Genetic Susceptibility to Rheumatoid Arthritis: An Emerging Picture

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1 Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 10, October 15, 2009, pp DOI /art , American College of Rheumatology REVIEW ARTICLE: EPIDEMIOLOGY OF THE RHEUMATIC DISEASES Genetic Susceptibility to Rheumatoid Arthritis: An Emerging Picture ANNE BARTON AND JANE WORTHINGTON Introduction During the past 2 years, there has been an explosion in the number of confirmed susceptibility loci identified for rheumatoid arthritis (RA) and other complex diseases. The largest genetic contribution to RA susceptibility remains the HLA DRB1 gene and the group of alleles collectively referred to as the shared epitope (1). It is unclear whether the locus predisposes to RA per se or to the development of anti citrullinated peptide antibodies, which in turn predispose to RA. Whether additional susceptibility loci reside within the HLA gene region remains a question of immense interest and is the focus of ongoing research efforts by a number of groups, but the extended linkage disequilibrium in the region makes addressing this issue very difficult (2 4). The second most important genetic contribution in Caucasian populations comes from the protein tyrosine phosphatase N22 (PTPN22) gene, in which a single-nucleotide polymorphism (SNP) encoding an arginine-to-tryptophan substitution at amino acid position 620 increases the risk of RA by 40 80% (for review, see ref. 5). However, the polymorphism is not present in Asian populations, in whom the PADI4 gene appears to be the second most important susceptibility locus after HLA DRB1 (6 10). There have previously been conflicting reports of association at this locus in Caucasian populations, but the largest meta-analysis performed to date has shown no evidence for association with the marker PADI_94 that has been consistently associated in Asian series (11). Thus, in RA, in contrast to other complex diseases, there is clear evidence of ethnic differences in genetic susceptibility factors. Several genome-wide association, candidate gene, and subsequent validation studies have been successful in identifying several other loci that have been confirmed in Supported by the Arthritis Research Campaign (grant 17552). Anne Barton, FRCP, PhD, Jane Worthington, PhD: University of Manchester, Manchester, UK. Address correspondence to Anne Barton, MD, Epidemiology Unit, Stopford Building, University of Manchester, Manchester, UK. anne.barton@manchester.ac.uk. Submitted for publication January 9, 2009; accepted in revised form April 24, more than 1 cohort (Table 1). These findings highlight a number of points worthy of discussion. Immune Pathways The majority of the SNP markers associated with RA susceptibility do not map within genes but lie close to strong candidates. Although fine mapping and functional studies will be required to confirm whether these candidate genes are involved in causation, it is nonetheless interesting to note that many of the genes are important in immune regulation. Indeed, many lie on the same pathway (12). For example, HLA DRB1, PTPN22, STAT4, CD40, CTLA4, IL2, IL21, and PRKCQ are all involved in T cell activation and signaling pathways, while C5, CD40, CTLA4, IL2, IL21, PRKCQ, PTPN22, STAT4, TNFAIP3, and TRAF1 are involved in apoptosis (13 21). Overlap With Other Autoimmune Diseases The idea that there are genes that predispose to multiple autoimmune diseases has been around for many years. Indeed, both the HLA region and the PTPN22 gene were known to be associated with multiple autoimmune diseases (5). What is surprising is how much overlap has now been identified for multiple loci across a number of autoimmune diseases (Figure 1). For example, all of the confirmed RA loci identified to date have also been associated with juvenile idiopathic arthritis (JIA) (Hinks A, et al: unpublished observation). Considerable overlap exists between loci identified for type 1 diabetes mellitus, celiac disease, Graves disease, and RA, suggesting that multiple risk factors influence the breakdown of self-tolerance and the onset of autoimmunity (22 25). It is likely that RAspecific loci exist, but of those tested so far, none has been associated exclusively with RA, with the possible exception of the shared epitope. The TRAF1/C5 locus appears to be associated with both JIA (26,27) and RA (12,28 31) but not, to date, with other autoimmune diseases (23). We can speculate that as-yet unidentified genetic polymorphisms determine the target(s) of the autoimmune process and thus 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 that develops. For many autoimmune diseases, the primary 1441

2 1442 Barton and Worthington Table 1. Non-HLA loci with confirmed evidence for association with RA in independent cohorts* Locus rs numbers Author (ref.) PTPN22 rs 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) rs WTCCC (1) Thomson et al (39) Plenge et al (40) rs Plenge et al (40) TNFAIP3 Intron 2 Orozco et al (41) STAT4 rs 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** rs Plenge et al (28) rs Chang et al (30) rs Barton et al (12) rs Kurreeman et al (29) Zervou et al (31) IL2RB rs WTCCC (1) Barton et al (63) 10p15 (PRKCQ) rs Barton et al (63) 12q13 (KIF5A) rs Barton et al (63) AFF3 rs WTCCC (1) Barton et al (64) CD40 rs Orozco et al (33) CTLA4 rs Barton et al (64) 4q27 (IL2-IL21) rs Zhernakova et al (65) Barton et al (64) (continued) susceptibility locus resides within the HLA gene complex, but specific associated alleles appear unique to particular diseases. A third possibility, therefore, is that it is the way in which antigens from infectious agents are presented by HLA molecules to an immune system prone to autoimmunity, because of the presence of other susceptibility alleles, that determines the type of autoimmune disease that ensues, possibly via the production of disease-specific autoantibodies. Ethnic Differences The majority of studies undertaken so far have been performed in populations of European ancestry and show remarkable consistency in findings across those populations. Investigations in other ethnic groups are starting to emerge, and clear differences in genetic susceptibility loci are being found. As described previously, the PADI4 gene, which is associated in multiple Asian populations, does

3 RA and Genetic Susceptibility 1443 Table 1. (Cont d) Locus rs numbers Author (ref.) MMEL1 rs WTCCC (1) Barton et al (63) PADI4 rs 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 for association but for which there were no data regarding whether these represent independent effects. Chinese population. not appear to be associated with RA susceptibility in Caucasians (11). Similarly, we found no evidence for association of an SNP in the CD244 gene, which was reported to be associated with RA in Japanese populations in a genome-wide association study in that population (32,33). In contrast, the functional polymorphism in the PTPN22 gene associated with RA susceptibility in Caucasians is extremely rare in Asian populations, and other polymorphisms within the gene show no evidence for association (34,35). However, the STAT4 gene is an example of a genetic variant that does confer susceptibility to RA across all populations tested to date (36,37). Modest Effects Can Highlight Important Pathways The combined proportion of the variance in RA susceptibility conferred by the shared epitope alone far outweighs that conferred by all the other susceptibility loci put together. It may be questioned, therefore, why it is necessary to continue to search for further RA susceptibility loci. One important reason is that although the novel loci confer only modest increases in susceptibility to disease, they may highlight pathways not previously thought to be important in etiology or that may be amenable to therapeutic intervention. For example, the CTLA4 gene has now been convincingly associated with RA susceptibility, but the increased risk conferred by carrying the associated variant is modest ( 15%) (11). Nonetheless, abatacept, a CTLA-4 analog, has been shown to be effective in the treatment of RA patients who have failed to respond to anti tumor necrosis factor therapy, highlighting the importance of the pathway (38). Figure 1. Overlap of rheumatoid arthritis (RA) susceptibility loci with Type 1 diabetes mellitus (T1D) and systemic lupus erythematosus (SLE). * different HLA alleles associate with the different autoimmune diseases. Multiple Effects One of the reasons that the non-hla SNP markers associated with RA may account for only a small contribution to the total variance in susceptibility is that the initial estimates of the effect size arising from genome-wide association studies may underestimate the effect size of the locus. There may be other associated variants at the same locus that, together, make a larger contribution than the individual effects. For example, 3 independent effects have been identified at the chromosome 6q23 susceptibility locus, individually conferring effect sizes of 10 20% (39,40). Carriage of the high-risk combinations of all 3 variants can increase susceptibility by 50% (41). Fine mapping and resequencing of the other RA susceptibility loci may identify additional variants in those regions that also confer susceptibility. This should become clearer over the next 12 months, because several of these loci are currently being intensively investigated by the Wellcome Trust Case Control Consortium extension study.

4 1444 Barton and Worthington Much of Genetic Variation Yet to Be Explained At the current time, however, approximately half of the genetic susceptibility to RA remains to be explained. Some may be accounted for by multiple effects at the loci already identified as outlined above. It is possible that there are additional susceptibility loci in regions of the genome that are not well covered by the whole-genome chip arrays. Alternatively, rare variants or copy number variation may contribute to susceptibility, but to date, these have not been extensively examined in complex diseases. However, the technology and analytical tools to address these possibilities are being developed and promise to yield results within the next 12 months or so. Alternatively, it may be that current methods to estimate both the size of the genetic contribution to disease and the amount accounted for by the loci identified at this time are too simplistic, for example, by not including the contribution of environmental risk factors. Summary At least 13 loci have now been confidently confirmed as being associated with RA susceptibility, and further insights into the genetic contribution to disease are likely to be revealed in the next 12 months. From the genes identified to date, it is clear that immune dysregulation plays a key role in susceptibility to RA, and that variation in the same loci may predispose to other autoimmune diseases. Although there are some inflammatory arthritis-specific genes, the majority do not show exclusive association with RA; therefore, it remains unclear as to what determines the pattern, extent, and progression of disease. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Baron had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Barton, Worthington. Acquisition of data. Barton, Worthington. Analysis and interpretation of data. Barton, Worthington. REFERENCES 1. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447: Vignal C, Bansal AT, Balding DJ, Binks MH, Dickson MC, Montgomery DS, et al. Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non-drb1 loci. Arthritis Rheum 2008;60: Lee HS, Lee AT, Criswell LA, Seldin MF, Amos CI, Carulli JP, et al. 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6 1446 Barton and Worthington with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum 2008;58: Martinez A, Varade J, Marquez A, Cenit MC, Espino L, Perdigones N, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum 2008;58: Palomino-Morales RJ, Rojas-Villarraga A, Gonzalez CI, Ramirez G, Anaya JM, Martin J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians. Genes Immun 2008;9: Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet 2008;40: Barton A, Eyre S, Ke X, Hinks A, Bowes J, Flynn E, et al. Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 2009;18: Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B, et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 2007;81: