Version May 2024
INTRODUCTION — The association of particular human leukocyte antigen (HLA) alleles with rheumatoid arthritis (RA) was first noted in the late 1970s, when the frequency of individuals with the HLA-Dw4 serotype was found to be increased among RA patients compared with healthy controls [1,2]. This particular serotype represented a set of alleles at the HLA-DRB1 gene locus. Subsequently, hundreds of studies have examined and expanded that association in order to better elucidate the genetic underpinnings of RA. Both linkage and association studies of the HLA-DRB1 gene have consistently confirmed that it is the major genetic susceptibility locus for RA. As such, it provides an important clue to RA pathogenesis.
Since approximately 2005, discoveries using high-throughput genotyping in large sample collections have identified over 100 additional genetic loci outside of the HLA locus that play a relatively modest role in RA risk, but implicate critical pathways in its pathogenesis [3]. Further investigation has also begun to fine-map these RA loci, including the DRB1 gene. However, the issue of clinical utility of genotyping in patients with RA remains unresolved.
The role of HLA and other susceptibility genes in RA will be addressed in this topic review. The epidemiology of, risk factors for, causes of, and pathogenesis of RA, as well as an overview of HLA genes and their nomenclature, are discussed separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "Pathogenesis of rheumatoid arthritis" and "Human leukocyte antigens (HLA): A roadmap".)
RHEUMATOID ARTHRITIS SUSCEPTIBILITY GENES
HLA alleles and susceptibility to rheumatoid arthritis — Both linkage and association studies have established that the human leukocyte antigen (HLA) DRB1 gene is the major genetic susceptibility locus for rheumatoid arthritis (RA). Subsequently, further studies in large data sets have also identified independent associations with other HLA genes: HLA-A [4], HLA-B [5], and HLA-DPB1 [5].
Interpretation of early studies of HLA associations in RA has been complicated by evolving changes in nomenclature and methods of HLA typing [6]. Originally, HLA typing was achieved with immunologic reagents. The methods subsequently used for HLA typing in RA have involved amplification by the polymerase chain reaction of the highly polymorphic second exon of the HLA-DRB1 gene, followed by probing with a DNA sequence-specific oligonucleotide probe. Direct nucleotide sequencing is an alternative method of genotyping. A newer technique for HLA typing has since been developed for further analysis of individuals with available dense single-nucleotide polymorphism (SNP) genotyping data over the HLA region [7]. (See "Human leukocyte antigens (HLA): A roadmap" and 'Individual amino acid sites and susceptibility to rheumatoid arthritis' below.)
Individual alleles and the shared epitope — Two alleles of the HLA-DRB1 gene, DRB1*04:01 and DRB1*04:04, primarily account for the originally observed serologic association of DR4 with RA in White American and European patients. In addition, serologic associations with DRB1*01 and DRB1*10 alleles have been noted in many such RA patients who are negative for DRB1*04 alleles. (See 'Associations in different ethnic populations' below.)
Since many of these most strongly associated RA alleles shared a region of highly similar amino acid sequence, it had been postulated that this portion of the DRB1 molecule (amino acids 67 to 74) controls susceptibility to disease [8]. The most strongly associated RA alleles code for HLA proteins that share a region of highly similar amino acid sequence at positions 70 to 74, called the shared epitope (SE; 70QKRAA74, 70QRRAA74, or 70RRRAA74 – one-letter amino acid code). This hypothesis had been further bolstered by the observation that among ethnic populations in which DRB1*04 alleles are rare, the alleles associated with RA still contain the SE. As an example, some Native American populations, such as the Yakima Nation, have a high prevalence of RA. DRB1*04 alleles are rare in this population, and RA is possibly associated with the DRB1*14:02 allele. This allele has an amino acid sequence from positions 67 to 74 that is identical to the SE [9].
The strength of the association of particular HLA susceptibility alleles with RA varies in different studies. To some degree, this variability is due to differences in the criteria for inclusion of patients, in genetic backgrounds of the populations studied, and in the HLA typing methods used. However, a remarkable degree of consensus emerges when these variables are controlled. If, for example, only White American and European patients are included and if the HLA typing is DNA-based, then similar results have been obtained in different reports [10-13]:
●HLA-DRB1*04:01 – Present in 50 to 61 percent of patients with RA with a relative risk of 5 to 11.
●HLA-DRB1*04:04 – Present in 27 to 37 percent with a relative risk of 5 to 14. In one report, an increased risk of RA was noted when there were two copies of the HLA-DRB1*04:04 allele or when it was present along with another gene encoding the SE [13].
●HLA-DRB1*01:01 – Present in 13 to 27 percent with a relative risk of 1 to 2.
●HLA-DRB1*10 – Present in 1.5 percent of RA patients with a relative risk of 2.3 [13].
Protective HLA alleles — While some specific HLA-DRB1 alleles confer a high risk for the development of RA, other alleles provide protection from disease risk. As an example, certain alleles with an aspartic acid (versus glutamine or arginine) at the 70th amino acid position result in an odds ratio (OR) of 0.23 and 0.34 for RA among English and Spanish populations, respectively [14], and in an OR of 0.52 among North American RA populations. In addition to the presence of aspartic acid at position 70, the presence of isoleucine at position 67 is also associated with a protective effect [15]. A large meta-analysis across multiple European populations has shown that HLA-DRB1*13:01 confers protection [16].
Individual amino acid sites and susceptibility to rheumatoid arthritis
Seropositive rheumatoid arthritis — A small number of individual amino acid sites within HLA-DRB1 that explain seropositive (rheumatoid factor [RF] positive or anti-citrullinated peptide antibody [ACPA]-positive) RA susceptibility have been identified. It has become possible to use large SNP genotyping data sets to infer HLA-DRB1 alleles indirectly using advanced statistical methods [7,17]. Using these approaches, a study of 20,000 individuals of European descent has demonstrated that individual amino acid sites within HLA-DRB1 explain seropositive RA risk susceptibility most effectively [5]. In particular, position 11 (and equivalently position 13, which is tightly linked to it) modulates more RA risk than any position in the genome; the presence of a valine at that site (or a histidine at position 13) confers an increased risk, with an allelic OR of approximately 4, whereas the presence of a serine (at position 13 or 11) confers a decreased risk, with an allelic OR of 0.4 (table 1) [5]. Additionally, positions 71 and 74 (located within the SE consensus sequence) mediate disease risk independently of the amino acid present at position 11/13 [5]. This study has also suggested that any individual of White European descent, instead of being classified as SE-positive or SE-negative, can be classified into 16 different risk categories solely based on their four-digit HLA-DRB1 type or the amino acids carried at positions 11/13, 71, and 74 of HLA-DRB1 [5]. The highest-risk categories correspond to SE-positive individuals, while the lower-risk categories are defined by protective HLA alleles (for example, HLA-DRB1*13:01 (table 1)).
Side chains of amino acids at positions 13, 71, and 74 point into the antigen-binding groove and together fall within a specific pocket within the DR molecule known as the P4 pocket. These results suggest that the P4 pocket may play an important role in differential antigen binding, affecting disease risk. Investigators have also studied the implications of variation in amino acid residues for citrullinated peptide antigen binding [18,19]. Citrullination is a process by which positively charged arginine residues are converted to uncharged citrulline. Modeling and structural studies have shown that the shared epitope P4 pocket of HLA-DRB1 binds citrulline more effectively than arginine [18,20]. HLA-DRB1 alleles that result in an electropositive P4 pocket increase the risk of RA, while those resulting in a neutral or negative charge in the P4 pockets are protective, as they are associated with a reduced risk of seropositive RA [21].
After controlling for HLA-DRB1 associations at positions 11/13, 71, and 74, independent associations with seropositive RA are observed at HLA-DPB1, corresponding to amino acid position 9 of that molecule; in HLA-B, corresponding to HLA-B*08 and equivalently to position 9 of that molecule [5]; and at HLA-A position 77 [4]. These amino acid sites also sit at the base of the binding groove of those proteins.
Seronegative rheumatoid arthritis — Seronegative RA is genetically distinct from seropositive RA. As amino acids associated with seronegative RA are also located within the peptide-binding grooves, distinct peptide autoantigens may be involved in the etiology of the two RA serotypes. The strongest genetic associations between HLA amino acids and seronegative RA are also located at HLA-DRB1 position 11 (but in contrast to seropositive RA correspond to HLA-DRB1*03) and HLA-B position 9 (corresponding to HLA-B*08) [4,22]. However, HLA-DRB1 positions 71 and 74 were not found to be associated with seronegative RA. Although the association with HLA-DRB1 position 11 is shared between seropositive and seronegative RA, the effects of individual amino acids are different; the carriage of a serine at HLA-DRB1 position 11 increases the risk of developing seronegative RA, but decreases the risk of developing seropositive RA. The pattern of association is different for different amino acids at the same position: the carriage of a glycine at HLA-DRB1 position 11 is protective for both serotypes. These studies confirm that seropositive and seronegative RA are two genetically distinct entities.
Mechanistic implications of the HLA associations — The identification of class I and II HLA allelic associations implicates both CD8+ and CD4+ T cells in the pathogenesis of RA. Theories that explain how expression of the HLA-DRB1 alleles mediate RA risk focus on the role of the HLA molecule in binding specific peptides and in presenting them to CD4+ T lymphocytes via recognition by the T-cell receptor. The polymorphic residues in the class II HLA molecule determine which peptides are bound. Molecules containing the SE bind a different repertoire of peptides than those not containing it [23,24].
In an attempt to explain how the SE functions in its contribution to RA, different models have been advanced [25]:
●One model suggests that certain pathogenic peptides bind risk alleles more efficiently and are more likely to be presented to T cells only by HLA-DRB1 risk alleles.
●In a second model, this differential peptide binding alters the specific T cells that are positively selected in the thymus, thereby leading to a different T-cell repertoire that could include autoreactive, pathogenic T cells.
●Still another theory suggests direct T-cell recognition of the HLA-DRB1 risk alleles, which is more dominant than recognition of the specific peptide bound by the DR molecule.
Relationship between HLA-DRB1 and ACPA — Anti-citrullinated peptide antibody (ACPA) status shows a stronger association with the presence of erosions than HLA alleles or the SE status; the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline is strongly associated with both prevalent erosions (OR = 2.5) and developing erosions at five years (OR = 10.2) [26]. Therefore, the presence of ACPA at disease onset is the strongest known predictor of later radiographic damage in patients with RA.
Since the identification of ACPA and the development of commercial tests that detect and determine the level of anti-CCP antibodies, there is emerging evidence that anti-CCP-positive and anti-CCP-negative RA may behave very differently and may actually comprise distinct diseases underpinned by distinct genetic contributions. This is particularly striking for the HLA-DRB1 gene in which, for example, the linkage to the HLA region observed in RA families is absent in anti-CCP-negative families [27]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
Subsequent studies have confirmed that there is a significant association between SE alleles and RA in patients who are anti-CCP antibody-positive [27-30]. For example, a significantly greater prevalence of anti-CCP antibodies was found in those who carried two SE alleles than in those with one or no allele (85, 58, and 30 percent, respectively). Hence, the SE seems to predispose to anti-CCP-positive RA, and the development of anti-CCP antibodies is likely to be an intermediate stage in disease pathogenesis and to mediate the effect of the SE with RA susceptibility and/or severity. Subsequent studies in much larger cohorts of anti-CCP-negative RA patients have, however, detected significant associations between the SE, HLA alleles, specific amino acids, and anti-CCP-negative RA [4,31]. The effect of the HLA on anti-CCP-negative RA susceptibility has been localized to HLA-DRB1 position 11/13 and HLA-B position 9, but different residues at position 11/13 confer risk and protection for anti-CCP-negative RA compared with anti-CCP-positive RA [4].
A gene environment interaction between smoking and SE carriage in ACPA-positive RA has been reported in two European populations [32,33] but has not been replicated in three populations from the United States [34]. Smoking has also been reported to be associated with the production of ACPA in SE-negative individuals, so the relationship appears complex [35].
It has been speculated that smoking leads to increased citrullination of proteins. Carriage of SE alleles in this environmental background increases susceptibility to RA because they bind citrullinated peptides more strongly and induce an exaggerated T-cell response. The exaggerated T-cell response, in turn, may drive the increased autoantibody production by B cells, including anti-CCP antibodies, seen in RA [36,37].
Non-classical HLA genes and non-HLA genes within the HLA region — The HLA region on chromosome 6 contains over 200 genes of immunologic relevance, including the HLA genes. Several early studies have suggested that loci other than HLA genes may also contribute to susceptibility to RA, but these studies were challenging to interpret due to the strong effects of the HLA alleles and to the high degree of linkage disequilibrium across the HLA region. For example, early reports of an association of RA with other classical HLA genes, such as alleles of HLA-DQA1, and with other non-HLA genes, such as tumor necrosis factor (TNF), were likely to be secondary to linkage to HLA-DRB1, -DPB1, -B, or -A risk alleles in White populations. The genes for TNF lie within the HLA region and have been a focus of intense interest, given the demonstration that TNF-alpha plays a central role in the inflammatory cascade in affected joints of patients with RA and the efficacy of TNF-alpha antagonists as therapeutic agents for patients with RA. Results of such investigations, however, have been conflicting; some studies report an association of particular TNF markers with RA [38-42], while others find no differences [43-47]. The association with TNF is most likely a function of alleles in linkage with HLA-B*08 [5].
A large-scale multi-ethnic fine-mapping study of the HLA region conducted in over 60,000 cases and controls from Japanese, Eastern Asian, and European populations identified an independent association with the non-classical HLA gene, HLA-DOA, with seropositive RA [48]. The associated allele appeared to be correlated with the expression of HLA-DOA, putatively demonstrating a new pathogenic mechanism for susceptibility alleles within the HLA region.
Associations in different ethnic populations — Data have accumulated on HLA associations with RA in a diverse range of ethnic groups, many of which display a very different genetic background from populations of White European ancestry [49,50]. Nevertheless, the majority of these studies confirm a significant increase in the frequency of alleles containing the SE in RA patients:
●DRB1*14:02 confers susceptibility to RA in the Yakima, Tlingit, and Pima Native American populations [9,19,51,52]. The DR4 specificity is also present and associated with RA in the Chippewa Indians [53].
●Among Japanese, the most prevalent DRB1*04 allele is DRB1*04:05, which contains the SE and which is increased in Japanese patients with RA [54].
●Both DRB1*04:05 and *04:04 are increased in Chinese RA patients [55].
However, a subsequent study in Han Chinese subjects, in which a deep sequencing of the HLA region was performed in ACPA-positive RA patients and healthy controls, identified HLA-DQA1 as the major genetic risk factor for seropositive RA in this population, instead of HLA-DRB1*04:05 [56].
In some population groups, such as the Spanish, the Basque, and Israeli Jews, DRB1*04 alleles are rare. In these settings, RA is associated with DRB1*01 or DRB1*10, two other alleles carrying the SE [57-60].
In other populations, such as African Americans, the majority of patients with RA do not carry the SE in their DRB1 genes [61]. Even in this study, however, DR4-positive (DR4+) susceptibility alleles were significantly increased among RF-positive patients. A similar observation was made in a study of Greek patients with RA; although 57 percent lacked the SE, its presence was still significantly increased compared with local controls (43 versus 15 percent) [62].
Indeed, further studies examining amino acid sites observed, similar to populations of European descent, that position 13 mediated much of the risk of RA in Asian populations, including patients from Japan, Korea, and China; and the same residues at that site that conferred risk in European populations also did so in Asian populations [63]. Similarly, residues that protected from risk in European populations at position 13 also protected from risk in Asian populations.
In African American populations, it was also observed that position 11 mediated risk of RA, with a similar risk profile as in Europeans [64]. A multinational Arab genome-wide association study also identified HLA-DRB1 amino acid position 11 as the strongest genetic risk factor for RA in this population [65].
Although the majority of studies seem to show that RA susceptibility genetic variations within the HLA are shared across populations, it should be noted that the HLA allele frequency remains highly population dependent: valine at HLA-DRB1 position 11 might be more frequent in RA cases compared with controls within each population, nonetheless, the prevalence of valine at position 11 is highly variable across populations. Moreover, studies of genetic variations outside the HLA region have shown that some non-HLA susceptibility polymorphisms are shared across populations, while others appear to be population-specific [3,65,66].
Rheumatoid arthritis susceptibility genes outside the HLA region — Although a role in conferring susceptibility to RA is well-accepted for HLA genes within the HLA region on chromosome 6, most investigators estimate that HLA contributes to less than 50 percent of the overall genetic risk. The availability of increasingly powerful molecular genetic techniques has ignited the search for other relevant genes in RA. This has generally taken two approaches: investigating candidate genes whose function suggests a possible role in disease pathogenesis, and screening the entire human genome using genome-wide association studies.
A number of genes outside of the HLA region also exhibit an association with RA, and some are associated with other autoimmune conditions as well. Over 150 confirmed associations with RA susceptibility have been reported [67]. Since 2007, there has been an explosion in the number of RA susceptibility genes identified and confirmed in well-powered cohorts [3,68,69]. For most of the reported associations, the actual causal variant has not been identified, and the gene thought to be responsible for the association may change as fine-mapping studies are undertaken. Most associated variants are intergenic or intronic variants that do not confer a change in the amino acid sequence of gene protein products. These studies are underway, so a better understanding of which genes are involved, whether the same variants are associated with multiple autoimmune diseases, and whether multiple variants at a locus contribute to susceptibility should become clearer as research progresses.
The R620W PTPN22 polymorphism has been consistently associated with RA in populations of northern European descent, but the variant does not exist in Japanese or Korean populations. The association with ACPA-positive RA is much stronger than with ACPA-negative RA [31]. STAT4, on the other hand, has been associated with RA in populations of both European and Asian ancestry and seems to be equally associated with ACPA-positive and -negative RA [31].
The identification of susceptibility loci for RA is a rapidly moving field, and there is an ever-expanding list of confirmed hits; six examples of this expanding list of genes include:
●PTPN22 gene – The protein tyrosine phosphatase N22 (PTPN22) gene helps regulate both T and B cells. The frequency of an SNP in the gene was increased in patients versus healthy controls in studies of multiple White North American and European populations but not in Koreans [50]. The SNP encodes an amino acid substitution at position 620 (R620W), which affects binding to an intracellular signaling molecule called Csk [70].
The polymorphism is associated with multiple autoimmune diseases, including type 1 diabetes, juvenile idiopathic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus (SLE), and Addison's disease.
In mice, the corresponding gene is a negative regulator of T cells [70]. The W620 variant of PTPN22*R620W binds Csk less efficiently than the R620 allele, which may predispose to autoimmunity by resulting in a failure to switch off T cells. In other experiments, however, the polymorphism has been shown to be a "gain-of-function" variant (ie, it increases the downregulation of T cells). This is postulated to predispose to autoimmunity by failure to delete autoreactive T cells during thymic development [71]. A study has also demonstrated that levels of the 620W PTPN22 variant are decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type 620R. Based upon mouse experiments, this difference was attributed to calpain-mediated degradation. Reduced levels of the protein correlated with an increased number of T cells and increased T-cell activation, and with dendritic-cell hyperresponsiveness [72].
●STAT4 gene – STAT4 encodes a transcription factor that transmits signals induced by several key cytokines, including interleukin (IL)-12 and type 1 interferons, as well as IL-23 [73]. STAT4-dependent signaling by IL-12 receptors plays a critical role in the development of Th1-type responses. A variant allele of STAT4 confers an increased risk of both RA and SLE [74]. Homozygosity of the risk allele is associated with a more-than-doubled risk of SLE and with a 60 percent increased risk of RA.
●TRAF1-C5 gene locus – The TRAF1 gene encodes TNF receptor-associated factor 1, and the C5 gene encodes complement component 5. A genome-wide analysis of North American and Swedish patients revealed that a common genetic variant at the TRAF1-C5 locus on chromosome nine, identified by the rs3761847 SNP, appeared to increase the risk of anti-CCP antibody-positive RA [75]. This association, however, was not seen in a cohort of Korean patients with RA [76]. By contrast, the rs7021206 SNP of the TRAF1 gene was associated with RA in populations of White European descent, as well as Korean populations [77].
●Chromosome 6q23 – An intergenic region between the OLIG3 and TNFAIP3 genes on chromosome 6q23 has been associated with RA susceptibility in both United States and United Kingdom populations [78,79]. The association in the region is complex with at least three variants independently contributing to overall susceptibility [80]. It is thought that the variants may be affecting the function and/or regulation of the TNFAIP3 gene as knock-out mice develop severe inflammation, which includes inflammation of joints [81]. However, although the intergenic region is certainly associated with RA susceptibility, the involvement of the TNFAIP3 gene in humans has not been confirmed. Using techniques to detect chromatin interactions, it has been shown that the DNA containing polymorphisms associated with RA interacts through chromatin looping with IL20RA, located 680 kb upstream. One of the risk alleles is correlated with an increased expression of IL20RA and is most likely located within an active enhancer in T cells [82].
●PADI-4 gene – Genes for enzymes that are responsible for post-translational modification of arginine to citrulline, an antigenic side chain against which autoantibodies are found in many patients with RA, contribute to the risk of developing disease. Of the four isotypes of PADI, types 2 and 4 are considered to be the most likely to be present in human synovium in which citrullination of matrix proteins could potentially create antigenic peptides [83-85]. Furthermore, levels of PAD-2 and PAD-4 were correlated with the level of inflammation in RA synovium [85].
In two case-control studies, significant association was noted between genetic variants coding for one of four such enzymes (peptidylarginine deiminase 4 or PADI4) and the presence of RA in a Japanese population [86,87]; an association has also been identified in patients from Europe, but with different genetic variants [88]. A large trans-ethnic association study confirmed two independent associations with SNPs at the PADI4-PADI2 locus and RA [68].
●CTLA-4 gene – A meta-analysis and separate well-powered validation studies have confirmed association of RA with variants within the CTLA-4 gene [89,90]. Previous work has shown that the associated variant maps within the 3' region of the CTLA-4 gene and is correlated with the ratio of soluble to full-length CTLA4 mRNA levels [91]. Interestingly, abatacept, a biologic drug in use for the treatment of RA, mimics the physiological role of CTLA-4. (See "Overview of biologic agents in the rheumatic diseases", section on 'Abatacept'.)
RHEUMATOID ARTHRITIS SEVERITY GENES
HLA alleles and severity of rheumatoid arthritis — Most studies support an association of the shared epitope (SE) with rheumatoid arthritis (RA) disease severity, based upon an association with erosive disease [92-95], but not all studies do so [96-98]. Studies have found a correlation between DRB1*04 RA-associated alleles and more severe, erosive disease, as measured by the severity of radiographic changes [93-95,99,100]; some have also noted an increase in DRB1*01 among patients with milder disease [100]. A large prospective study that was performed in over 2000 patients of White British origin concluded that the hierarchy of HLA-DRB1 alleles with regards to RA susceptibility is exactly the same for disease severity, measured as the extent of radiographic damage or by mortality [101]. Therefore, the 16 different risk categories defined by amino acids at positions 11/13, 71, and 74 of HLA-DRB1 (see 'Individual amino acid sites and susceptibility to rheumatoid arthritis' above) also represent 16 different severity categories. However, the clinical utility of this genetic stratification system remains to be evaluated. Moreover, it seems that the association of HLA with severe disease acts mainly through the presence of anti-citrullinated peptide antibody (ACPA), and it is clear that ACPA status is a better predictor of erosions than are human leukocyte antigen (HLA) alleles or the SE status. (See 'Relationship between HLA-DRB1 and ACPA' above.)
This association between HLA-DRB1*04 alleles and erosive disease has been confirmed among non-White patients as well, including Koreans [102] and Japanese [103].
The specific combination of SE-positive alleles also may be important. One report evaluated a large group of patients with severe RA, including many with Felty syndrome [104]. A hierarchy of risk was found, depending upon the particular combination of HLA-DRB1 alleles: the relative risk was 5 with the heterozygous HLA-DRB1*04/X combination (where X is any allele other than HLA-DRB1*04 or HLA-DRB1*01); 16 with HLA-DRB1*04/HLA-DRB1*01; 25 with DRB1*04/HLA-DRB1*04 combinations; and 49 with HLA-DRB1*04:01/04:04 (Dw4/Dw14).
The presence of an SE in an HLA-DRB1 allele may predispose to other extraarticular disease manifestations as well. This was illustrated in a group of rheumatoid factor (RF)-positive patients with erosive disease, almost one-half of whom had two SE-positive alleles [105]. Individuals whose SEs were contained in DR4+ alleles (HLA-DRB1*04:01, *04:04, and/or *04:08) had the highest risk of extraarticular disease, including rheumatoid vasculitis, rheumatoid lung disease, and Felty syndrome. Patients heterozygous for two SE-containing alleles, one DR4+ and one DR4-, had disease of intermediate severity.
HLA genes and prognosis — The presence of ACPA at disease onset is the strongest predictor of later radiographic damage in patients with RA [26]. Most studies also support an association of the SE with erosive disease [92]. The role of genetic predictors of disease outcome remains a focus of active research for the following reasons: (1) the relative effect of ACPA titers and HLA alleles on several measures of disease outcome is still unknown; (2) genetic markers are likely to have added value to ACPA on the prediction of severity; and (3) there is substantial interest in the prediction of disease onset (inextricably linked to future severity) before ACPA seroconversion (for example, in cohorts of first-degree relatives of patients with RA).
The presence of the SE alleles is not only associated with more severe joint injury, but also with increased risk of cardiovascular disease and mortality. In 2004, a meta-analysis of the impact of SE-positive alleles on erosive disease summarized the results of 10 studies (1027 patients) and found that carriage of one or two such alleles was associated with an odds ratio (OR) of having joint erosion of approximately 2 [106]. The retrospective association of specific HLA alleles with severe RA raised the question of whether typing may be useful to predict which patients will progress to destructive disease, as HLA markers, unlike levels of serologic markers like RF or acute phase reactants, are stable over time and are not subject to fluctuation with disease course or treatment.
Cardiovascular disease is a common comorbidity in RA and is associated with reduced life expectancy in patients with RA. Several studies have shown that carrying two copies of SE alleles is associated with premature mortality and with cardiovascular mortality, and this effect appears independent of ACPA status [107-111]. Indeed, one study reported that patients with inflammatory polyarthritis who were smokers, had ACPA, and carried two copies of SE alleles had a 7.8-fold increased risk of premature mortality from cardiovascular disease compared with patients without these risk factors [107].
Indeed, further studies reexamined RA clinical outcomes and mortality in light of position 11 residues and found that residues that drive risk at that site are connected to worse clinical outcomes, including increased mortality [101,112].
Rheumatoid arthritis severity genes outside the HLA region — Some genetic loci outside the HLA region have been associated with disease severity (reviewed in [113]). A number of non-HLA genetic loci have been investigated to assess whether they can predict severity. Since the power of severity studies is much lower than the power of susceptibility studies, the results of many severity studies are still conflicting, but the emerging picture suggests that some genetic variants associated with susceptibility are also associated with severity, while others are associated either only with susceptibility or only with severity. The number of confirmed genetic predictors located outside the HLA region is small. As examples:
●Genetic variants located near the TRAF1 gene, known to be associated with susceptibility to RA, have been shown to be associated with radiographic damage in multiple independent studies in populations of different ethnicities [114-117].
●An SNP located near the FOXO3 gene has been shown to be associated with prognosis in several tumor necrosis factor (TNF) alpha-driven diseases (Crohn disease, RA, malaria). This SNP leads to altered production of pro- and antiinflammatory cytokines by monocytes through a transforming growth factor (TGF) beta-1-dependent pathway. In RA, minor allele carriage of the SNP reduces TNF-alpha, interleukin (IL)-6, IL-1-beta, and IL-8 production, and increases IL-10 production. The SNP is associated with a milder course of disease (ie, less joint damage over time) [118]. Although associated with RA severity in patients with RA, FOXO3 genetic variants are not associated with an increase in susceptibility to RA in healthy individuals.
GENES DETERMINING RESPONSE TO TREATMENT IN RHEUMATOID ARTHRITIS — Studies to determine genetic predictors of treatment response [113,119-121], including genome-wide association studies for responsiveness to methotrexate [122] or to tumor necrosis factor (TNF) inhibitor therapy [123], have not yet produced clinically actionable or reproducible results. Although some data suggest that knowledge of a patient's human leukocyte antigen (HLA) status may be useful in predicting the response to specific therapies, results have been conflicting. As an example, a large study performed in 1846 patients enrolled at initiation of TNF inhibitor suggested that the 16 susceptibility/severity categories defined by HLA-DRB1 amino acids at position 11/13, 71, and 74 also represented TNF inhibitor-response categories, with carriers of high-risk/high-severity haplotypes likely to respond better to treatment [101], but these results have not been confirmed [124]. Another study performed with nonbiologic disease-modifying antirheumatic drugs (DMARDs) observed a marked difference in treatment response in patients when stratified by shared epitope (SE) status [125]. Response rates were higher in those without the SE compared with those with a single copy or two copies (also termed a single or double dose; 83, 36, and 25 percent, respectively).
These results might suggest that patients with one or especially two copies of the SE (one copy on the maternal and one copy on the paternal chromosome) may benefit from earlier, more aggressive treatment to control disease. A patient's genetic profile is likely to influence clinical decision-making in the future (precision medicine). However, limited numbers of patients have been studied, and further evidence is required [126,127]. Thus, additional prospective and longer-term studies are needed to better assess the role of testing for the SE or HLA-DRB1 amino acids or haplotypes in choosing treatment for patients with RA. Such testing is only appropriately performed as a research tool.
CLINICAL USE OF GENETIC MARKERS
For diagnosis or screening of rheumatoid arthritis — Genetic markers are not useful for diagnosis or screening of rheumatoid arthritis (RA). Although certain human leukocyte antigen (HLA) alleles are strongly associated with severe RA, these alleles are common in the normal population. The absolute risk of developing RA among White individuals carrying HLA-DRB1 alleles *0401, *0404, or *0101 is approximately 1 in 46 [128]. The highest calculated absolute risk is present in individuals expressing both HLA-DRB1*0401 and *0404, but this is still only approximately one in seven. Even knowing the genotype at the second confirmed RA susceptibility locus, the PTPN22 gene, the predictive value remains too low to be useful for either diagnosis or population screening.
Presence of anticyclic citrullinated peptide (anti-CCP) antibodies does predict the future development of RA, particularly severe RA, and one report suggested that the presence of two copies of the shared epitope (SE) with one or two copies of PTPN22 risk alleles increased the risk of developing anti-CCP-positive RA by 25-fold [129]. Separate investigations have shown an interactive relationship between smoking, HLA alleles, and anti-CCP antibody development [32].
The combination of a large number of disease-associated genetic susceptibility polymorphisms (within and outside the HLA) into genetic risk scores (GRS) might have the potential, in the future, to help clinicians with the differential diagnosis of inflammatory polyarthritis. One publication reports the development of a genetic probability tool, which helps clinicians to distinguish between RA, systemic lupus erythematosus (SLE), spondyloarthritis, psoriatic arthritis, and gout [130]. For all patients included in the study, at least one disease could be ruled out, while in 45 percent of patients, a diagnosis was suggested with a 64 percent positive predictive value [130]. However, the performance of genetic diagnostic tools remains to be assessed prospectively in a clinical setting; controlled trials comparing standard practice with the use of genetic probability tools are required before clinical utility can be claimed.
For estimating prognosis — Routine typing for HLA markers and SE status cannot be recommended, given the predictive value of other markers, including anti-CCP antibodies and rheumatoid factor (RF), and given the limited availability and potential cost of the technology required to type for SE alleles.
Once the diagnosis of RA is established, genotyping for SE alleles may help predict which patients are at highest risk of severe and erosive disease, and thus which are candidates for early and aggressive intervention. This information may be less important clinically if patients with early RA are aggressively treated with potent disease-modifying antirheumatic drug (DMARD) regimens, consistent with recommended approaches to disease management.
RF testing and anti-CCP antibody testing are the most useful tests that are widely available in predicting which patients with early inflammatory arthritis will develop erosions [26]. The presence of erosions is a predictor of poor prognosis, regardless of HLA type. The presence of HLA SE alleles is strongly correlated with the presence of anti-CCP antibodies. Whether knowledge of SE status provides additional predictive value for the development of erosive disease beyond knowledge of anti-CCP status alone remains uncertain [26,131].
It is also unclear whether genetic markers can be identified that could predict a subgroup which would not require such aggressive intervention and could be spared the risk of potential adverse events.
Role of ethnicity — Most of the information and hypotheses regarding clinical utility of genetic testing are based primarily upon data derived from White North American and northern European patients and patients of Asian ancestries. HLA typing of patients from other ethnic groups will have different implications. As an example, the lack of a disease-associated HLA-DRB1*04 allele in an African American patient does not necessarily imply that they are not at high risk of developing erosive disease [132]. On the other hand, as described above, most populations show a strong association with one or more SE-positive DR alleles; testing methods should be easily adaptable to inclusion of those alleles for appropriate ethnic groups in any RA-oriented "panel" of susceptibility alleles. However, prediction models will depend on the prevalence of the tested susceptibility alleles in the population of interest, and will therefore be population-dependent.
SUMMARY AND RECOMMENDATIONS
●Rheumatoid arthritis susceptibility – Two alleles, human leukocyte antigen (HLA)-DRB1*0401 and HLA-DRB1*0404, primarily account for the originally observed serologic association of HLA-DRB1*04 alleles with rheumatoid arthritis (RA) in White individuals.
Some HLA-DRB1 alleles protect against the development of RA rather than enhance the risk. HLA-DRB1 risk is best explained by a single amino acid position at the base of the binding groove, position 13 (or equivalently position 11).
Patients from other ethnicities display a different genetic background from White individuals, but most studies confirm the role of HLA-DRB1 position 11/13 across different ethnic groups. (See 'HLA alleles and susceptibility to rheumatoid arthritis' above.)
●Rheumatoid arthritis severity – HLA-DRB1 susceptibility alleles are also severity alleles: the hierarchy of HLA-DRB1 alleles or amino acids with regards to RA susceptibility, ranging from risk to protective, is the same for disease severity. Certain risk alleles may also predispose to extraarticular disease manifestations. A small number of non-HLA genetic loci also appear associated with more severe disease. (See 'HLA alleles and severity of rheumatoid arthritis' above and 'Rheumatoid arthritis severity genes outside the HLA region' above.)
●Shared epitope hypothesis – Theories to explain how expression of the shared epitope (SE) contributes to RA focus on the role of the HLA molecule in binding specific peptides and in presenting them to CD4+ T lymphocytes via recognition by the T-cell receptor. Molecules containing the SE bind a different array of peptides than those not containing it. Several different models have been proposed to explain how the SE functions to contribute to RA. (See 'Mechanistic implications of the HLA associations' above.)
●Seropositive versus seronegative rheumatoid arthritis – There is emerging evidence that anti-citrullinated peptide antibody (ACPA)-positive and ACPA-negative RA may represent distinct diseases underpinned by distinct genetic contributions within and outside the HLA region. The SE predisposes mainly (but not only) to ACPA-positive RA, and the development of ACPA may be an intermediate step mediating the effect of the SE with RA susceptibility and/or severity. The effect of the HLA on ACPA-negative RA susceptibility is smaller and has been localized to some HLA positions also involved in ACPA-positive RA, but different amino acids confer risk and protection for ACPA-negative versus ACPA-positive RA. (See 'Relationship between HLA-DRB1 and ACPA' above.)
●Non-HLA rheumatoid arthritis susceptibility genes – HLA may contribute less than 50 percent of the overall genetic risk for RA. Loci within the HLA region other than HLA-DRB1 also contribute to susceptibility, and a number of genes outside of the HLA region also exhibit an association with RA, some of which are also associated with other autoimmune conditions. Most associated variants outside the HLA region are intergenic or intronic variants that do not confer a change in the amino acid sequence of gene protein products. (See 'Rheumatoid arthritis susceptibility genes outside the HLA region' above.)
●Clinical use of genetic markers – Knowledge of a patient's HLA status and other genetic markers may be useful with further developments in diagnosis and screening, in estimating prognosis, and in predicting the response to specific therapies, but a role for HLA testing in RA outside the research setting has not been established. However, most of the information and hypotheses regarding clinical utility of genetic testing are based primarily upon data derived from White North American and northern European patients, and HLA typing of patients from other ethnic groups will have different implications. (See 'Clinical use of genetic markers' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Anne Barton, FRCP, PhD and Soumya Raychaudhuri, MD, PhD, who contributed to an earlier version of this topic review.
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