Genetic Susceptibility to Rheumatoid Arthritis:An Emerging PictureANNE BARTON AND JANE WORTHINGTON

IntroductionDuring the past 2 years, there has been an explosion in thenumber of confirmed susceptibility loci identified forrheumatoid arthritis (RA) and other complex diseases. Thelargest genetic contribution to RA susceptibility remainsthe HLA–DRB1 gene and the group of alleles collectivelyreferred to as the shared epitope (1). It is unclear whetherthe locus predisposes to RA per se or to the developmentof anti–citrullinated peptide antibodies, which in turnpredispose to RA. Whether additional susceptibility locireside within the HLA gene region remains a question ofimmense interest and is the focus of ongoing researchefforts by a number of groups, but the extended linkagedisequilibrium in the region makes addressing this issuevery difficult (2–4).

The second most important genetic contribution in Cau-casian populations comes from the protein tyrosine phos-phatase N22 (PTPN22) gene, in which a single-nucleotidepolymorphism (SNP) encoding an arginine-to-tryptophansubstitution at amino acid position 620 increases the riskof RA by 40–80% (for review, see ref. 5). However, thepolymorphism is not present in Asian populations, inwhom the PADI4 gene appears to be the second mostimportant susceptibility locus after HLA–DRB1 (6–10).There have previously been conflicting reports of associa-tion at this locus in Caucasian populations, but the largestmeta-analysis performed to date has shown no evidencefor association with the marker PADI_94 that has beenconsistently associated in Asian series (11). Thus, in RA,in contrast to other complex diseases, there is clear evi-dence of ethnic differences in genetic susceptibility fac-tors.

Several genome-wide association, candidate gene, andsubsequent validation studies have been successful inidentifying several other loci that have been confirmed in

more than 1 cohort (Table 1). These findings highlight anumber of points worthy of discussion.

Immune PathwaysThe majority of the SNP markers associated with RA sus-ceptibility do not map within genes but lie close to strongcandidates. Although fine mapping and functional studieswill be required to confirm whether these candidate genesare involved in causation, it is nonetheless interesting tonote that many of the genes are important in immuneregulation. Indeed, many lie on the same pathway (12). Forexample, HLA–DRB1, PTPN22, STAT4, CD40, CTLA4, IL2,IL21, and PRKCQ are all involved in T cell activation andsignaling pathways, while C5, CD40, CTLA4, IL2, IL21,PRKCQ, PTPN22, STAT4, TNFAIP3, and TRAF1 are in-volved in apoptosis (13–21).

Overlap With Other Autoimmune DiseasesThe idea that there are genes that predispose to multipleautoimmune diseases has been around for many years.Indeed, both the HLA region and the PTPN22 gene wereknown to be associated with multiple autoimmune dis-eases (5). What is surprising is how much overlap has nowbeen identified for multiple loci across a number of auto-immune diseases (Figure 1). For example, all of the con-firmed RA loci identified to date have also been associatedwith juvenile idiopathic arthritis (JIA) (Hinks A, et al:unpublished observation). Considerable overlap exists be-tween loci identified for type 1 diabetes mellitus, celiacdisease, Graves’ disease, and RA, suggesting that multiplerisk factors influence the breakdown of self-tolerance andthe onset of autoimmunity (22–25). It is likely that RA-specific loci exist, but of those tested so far, none has beenassociated exclusively with RA, with the possible excep-tion of the shared epitope. The TRAF1/C5 locus appears tobe associated with both JIA (26,27) and RA (12,28–31) butnot, to date, with other autoimmune diseases (23). We canspeculate that as-yet unidentified genetic polymorphismsdetermine the target(s) of the autoimmune process andthus the nature of the disease that develops. Alternatively,it may be the environmental triggers, such as infection,that are the important determinants of the disease thatdevelops. For many autoimmune diseases, the primary

Supported by the Arthritis Research Campaign (grant17552).

Anne Barton, FRCP, PhD, Jane Worthington, PhD: Univer-sity of Manchester, Manchester, UK.

Address correspondence to Anne Barton, MD, Epidemiol-ogy Unit, Stopford Building, University of Manchester,Manchester, UK. E-mail: anne.barton@manchester.ac.uk.

Submitted for publication January 9, 2009; accepted inrevised form April 24, 2009.

Arthritis & Rheumatism (Arthritis Care & Research)Vol. 61, No. 10, October 15, 2009, pp 1441–1446DOI 10.1002/art.24672© 2009, American College of Rheumatology

REVIEW ARTICLE: EPIDEMIOLOGY OF THE RHEUMATIC DISEASES

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susceptibility locus resides within the HLA gene complex,but specific associated alleles appear unique to particulardiseases. A third possibility, therefore, is that it is the wayin which antigens from infectious agents are presented byHLA molecules to an immune system prone to autoimmu-nity, because of the presence of other susceptibility alleles,that determines the type of autoimmune disease that en-sues, possibly via the production of disease-specific auto-antibodies.

Ethnic Differences

The majority of studies undertaken so far have been per-formed in populations of European ancestry and showremarkable consistency in findings across those popula-tions. Investigations in other ethnic groups are starting toemerge, and clear differences in genetic susceptibility lociare being found. As described previously, the PADI4 gene,which is associated in multiple Asian populations, does

Table 1. Non-HLA loci with confirmed evidence for association with RA in independentcohorts*

Locus rs numbers Author (ref.)

PTPN22 rs2476601 Begovich et al (42)Hinks et al (43)Orozco et al (44)Zhernakova et al (45)Van Oene et al (46)Seldin et al (47)Plenge et al (48)Harrison et al (49)Pierer et al (50)Wesoly et al (51)Michou et al (52)Kokkonen et al (53)Majorczyk et al (54)Naseem et al (55)Karlson et al (56)Mastana et al (57)†Farago et al (58)

6q23 (intergenic)‡ rs6920220 WTCCC (1)Thomson et al (39)Plenge et al (40)

rs10499194 Plenge et al (40)TNFAIP3 Intron 2 Orozco et al (41)STAT4 rs7574865 Remmers et al (36)

Lee et al (37)§Barton et al (12)Kobayashi et al (59)¶Orozco et al (60)Zervou et al (31)Martinez et al (61)Palomino-Morales et al (62)#

TRAF1/C5** rs3761847 Plenge et al (28)rs7021049 Chang et al (30)rs10760130 Barton et al (12)rs10818488 Kurreeman et al (29)

Zervou et al (31)IL2RB rs743777 WTCCC (1)

Barton et al (63)10p15 (PRKCQ) rs4750316 Barton et al (63)

Raychaudhuri et al (11)12q13 (KIF5A) rs1678542 Barton et al (63)

Raychaudhuri et al (11)AFF3 rs10865035 WTCCC (1)

Barton et al (64)CD40 rs4810485 Raychaudhuri et al (11)

Orozco et al (33)CTLA4 rs3087243 Raychaudhuri et al (11)

Barton et al (64)4q27 (IL2-IL21) rs6822844 Zhernakova et al (65)

Raychaudhuri et al (11)Barton et al (64)

(continued)

1442 Barton and Worthington

not appear to be associated with RA susceptibility in Cau-casians (11). Similarly, we found no evidence for associa-tion of an SNP in the CD244 gene, which was reported tobe associated with RA in Japanese populations in a ge-nome-wide association study in that population (32,33). Incontrast, the functional polymorphism in the PTPN22gene associated with RA susceptibility in Caucasians isextremely rare in Asian populations, and other polymor-phisms within the gene show no evidence for association(34,35). However, the STAT4 gene is an example of agenetic variant that does confer susceptibility to RA acrossall populations tested to date (36,37).

Modest Effects Can Highlight Important PathwaysThe combined proportion of the variance in RA suscepti-bility conferred by the shared epitope alone far outweighsthat conferred by all the other susceptibility loci put to-gether. It may be questioned, therefore, why it is necessaryto continue to search for further RA susceptibility loci.One important reason is that although the novel loci conferonly modest increases in susceptibility to disease, theymay highlight pathways not previously thought to be im-portant in etiology or that may be amenable to therapeuticintervention. For example, the CTLA4 gene has now beenconvincingly associated with RA susceptibility, but theincreased risk conferred by carrying the associated variantis modest (�15%) (11). Nonetheless, abatacept, a CTLA-4analog, has been shown to be effective in the treatment ofRA patients who have failed to respond to anti–tumornecrosis factor therapy, highlighting the importance of thepathway (38).

Multiple EffectsOne of the reasons that the non-HLA SNP markers asso-ciated with RA may account for only a small contributionto the total variance in susceptibility is that the initialestimates of the effect size arising from genome-wideassociation studies may underestimate the effect size ofthe locus. There may be other associated variants at thesame locus that, together, make a larger contribution thanthe individual effects. For example, 3 independent effectshave been identified at the chromosome 6q23 suscepti-bility locus, individually conferring effect sizes of 10–20%(39,40). Carriage of the high-risk combinations of all 3variants can increase susceptibility by 50% (41). Finemapping and resequencing of the other RA susceptibilityloci may identify additional variants in those regions thatalso confer susceptibility. This should become clearer overthe next 12 months, because several of these loci are cur-rently being intensively investigated by the WellcomeTrust Case–Control Consortium extension study.

Figure 1. Overlap of rheumatoid arthritis (RA) susceptibility lociwith Type 1 diabetes mellitus (T1D) and systemic lupus erythem-atosus (SLE). * � different HLA alleles associate with the differentautoimmune diseases.

Table 1. (Cont’d)

Locus rs numbers Author (ref.)

MMEL1 rs10910099 WTCCC (1)Barton et al (63)Raychaudhuri et al (11)

PADI4 rs2240340 Suzuki et al (6)¶Ikari et al (7)¶Kang et al (8)§Takata et al (9)¶Fan et al (10)††

* All cohorts were of European descent unless otherwise indicated. RA � rheumatoid arthritis; WTCCC �Wellcome Trust Case-Control Consortium study.† South Asian population.‡ Three independent effects exist at this locus.§ Korean population.¶ Japanese population.# Colombian population.** The different single-nucleotide polymorphisms listed reflect those tested that showed evidence forassociation but for which there were no data regarding whether these represent independent effects.†† Chinese population.

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Much of Genetic Variation Yet to Be ExplainedAt the current time, however, approximately half of thegenetic susceptibility to RA remains to be explained. Somemay be accounted for by multiple effects at the loci alreadyidentified as outlined above. It is possible that there areadditional susceptibility loci in regions of the genome thatare not well covered by the whole-genome chip arrays.Alternatively, rare variants or copy number variation maycontribute to susceptibility, but to date, these have notbeen extensively examined in complex diseases. However,the technology and analytical tools to address these pos-sibilities are being developed and promise to yield resultswithin the next 12 months or so. Alternatively, it may bethat current methods to estimate both the size of the ge-netic contribution to disease and the amount accounted forby the loci identified at this time are too simplistic, forexample, by not including the contribution of environ-mental risk factors.

SummaryAt least 13 loci have now been confidently confirmed asbeing associated with RA susceptibility, and further in-sights into the genetic contribution to disease are likely tobe revealed in the next 12 months. From the genes identi-fied to date, it is clear that immune dysregulation plays akey role in susceptibility to RA, and that variation in thesame loci may predispose to other autoimmune diseases.Although there are some inflammatory arthritis-specificgenes, the majority do not show exclusive association withRA; therefore, it remains unclear as to what determines thepattern, extent, and progression of disease.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors ap-proved the final version to be submitted for publication. Dr. Baronhad full access to all of the data in the study and takes responsi-bility for the integrity of the data and the accuracy of the dataanalysis.Study conception and design. Barton, Worthington.Acquisition of data. Barton, Worthington.Analysis and interpretation of data. Barton, Worthington.

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