Furthermore, a comparison of the frequencies in RF-negative against RF-positive men also yielded a significant association with RF-negative disease ( em P /em = 0
Furthermore, a comparison of the frequencies in RF-negative against RF-positive men also yielded a significant association with RF-negative disease ( em P /em = 0.01). 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 ( em CYBB /em , em CYBA /em , em NCF4 /em , em NCF2 /em , and em RAC2 /em ) 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 em NCF4 /em (rs729749, em P /em = 0.001), em NCF2 /em (rs789181, em Rabbit Polyclonal to BID (p15, Cleaved-Asn62) P /em = 0.02) and em RAC2 /em (rs1476002, em P /em = 0.05). No associations were CM-4620 detected in em CYBA /em or em CYBB /em . By stratifying for autoantibody status, we identified a strong association for rs729749 (in em NCF4 /em ) in autoantibody unfavorable 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; em P /em = 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. Introduction Rheumatoid arthritis (RA) is CM-4620 usually a chronic inflammatory disease that leads to erosion and deformation of the joints. The prevalence in the general population is usually 0.5% to 1%, and women are at two to three times greater risk for developing the disease. Twin studies show a concordance rate of 12% to 15% in monozygotic twins and 4% in dizygotic twins, and the genetic heritability is estimated at 60% [1]. Despite much effort to identify arthritis causing genes, only few genetic loci have been confirmed to be associated with RA, among which are the human leucocyte antigen ( CM-4620 em HLA /em ) locus and the protein tyrosine phosphatase non-receptor 22 gene ( em PTPN22 /em ) [2-4]. RA is usually a heterogeneous disease with symptoms and disease progression that vary between patients. Classification of common RA requires fulfilment of four out of seven criteria established by the American College of Rheumatology [5]. The heterogeneity of the symptoms in RA probably mirrors the underlying genetic contribution; hence, the various combinations of symptoms observed in patients are probably caused by different combinations of risk alleles. In the search for markers that can predict development of the disease before its onset, several autoantibodies, including rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (anti-CCP antibodies), have been detected [6-8]. RFs, autoantibodies that recognize the Fc a part of immunoglobulins [9], are present in 60% to 70% of RA patients and have been found to be associated with more severe clinical manifestations [10,11]. Anti-CCP antibodies are present in 50% to 60% of RA patients and have also been shown to predict more severe disease [10,12-14]. Interestingly, recent data suggest that the em HLA-DRB1 /em locus, which has been shown to be associated with RA, is only associated with the presence of anti-CCP antibodies, and this association is impartial of both RA development and the presence of RFs [15]. Together with recent data describing the conversation between environmental factors and genetic predisposition [16,17], these findings support the hypothesis that several impartial disease mechanisms may lead to development of RA. They also emphasize the need to use relevant subgroups of RA patients in genetic association studies. Various approaches have been used to identify genes that contribute to common diseases such as RA [18,19]. Because of increasing knowledge of gene functions and immunological pathways, a candidate gene approach can be more efficient in terms of both cost and time than traditional linkage analysis or genome-wide approaches. The selection of genes in a candidate gene study can be based on previous knowledge of gene functions CM-4620 as well as on disease or immunological mechanisms. It can also be based on findings in.