Rheumatoid Arthritis
A number sign (#) is used with this entry because multiple factors, including HLA type (see HLA-DRB1; 142857), influence the susceptibility to rheumatoid arthritis.
Evidence suggests that several polymorphisms in various genes may also be associated with susceptibility to rheumatoid arthritis, including SLC22A4 (604190.0001), PTPN8 (600716.0001) MHC2TA (600005.0007), IRF5 (607218.0002), and NFKBIL1 (601022.0001). Also see MOLECULAR GENETICS.
DescriptionRheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component.
InheritanceOccasional families show a considerable number of cases of this common disorder. A simple mendelian mechanism could not be proved, however. Indeed, some (Burch et al., 1964) could not demonstrate significant familial aggregation.
Lynn et al. (1995) conducted family studies and segregation analyses of RA based on consecutive patients with RA ascertained without regard to family history or known risk factors. Included in the analyses were first-degree relatives from 135 simplex and 30 multiplex families. A highly penetrant recessive major gene, with a mutant allele frequency of 0.005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. Although both proband gender and age at onset were identified as important risk factors, proband gender appeared to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. For future genetic analyses, Lynn et al. (1995) suggested that families with an excess of affected males having a young age at onset might be most informative in identifying the putative recessive gene and its modifiers.
Hasstedt et al. (1994) studied 28 pedigrees ascertained through pairs of first-degree relatives with RA. RA was confirmed in 77 pedigree members, including probands; the absence of disease was verified in an additional 261 pedigree members. Members of the pedigrees were typed serologically for HLA. Analyses supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 0.0216, and estimated the lifetime penetrance as 41% in male homozygotes and 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variants with HLA genotypes to genetic or environmental effects shared by sibs. The genetic model inferred in this analysis was considered consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounted for approximately one-half of familial RA, although it accounted for only approximately one-fifth of the RA in the population.
PathogenesisUpregulation of proinflammatory cytokines in RA synovium and synovial fluid is a feature of active disease and intense inflammation. Antiinflammatory mediators are also present and activated in RA but fail to counterregulate the proinflammatory cytokines. Muller-Ladner et al. (2000) found that the IL4-STAT (STAT6; 601512) pathway is activated in patients with short-term (less than 1 year) and long-term (more than 2 years) RA and may contribute to downregulation of the immunologic activity in RA synovium.
In a T-cell receptor transgenic mouse model, an inflammatory arthritis that resembles human RA is initiated by T cells but is sustained by antibodies to GPI (172400). Using ELISA analysis, Schaller et al. (2001) detected high levels of antibody to GPI, independent of the presence of rheumatoid factor, in serum and synovial fluid of most RA patients; antibodies to GPI were rare in controls or in patients with Lyme arthritis or Sjogren syndrome. In addition, the authors found high levels of GPI in sera and synovial fluid and the presence of GPI-containing immune complexes in RA synovial fluid. Immunohistochemical analysis and confocal microscopy demonstrated intense expression of GPI on the surface of endothelial cells of synovial arterioles and some capillaries, but not venules or in other tissues. Intense patchy expression was observed on the surface lining of hypertrophic synovium, particularly where the hypertrophic villus formed; this expression pattern resembled that for vascular permeability factor (VEGF/VPF; 192240). Schaller et al. (2001) suggested that GPI may be presented to the immune system either on endothelial cell surfaces or as a soluble protein in synovial fluid of inflamed RA joints, leading to antibody binding or to immune complex formation with complement activation, respectively. In either case, they concluded that there is a role for autoantibody in the pathology of RA and that there may be scope for antibody treatments for the disease.
Using a rheumatoid factor (RF+) transgenic B cell hybridoma line originally isolated from an autoimmune MRL/lpr mouse used as a model for SLE, Leadbetter et al. (2002) determined that these cells respond only to IgG2a immune complexes containing DNA and not to haptens or proteins. After ruling out complement receptors (i.e., CD21/CR2, 120650) as a potential second receptor on B cells, screening of cells expressing the adaptor protein Myd88 (602170), through which all toll-like receptors signal, revealed that RF+ B cells lacking Myd88 are completely unresponsive to IgG2a antinucleosome monoclonal antibodies (mAb). TLR9 (605474) responsiveness to CpG oligodeoxynucleotides (ODN) is presumed to require endosome acidification. The response to stimulation of RF+ B cells by IgG2a mAb or CpG-ODN, but not by TLR2 (603028) or TLR4 (603030) agonists, was blocked by inhibitors of endosome acidification, notably chloroquine, suggesting a mechanistic basis for its efficacy in the treatment for both RA and SLE. Leadbetter et al. (2002) proposed that other endogenous subcellular nucleic acid-protein autoantigens may signal through other TLRs to abrogate peripheral B-cell tolerance. They also suggested that infectious agent PAMP (patterns associated with microbial pathogens) engaging TLRs may create a synergy with autoantibody-autoantigen immune complexes, thus explaining the association between infection and autoimmune disease flares.
Nedvetzki et al. (2003) identified a CD44 variant (107269), designated CD44vRA, in synovial fluid aspirated from 23 of 30 patients with rheumatoid arthritis. Functional expression studies in human cells showed that the CD44vRA variant interacted with FGF2 (134920) via the heparan sulfate on exon v3 in a way that enhanced binding and activation of soluble FGFR1 (136350) to a greater extent than CD44v3-v10. Synovial fluid cells from RA patients bound soluble FGFR1 more intensively than control cells. Nedvetzki et al. (2003) postulated that activation of FGFR1 may play a role in the RA inflammatory process.
Seyler et al. (2005) analyzed synovial tissue specimens from 72 patients with RA for TNFSF13 (604472) and TNFSF13B (603969) production and TNFSF13/TNFSF13B receptor expression. In synovitis with ectopic germinal centers present, inhibiting TNFSF13 and TNFSF13B with a TACI (TNFRSF13B; 604907):Fc fusion protein resulted in destruction of the germinal centers and marked inhibition of IFN-gamma (147570) and Ig transcription, whereas similar inhibition in the aggregate and diffuse types of synovitis enhanced IFN-gamma production and did not affect Ig levels. These differential immunomodulatory effects correlated with the presence of TACI-positive T cells in aggregate and diffuse synovitis and their absence in synovitis with germinal centers. Seyler et al. (2005) proposed that TNFSF13 and TNFSF13B regulate B-cell as well as T-cell function and have both pro- and antiinflammatory effects in RA.
Boilard et al. (2010) investigated the role of platelets in rheumatoid arthritis. Boilard et al. (2010) identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluids from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1 (see 147760). Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, Boilard et al. (2010) identified the collagen receptor glycoprotein VI (GP6; 605546) as a key trigger for platelet microparticle generation in arthritis pathophysiology. Boilard et al. (2010) concluded that their findings demonstrated a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.
Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis and multiple sclerosis (126200), and of monocyte-specific eQTLs among Alzheimer disease (104300) and Parkinson disease (168600) variants. Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
Ito et al. (2014) isolated arthritogenic T-cell receptors (TCRs) from mice engineered to generate T cells mediating autoimmune arthritis, which resembles human RA, and characterized the self antigens that they recognized. One of them was the ubiquitously expressed 60S ribosomal protein L23A (RPL23A; 602326), with which T cells and autoantibodies from RA patients reacted.
MappingLinkage to HLA on Chromosome 6p21
Cornelis et al. (1998) performed a genome scan with 114 European Caucasian rheumatoid arthritis sib pairs from 97 nuclear families. Linkage was significant only for HLA and nominal for 19 markers in 14 other regions. Four of the loci implicated in IDDM potentially overlap with these regions: IDDM6 (601941), IDDM9, IDDM13 (601318), and DXS998. The first 2 of these candidate regions, defined in the rheumatoid arthritis genome scan on 18q22-q23 and 3q13, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (p = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA; HLA had previously been estimated to account for one-third of the genetic component. The candidate genes in this area included those coding for CD80 (112203) and CD86 (601020), molecules involved in antigen-specific T-cell recognition.
The expressed T-cell receptor (TCR) consists of an alpha (see 186880) and beta (see 186930), or gamma (see 186970) and delta (see 186810) chain heterodimer. More than 95% of peripheral T lymphocytes expressed TCR alpha/beta chains. Nanki et al. (1996) stated that the TCR variable regions of functional alpha and beta chains are constructed by rearrangement of variable (V), diversity (D) (beta chain only), and joining (J) gene segments with additional noncoding (N) regions. The expressed TCRBV gene repertoires in peripheral blood lymphocytes are controlled genetically and primarily by HLA. The regulation of the human TCRBJ gene repertoire had been difficult to analyze because of the potentially complex number of BJ gene rearrangements. To overcome this problem, Nanki et al. (1996) developed a PCR-ELISA method to study BJ gene expression, and compared peripheral T lymphocytes from 12 pairs of monozygotic twins, including 6 rheumatoid arthritis discordant pairs, and 5 normals. Because monozygotic twins share identical genetic backgrounds, the investigators reasoned that differences in the twins' TCRBJ repertoires might be due to environmental or stochastic factors. If a systemic autoimmune disease, such as RA, was triggered by a single potent environmental stimulus, the peripheral T-lymphocyte TCRBJ repertoire might be skewed. In contrast, an antigenic peptide would not necessarily expand T cells with specific TCRBV gene products, which interact primarily with the MHC backbone. Nanki et al. (1996) was surprised to find that TCRBJ expression is controlled genetically. Even a chronic autoimmune syndrome such as RA has little influence on the overall pattern of TCRBJ expression. The BJ gene repertoires of monozygotic twins were more similar than those of unrelated individuals and the inflammation of RA did not induce specific changes in the genetically determined pattern of BJ expression.
The HLA-DRB1 (142857) locus has been shown to be linked to and associated with RA susceptibility. In addition to the HLA-DRB1 locus, it was considered likely that genes with weaker effects are also involved. Cox et al. (1999) used a combined sib-TDT (transmission/disequilibrium test) and TDT, in addition to parametric and nonparametric linkage methods, to investigate candidate genes of the interleukin-1 (IL1) gene cluster (see IL1A; 147760) on 2q13, since IL1 is an important cytokine in the control of the inflammatory response central to RA pathology. Several tightly linked IL1 cluster markers yielded suggestive evidence for linkage in those families in which affected sibs did not share 2 HLA-DRB1 alleles identical by descent. The evidence was significant in those with severe disease, as assessed by the presence of bone erosions.
Jawaheer et al. (2001) reported a genomewide screen of multiplex families with RA gathered in the U.S. by a consortium of investigators. Using 379 microsatellite markers, they screened for allele sharing in 257 families containing 301 affected sib pairs. The results suggested that genes in the HLA complex play a major role in RA susceptibility, but that several other regions also contribute significantly to overall genetic risk. Some of these regions had previously been implicated in other diseases of an autoimmune nature, including systemic lupus erythematosus (152700), inflammatory bowel disease (266600), multiple sclerosis (126200), and ankylosing spondylitis (106300).
Using 54 markers distributed across the entire HLA complex, Jawaheer et al. (2002) performed an extensive haplotype analysis in a set of 469 multiplex families with RA. The results showed that, in addition to associations with the DRB1 alleles, at least 2 additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral Al-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. The data emphasized the importance of defining haplotypes when trying to understand HLA associations with disease, and clearly demonstrated that such associations with RA are complex and cannot be completely explained by the DRB1 locus.
In a set of Japanese patients with RA and a control group, Ota et al. (2001) identified a second HLA-DRB1-independent RA susceptibility locus at the telomeric end of the HLA class III region, almost 1 Mb away from HLA-DRB1. Zanelli et al. (2001) and Jawaheer et al. (2002) likewise reported findings indicating the existence of a second RA susceptibility locus at the telomeric end of the HLA region. Using microsatellites, Ota et al. (2001) narrowed the second RA susceptibility region to 70 kb telomeric of the TNFA gene (191160).
John et al. (2004) compared the utility of single-nucleotide polymorphisms (SNPs) with that of microsatellites for linkage analysis in a whole-genome screen of 157 families with multiple cases of RA. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P = 0.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, 4 loci were detected at a nominal significance level (P less than 0.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. Thus, they demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allowed loci to be defined more precisely.
Associations Pending Confirmation
In 4 patients with rheumatoid arthritis, Bell et al. (1992) found deficiency of monocyte esterase (114835).
In a metaanalysis of 4 major RA genomewide linkage studies, Fisher et al. (2003) found that, in addition to the HLA locus (p less than 0.00002), the strongest evidence for an RA susceptibility locus was on chromosome 16 (p = 0.004), a locus that had not been identified as statistically significant in any of the 4 individual RA genome searches. In total, 12 regions achieved a significant (p less than 0.05) summed rank, and 4 of these regions (on chromosomes 6p, 6q, 12p, and 16cen) reached a significance value of p less than 0.01.
Amos et al. (2006) performed a genomewide linkage scan using more than 5,700 informative SNPs in 642 Caucasian families containing 1,371 affected sib pairs with rheumatoid arthritis and found nearly significant linkage at chromosome 2q33 (lod score, 3.52). A suggestive locus was identified at chromosome 11p12 (lod score, 3.09). The median age at onset in this patient population was 39 years.
Using numerous SNPs and insertion/deletion polymorphisms of 4 genes located in the 70-kb region on chromosome 6 identified by Ota et al. (2001) as harboring a second RA susceptibility locus, Okamoto et al. (2003) identified the locus as the T allele at position -62 of the T/A SNP in the promoter region of the NFKBIL1 gene (601022.0001) on chromosome 6p21. The T allele (-62T) is a putative binding site for the transcription factor delta-EF1 (TCF8; 189909) (Allcock et al., 2001). In contrast, the nonsusceptible allele (-62A) is likely to disrupt this motif for delta-EF1.
In a genomewide association study involving 2 large groups of case subjects with autoantibodies against cyclic citrullinated peptide (CCP), Plenge et al. (2007) identified a SNP on chromosome 9, rs3761847, that showed association with rheumatoid arthritis for all samples tested (OR = 1.32, 95% confidence interval, 1.23 to 1.42; P = 4 x 10(-14)). This SNP showed the strongest association among several in a 100-kb region containing the TRAF1 (601711) and C5 (120900) genes. No coding SNP was found that could explain the association.
In a genomewide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America, Gregersen et al. (2009) found an association with a SNP rs13031237 in the REL (164910) gene on chromosome 2p13 (p = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed the association for rs13031237 (odds ratio of 1.25; p = 3.08 x 10(-14)). Using the combined dataset, the authors found an allelic odds ratio of 1.21 (p = 2.60 x 10(-11)) for rs13017599. The combined dataset also provided support for associations at both CTLA4 (123890) on chromosome 2q33 (rs231735; OR = 0.85; p = 6.25 x 10(-9)) and BLK (191305) on chromosome 8p23 (rs2736340; p = 5.69 x 10(-9)).
Molecular GeneticsPatients 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.
Okada et al. (2014) performed a genomewide association study metaanalysis in a total of greater than 100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating approximately 10 million SNPs. The authors discovered 42 novel RA risk loci at a genomewide level of significance, bringing the total to 101. Okada et al. (2014) then devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci, and pathway analyses, as well as novel methods based on genetic overlap with human primary immunodeficiency, hematologic cancer somatic mutations, and knockout mouse phenotypes, to identify 98 biologic candidate genes at these 101 risk loci. Okada et al. (2014) demonstrated that these genes are the targets of approved therapies for RA, and further suggested that drugs approved for other indications may be repurposed for the treatment of RA. Okada et al. (2014) concluded that their comprehensive genetic study shed light on fundamental genes, pathways, and cell types that contribute to RA pathogenesis, and provided empirical evidence that the genetics of RA can provide important information for drug discovery.
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 rs7574865 and including rs11889341, rs8179673, and 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 (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 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, 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 (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 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 a United Kingdom 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 rs6920220 and rs13207033, the latter of which was perfectly correlated with rs10499194, a SNP previously associated with RA. A number of additional potential RA markers were found, including rs5029937, located in intron 2 of the TNFAIP3 gene. Of the 18 associated SNPs, rs6920220, rs13207033, and rs5029937 remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of 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 rs2004640 (607218.0002). The strongest association was exhibited by rs3807306 (p = 0.00063), particularly in a subgroup of anti-CCP-negative RA patients (p = 0.000091), and rs3807306 was in linkage disequilibrium (r(2) = 0.67) with 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 (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 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 (rs3890745, p = 0.0035 replication, p = 1.1 x 10(-7) overall), and KIF5A-PIP4K2C (617104) (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 (rs3766379 and 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) (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 (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 (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 (rs10865035 and 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 (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 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 (rs3093023, p = 3.3 x 10(-7), OR = 1.13). Kochi et al. (2010) noted that the landmark SNP in their Japanese population, rs3093024, was in almost absolute linkage disequilibrium with 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.
Animal ModelStudies supporting a role for HLA-DQ polymorphism in human rheumatoid arthritis were supported by Nabozny et al. (1996