were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The tryptophan–tryptophan–cysteine–cysteine haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used to estimate the genetic impact of the PSORS1 risk allele. Results Whereas an earlier-described association of allele TNF*-238A with psoriasis could be confirmed, our study revealed that this association was completely dependent on concomitant carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint manifestations, strong association with the allele TNF*-857T was detected (OR = 1.956; P value corrected for multiple testing, Pcorr = 0.0025) also in patients negative for the PSORS1 risk allele. Conclusion Our results indicate genetic differences between psoriasis vulgaris patients with and without joint manifestation. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect linkage disequilibrium with PSORS1, TNF*-857T may represent a risk factor for PsA independent of PSORS1. A potential pathophysiologic relevance of the elucidated genetic association is further suggested by previously reported experimental evidence for a functional impact of the respective TNF polymorphism on TNFalpha expression levels.
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.