Patients with vascular complications of RA have an expansion of CD4 (186940)-positive/CD28 (186760)-null T cells that may be involved in endothelial cell damage. By flow cytometric and RT-PCR analyses, Yen et al. (2001) showed that CD4-positive/CD28-null T-cell clones ... Patients with vascular complications of RA have an expansion of CD4 (186940)-positive/CD28 (186760)-null T cells that may be involved in endothelial cell damage. By flow cytometric and RT-PCR analyses, Yen et al. (2001) showed that CD4-positive/CD28-null T-cell clones from RA vasculitis patients frequently expressed the stimulatory receptor KIR2DS2 (604953) in the absence of inhibitory receptors such as KIR2DL2 (604937) or KIR2DL3 (604938). Yen et al. (2001) noted that KIR genes are variably present in the Caucasian population, with the majority positive for inhibitory KIR. Comparable numbers of normal individuals and RA patients could be typed for either KIR2DS1 (604952) or KIR2DS2, whereas patients with unequivocal vasculitis had a highly significant association with KIR2DS2, suggesting that KIR2DS2 affects not the risk of developing RA but rather the risk of developing vascular complications. HLA-C polymorphisms (142840) are recognized by KIR2DS family proteins. HLA-C genotyping revealed that all RA patients had a decreased frequency of HLA-C*04 and an increased frequency of HLA-C*05, but RA vasculitis patients had a frequency of HLA-C*03 nearly double that of normal individuals and much higher than that of other RA patients. Logistic regression analysis determined that both HLA-C*03 and KIR2DS2 are independent, significant risk factors for RA vasculitis. Yen et al. (2001) concluded that MHC class I-recognizing receptors are implicated in the pathogenesis of RA vasculitis and possibly of other acute and chronic diseases characterized by vascular inflammation. Vandenbroeck et al. (2003) typed 4 microsatellite markers, located in a 118-kb interval that contains both the interferon-gamma (IFNG; 147570) and interleukin-26 (IL26; 605679) genes on chromosome 12q15, in 251 patients with RA and 198 controls. Marker D12S2510, which is located 3 kb 3-prime from the IL26 gene, was significantly associated with RA in women (p = 0.008) but not in men. A 3-marker haplotype, IFNGCA*13;D12S2510*8;D12S2511*9, was inferred that showed significant underrepresentation in women but not men with RA. Vandenbroeck et al. (2003) concluded that common polymorphisms in the IFNG/IL26 gene region may contribute to sex bias in susceptibility to RA. Lard et al. (2003) compared allele frequencies of the promoter -2849A/G polymorphism of the IL10 gene (124092.0002) in 283 patients with RA, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The IL10 genotype was not associated with the incidence of RA, but instead correlated with disease progression, with a significantly higher rate of joint destruction at 2 years observed in patients with a -2849G allele (p less than 0.001). No differences in the invasiveness of fibroblast-like synoviocyte were observed between -2849G and non-G patients, but patients with the G allele, which is associated with high IL10 production, had higher autoantibody titers at baseline. Among 156 RA patients, comprising 68 nonresponders and 88 responders to methotrexate treatment, Rizzo et al. (2006) found a significant association between favorable response and lack of the 14-bp polymorphism in the HLA-G gene (142871). The -14/-14 HLA-G genotype resulted in increased soluble HLA-G and conferred an odds ratio of 2.46 for responsiveness to methotrexate. Rizzo et al. (2006) postulated that the -14/-14 genotype allows the production of adequate levels of the HLA-G antiinflammatory molecule and a consequently positive therapeutic result in RA patients treated with methotrexate. Vyse and Todd (1996) gave a general review of genetic analysis of autoimmune disease, including rheumatoid arthritis. Feldmann et al. (1996) reviewed molecular mechanisms involved in rheumatoid arthritis. Kurreeman et al. (2011) demonstrated proof of concept that it is possible to use electronic health record (EHR) data linked with biospecimens to establish a multiethnic case-control cohort for genetic research of a complex disease, RA. In 1,515 EHR-derived RA cases and 1,480 controls matched for both genetic ancestry and disease-specific autoantibodies (anticitrullinated protein antibodies; ACPA), Kurreeman et al. (2011) demonstrated that the odds ratios and aggregate genetic risk score of known RA risk alleles measured in individuals of European ancestry within the EHR cohort are nearly identical to those derived from a genomewide association study of 5,539 autoantibody-positive RA cases and 20,169 controls. Kurreeman et al. (2011) extended their approach to other ethnic groups and identified a large overlap in the genetic risk score among individuals of European, African, East Asian, and Hispanic ancestry and demonstrated that the distribution of a genetic risk score based on 28 non-HLA risk alleles in ACPA+ cases partially overlaps with the ACPA- subgroup of RA cases. - Association with HLA-DRB1 Weyand et al. (1992) found that severity of RA, as reflected in the occurrence of extraarticular manifestations, was associated with homozygosity of a particular HLA-DRB1 allele, namely, 0401 (see 142857). Although genetically homogeneous, the clinical manifestations were heterogeneous; in addition to striking rheumatoid nodules, these included rheumatoid lung disease, rheumatoid vasculitis, Felty syndrome (134750), and rheumatoid vasculitic mononeuritis. HLA-DRB1 alleles encoding the 'shared epitope' are associated with susceptibility to RA (Gregersen et al., 1987). Because peripheral blood T cells have age-inappropriate telomeric erosion in RA, Schonland et al. (2003) examined whether HLA-DRB1*04 alleles confer risk for T-cell senescence. They found that in healthy individuals, HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4+ T cells and granulocytes, with accelerated telomeric erosion during the first 2 decades of life followed by reduced homeostatic T-cell proliferation during adulthood. Telomeric repair mechanisms were intact in HLA-DRB1*04+ donors. Schonland et al. (2003) proposed that HLA-DRB1*04 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in RA. Kallberg et al. (2007) investigated gene-gene and gene-environment interactions in rheumatoid arthritis, specifically, the interaction between 2 major genetic risk factors of RA, the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W were seen in all 3 studies regarding rheumatoid arthritis testing positive for antibodies to citrullinated proteins (anti-CCP). Hill et al. (2003) proposed an etiologic hypothesis that may explain the strong interaction between smoking and HLA-DRB1 SE alleles, that smoking may contribute to citrullination of proteins in the lung and that immune activation against such posttranslationally modified proteins may occur preferentially in individuals carrying HLA-DRB1 SE alleles, since citrullination may specifically increase the affinity between a protein and an SE-containing HLA-DR-beta chain. This hypothesis was made even more attractive by the demonstration by Lundberg et al. (2005) that citrullination of self-antigens may make them more immunogenic and arthritogenic, and that transfer of antibodies to citrullinated fibrinogen (see 134820) enhances the development of antibody-transferred arthritis in mice (Hill et al., 2003). Mahdi et al. (2009) tested the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of the association between smoking, HLA-DRB1 shared epitope alleles, and PTPN22 association with rheumatoid arthritis susceptibility. In 1,497 individuals from 3 RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43 to 63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 (600716.0001), and smoking showed the strongest association with the anti-CEP-1-positive subset (odds ratio of 37, compared to an odds ratio of 2 for the corresponding anti-CEP1-negative, anti-CCP-positive subset). Mahdi et al. (2009) concluded that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of rheumatoid arthritis. The Wellcome Trust Case Control Consortium (2010) undertook a large direct genomewide study of association between copy number variants (CNVs) and 8 common human diseases. Using a purpose-designed array, they typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs greater than 500 basepairs. The Wellcome Trust Case Control Consortium (2010) identified several biologic artifacts that led to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed 3 loci where CNVs were associated with disease: HLA for Crohn disease (266600), rheumatoid arthritis, and IDDM (222100); IRGM (608282) for Crohn disease; and TSPAN8 (600769) for type 2 diabetes (125853). In each case the locus had previously been identified in SNP-based studies, reflecting the observation of The Wellcome Trust Case Control Consortium (2010) that most common CNVs that are well-typed on their array are well-tagged by SNPs and so have been indirectly explored through SNP studies. The Wellcome Trust Case Control Consortium (2010) concluded that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. - Association with PTPN22 Begovich et al. (2004) reported the association of RA susceptibility with the minor allele, 1858T, of the R620W SNP in PTPN22. They showed that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with CSK (124095), potentially altering these proteins' normal function as negative regulators of T cell activation. To determine whether other genetic variants in PTPN22 contribute to the development of rheumatoid arthritis, Carlton et al. (2005) sequenced the coding region of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. They then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls, and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls. Analyses of these results predicted 10 common (frequency more than 1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the W620 risk allele (600716.0001) was strongly associated with disease in both the sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, did not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified 2 SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least 1 additional variant in the PTPN22 gene region influence RA susceptibility. The Wellcome Trust Case Control Consortium (2007) described a joint genomewide association study, using the Affymetrix GeneChip 500K Mapping Array Set, undertaken in the British population, which examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Their study identified 3 associations for rheumatoid arthritis, including a marker perfectly correlated with the PTPN22 R620W allele. - Association with SLC22A4 Tokuhiro et al. (2003) found that an intronic SNP in the RUNX1 (151385) binding site of SLC22A4 (604190.0001), designated slc2F2, is associated with rheumatoid arthritis. The slc2F2 SNP, found in intron 1, consists of a susceptible T allele and a nonsusceptible C allele. Data suggested that RUNX1 suppresses expression of SLC22A4 and that the susceptible T allele tends to express fewer SLC22A4 transcripts owing to a stronger suppressive effect of RUNX1 on this allele. - Association with PADI4 Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of citrullinating enzymes (peptidylarginine deiminases, encoded by PADI genes) in rheumatoid arthritis. Although no common locus apart from the HLA region was suggested by all linkage studies, some suggested that 1p36 contains a susceptibility locus for rheumatoid arthritis. This region includes 4 peptidylarginine deiminase genes. These genes encode enzymes that are functionally associated with the production of rheumatoid arthritis-specific autoantibodies. The PADIs posttranslationally convert arginine residues to citrulline. Citrullinated epitopes involved in a peptidic link are the most specific targets of rheumatoid arthritis-specific autoantibodies. Citrullination is related to 2 rheumatoid arthritis-specific autoantibody systems: those directed against perinuclear factor/keratin and against Sa. The clinical importance of measuring antibodies to citrullinated peptide and the specificity of autoantibodies suggests a specific role of citrullination and PADIs in the pathophysiology of rheumatoid arthritis. In addition, the appearance of antibodies to citrullinated peptide in sera from affected individuals in the very early phase of disease manifestation implies that citrullination is involved in the triggering phase or the acute phase of the disease. Citrullinated peptides have been identified in rheumatoid arthritis synovial tissue, suggesting the involvement of PADIs in the pathomechanisms of rheumatoid arthritis. Suzuki et al. (2003) used a case-control linkage disequilibrium study to show that of the cluster of PADI genes in the 1p36 region, PADI type 4 (PADI4; 605347) is a susceptibility locus for rheumatoid arthritis. This susceptibility gene could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context. By genomewide association studies in 940 Japanese individuals with rheumatoid arthritis and 940 healthy Japanese controls, Tamiya et al. (2005) confirmed the association between PADI4 and rheumatoid arthritis. - Association with STAT4 In a multistage case-control disease-association analysis of chromosome 2q33 involving a total of 3,149 patients with rheumatoid arthritis and 3,516 controls, Remmers et al. (2007) found that a 4-SNP haplotype (marked by dbSNP rs7574865 and including dbSNP rs11889341, dbSNP rs8179673, and dbSNP rs10181656) in intron 3 of the STAT4 gene was associated with RA. In the North American Rheumatoid Arthritis Consortium (NARAC) series and a replication series, the minor T allele of the most strongly associated SNP (dbSNP rs7574865) was present in 27% of chromosomes of patients with rheumatoid arthritis compared with 22% of those of controls (p = 2.81 x 10(-7)). Metaanalysis including a third patient series yielded a p value of 4.64 x 10(-8). Homozygosity of the risk allele compared to absence of the allele was associated with a 60% increased risk for rheumatoid arthritis, and the risk allele was also associated with systemic lupus erythematosus (SLE; 152700). Martinez et al. (2008) genotyped 575 Spanish patients with RA for dbSNP rs7574865 and confirmed the association with RA (p = 1.2 x 10(-6); odds ratio, 1.59). - Association with Chromosome 6q23 In a genomewide association screen, the Wellcome Trust Case Control Consortium (2007) (WTCCC) identified 9 single SNPs putatively associated with rheumatoid arthritis at a high probability. One SNP, dbSNP rs6920220, was unequivocally replicated in a validation study by Thomson et al. (2007). They demonstrated that this SNP maps to 6q23, between the genes encoding oligodendrocyte lineage transcription factor-3 (OLIG3; 609323) and tumor necrosis factor-alpha-induced protein-3 (TNFAIP3; 191163). Plenge et al. (2007) also identified an SNP at 6q23 (dbSNP rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genomewide association scan and in 5,541 additional case-control samples. Plenge et al. (2007) demonstrated that this SNP is located 3.8 kb from dbSNP rs6920220 identified by Thomson et al. (2007). They showed, furthermore, that these 2 SNP associations are statistically independent, are each reproducible, and defined risk and protective haplotypes for rheumatoid arthritis at 6q23. In U.K. study of 3,962 RA patients and 3,531 healthy controls of Caucasian Northern European descent, Orozco et al. (2009) found 18 SNPs associated with RA in the chromosome 6q23 region. The SNPs showing the strongest association were dbSNP rs6920220 and dbSNP rs13207033, the latter of which was perfectly correlated with dbSNP rs10499194, a SNP previously associated with RA. A number of additional potential RA markers were found, including dbSNP rs5029937, located in intron 2 of the TNFAIP3 gene. Of the 18 associated SNPs, dbSNP rs6920220, dbSNP rs13207033, and dbSNP rs5029937 remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of dbSNP rs6920220 and dbSNP rs5029937 together with the absence of the protective allele of dbSNP rs13207033 was strongly associated with RA (p = 5.2 x 10(-9); OR, 1.86) when compared with carriage of none. - Association with IRF5 Sigurdsson et al. (2007) analyzed 5 SNPs in the IRF5 gene (607218) in Swedish patients with rheumatoid arthritis and found that 4 of the 5 SNPs were associated with RA, including dbSNP rs2004640 (607218.0002). The strongest association was exhibited by dbSNP rs3807306 (p = 0.00063), particularly in a subgroup of anti-CCP-negative RA patients (p = 0.000091), and dbSNP rs3807306 was in linkage disequilibrium (r(2) = 0.67) with dbSNP rs2004640. The association with IRF5 was replicated in a cohort of Dutch RA patients. - Association with CD40 To identify rheumatoid arthritis risk loci in European populations, Raychaudhuri et al. (2008) conducted a metaanalysis of 2 published genomewide association studies totaling 3,393 cases and 12,462 controls. They genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive RA cases and 5,807 matched controls from 8 separate collections. Raychaudhuri et al. (2008) identified a common variant at the CD40 gene locus (dbSNP rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, odds ratio = 0.87). Along with other associations near TRAF1 (601711) and TNFAIP3, Raychaudhuri et al. (2008) concluded that this implied a central role for the CD40 signaling pathway in RA pathogenesis. - Association with CCL21 In a metaanalysis of 2 published genomewide association studies totaling 3,393 cases and 12,462 controls to identify rheumatoid arthritis risk loci in European populations, Raychaudhuri et al. (2008) identified association of the CCL21 gene locus (602737), a gene involved in lymphocyte trafficking, at dbSNP rs2812378 (P = 0.00097 replication, P = 2.8 x 10(-7) overall). They also identified evidence of association at 4 additional gene loci, including MMEL1-TNFRSF14 (dbSNP rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), and KIF5A-PIP4K2C (dbSNP rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall). - Association with CD244 Suzuki et al. (2008) identified a linkage disequilibrium block associated with rheumatoid arthritis in the chromosome 1q region containing multiple SLAM (signaling lymphocyte activation molecule) family genes. In this block, the association peaked at 2 functional SNPs (dbSNP rs3766379 and dbSNP rs6682654) in CD244 (see 605554.0001) in 2 independent RA cohorts from Japan (P = 3.23 x 10(-8) and P = 7.45 x 10(-8)). Suzuki et al. (2008) also identified a Japanese cohort with systemic lupus erythematosus that had a similar genotype distribution as the RA cohorts. - Association with CD2/CD58 To discover new rheumatoid arthritis risk loci, Raychaudhuri et al. (2009) systematically examined 370 SNPs from 179 independent loci with P less than 0.001 in a published metaanalysis of RA genomewide association studies of 3,393 cases and 12,462 controls (Raychaudhuri et al., 2008). The authors used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. Twenty-two loci with a significant degree of functional connectivity were identified and genotyped in an independent set of 7,957 cases and 11,958 matched controls. Raychaudhuri et al. (2009) validated association at the CD2/CD58 locus (see 153420) (dbSNP rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall). - Association with CD28 Using GRAIL to score candidate susceptibility SNPs identified by Raychaudhuri et al. (2008) for functional relationships to genes in 16 established RA disease loci, followed by genotyping in an independent set of 7,957 cases and 11,958 matched controls, Raychaudhuri et al. (2009) validated association at the CD28 (186760) locus (dbSNP rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall). - Association with PRDM1 Using GRAIL to score candidate susceptibility SNPs identified by Raychaudhuri et al. (2008) for functional relationships to genes in 16 established RA disease loci, followed by genotyping in an independent set of 7,957 cases and 11,958 matched controls, Raychaudhuri et al. (2009) validated association at the PRDM1 (603423) locus (dbSNP rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). - Association with AFF3 Barton et al. (2009) identified an association between SNPs in the AFF3 gene (601464) on chromosome 2q11.2 (dbSNP rs10865035 and dbSNP rs9653422) and susceptibility to rheumatoid arthritis in a combined sample cohort of 6,819 RA cases and 12,650 controls (OR 1.12; p = 2.8 x 10(-7)) from 3 independent U.K. case-control series. - Association with CCR6 Kochi et al. (2010) identified a polymorphism in CCR6 (601835) that was associated with rheumatoid arthritis susceptibility and was validated in 2 independent replication cohorts from Japan (dbSNP rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, p = 7.7 x 10(-19)). Kochi et al. (2010) identified a triallelic dinucleotide polymorphism of CCR6, which they termed CCR6DNP, in strong linkage disequilibrium with dbSNP rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with expression levels of CCR6 and was associated with the presence of interleukin-17 (IL17; 603149) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves (275000) and Crohn (see 266600) diseases. Kochi et al. (2010) concluded that CCR6 is critically involved in IL17-driven autoimmunity in human diseases. Stahl et al. (2010) also identified an association at the CCR6 region with rheumatoid arthritis in European populations by performing a metaanalysis of genomewide association studies from a collection of 5,539 autoantibody-positive rheumatoid arthritis cases and 20,169 controls, in which the strongest signal was observed at a SNP in CCR6 (dbSNP rs3093023, p = 3.3 x 10(-7), OR = 1.13). Kochi et al. (2010) noted that the landmark SNP in their Japanese population, dbSNP rs3093024, was in almost absolute linkage disequilibrium with dbSNP rs3093023 in the European population (r(2) greater than 0.99). - Association With FCGR3B Among 1,115 patients with rheumatoid arthritis and 654 controls, Robinson et al. (2012) found a significant association between FCGR3B (610665) deletions and disease (OR = 1.50, p = 0.028). The association was more apparent in rheumatoid factor (RF)-positive disease (OR = 1.61, p = 0.011). Robinson et al. (2012) noted that the general association (p = 0.028) would not remain significant if corrected for multiple testing, but the evidence was strengthened by the stronger association in the RF-positive group of patients. The level of FCGR3B expression on neutrophils was shown to correlate with gene copy number. The results implicated an important role for neutrophils in the pathogenesis of RA, potentially through reduced FCGR3B-mediated immune complex clearance. No association was found between FCGR3A (146740) copy number and disease. The authors used a novel quantitative sequence variant assay in the study.