Adaptive Medicine 3(2): 73-84, 2011 DOI: 10.4247/AM.2011.

ABB005

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Review

Rheumatoid Arthritis: An Orchestra of Genetic, Autoimmune and Environmental Factors

Wenfeng Tan 1, Weiting Hung 2, and Betty P. Tsao 1
1 2

Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China

Clinical presentation of rheumatoid arthritis (RA) may be the results of a combination of genetic and environmental risk factors resulting in a prominent autoimmune component. Evidence from case-control studies, either using the candidate gene or genome-wide association approaches, have revealed more than 30 loci that are associated with RA susceptibility. Many RA-associated gene variants are involved in pathways of T-cell, B-cell and NF-B signaling. HLA-DRB1 shared epitope is a major determinant of genetic predisposition to RA development in different ethnic groups, which is involved in T-cell antigen presentation and the production of anti-cyclic citrullinated peptides antibodies (ACPA). The presence or absence of ACPA appears to stratify RA patients into two distinct subsets with different genetic profiles, clinical courses and histological findings. In addition to the shared epitope, a growing number of gene variants is associated with RA in multiple ethnic groups, including STAT4, AFF3, CCR6, CCL21, and BLK. Some of the RA-associated gene variants may be particularly important in a specific ethnic group; for example, PTPN22 in populations of European ancestry and PADI4 in Asians. Emerging evidence has shown that many disease-associated loci are shared among multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, inflammatory bowel disease and multiple sclerosis, suggesting the presence of common pathways in the pathophysiology of these diseases. In addition to genetic risk factors, recent data have implicated cigarette smoking and infection of P. ginivitis as environmental risk factors that may potentiate disease risk in genetically susceptible individuals. Frequent and long-term exposure to insecticides also may increase risks for RA development. Further studies to understand functional consequences of disease-associated gene variants and gene-environment interactions that impact on the immune system are likely to lead to the development of novel therapies and/or prevention strategies for RA. Key Words: genetic epidemiology, GWAS, autoimmune, smoking, periodontal disease, rheumatoid arthritis

Introduction
Rheumatoid arthritis (RA) (MIM180300) is the most common inflammatory arthritis affecting 0.5-1% of populations worldwide, and is approximately 2 to 3 times higher in women than men. RA is characterized by inflammatory polyarthritis, destruction of cartilage and underlying bone as well as the presence of autoantibodies (rheumatoid factor [RF] and antibodies to cyclic citrullinated peptide [ACPA]). Although the etiology is not fully understood, the puzzle of RA pathogenesis is slowly fitting together during the past decades. It is known that a combination of genetic and environmental risk factors contributes to breaching of the immune tolerance, leading to autoimmune manifestations of RA (25,103). In this article, we will outline the key findings regarding the pathogenesis of RA, focusing on the interactions between genetic, autoimmunity and environment in the development of RA.

Genetic Risk in RA
Major Histocompatibility Complex (MHC)-Region Cumulative evidence from the twin studies (70), family studies (2, 48), and genome-wide linkage scans (31, 49, 58, 95, 97-99, 102, 113) has strongly indicated that genetic contribution to RA susceptibility. The most robust risk factor that has been reproducibly identified in multiple populations is HLA-DRB1 variants located in the short arm of chromosome 6 (6p21.3) encoding the MHC class II molecules. A genetic link between HLA-DR and RA was initially described in the 1970s, showing HLA-DR4 occurred in 70% of RA patients but only present in 30% of controls (103). In the 1980s, Gregersen et al. proposed the shared epitope hypothesis (32). According to this hypothesis, individuals who share a

Corresponding author: Betty P. Tsao, Ph.D., Division of Rheumatology, Department of Medicine, Rehabilitation Center, Room 32-59, 1000 Veteran Avenue, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-1670, USA. Tel: +1-310-825-8906, Fax: +1-310-8256903, E-mail: Btsao@mednet.ucla.edu Received: April 22, 2011; Revised: May 28, 2011; Accepted: June 10, 2011. 2011 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X. http://www.sast.org.tw

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conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) at positions 70-74 in the third hypervariable region of the DRB1 chain show an increased risk for disease. Subsequently, numerous studies have confirmed the association between RA and allelic variants at HLA-DRB1 including HLA-DRB1 *04 allele group (e.g. *04:01, *04:04, *04:05 and *04:08), HLADRB1 *01:01 or *01:02, HLA-DRB1*14:02 and HLADRB1*10:01 (46). The risk alleles with the greatest association with RA are *04:01, *04:04, *01:01, and *14:02. The HLA-DRB1 may also predict the earlier age of RA onset and more severe disease. RA patients who carry two copies of risk alleles tend to have a greater prevalence of extra-articular disease and bone erosions than patients who carry a single copy of the risk allele (16, 29). More recently, studies have shown that HLA-DRB1 shared epitope alleles only influence the development of seropositive RA, and more specifically for ACPA positive RA (45, 57). The MHC region spans 3.6 megabases (Mb) and contains a wide range of other immunologically relevant genes. Several candidate genes within the MHC have been implicated contributing to the susceptibility of RA, including MHC I chain related gene A (MICA) (56), the MHC class II gene HLA-DQB1*03:01 (81), the MHC class III genes tumor necrosis factor alpha (TNFA) and nuclear factor inhibitor of kappa B-like (NFKBIL1) (54). However, these genes have not been comprehensively tested in large case-control populations, and conflicting reports in different ethnicities make them inconclusive (67, 75). Thus, it will need further work to provide additional insight into these MHC genes. Non-MHC Genes HLA-DRB1 gene has been estimated accounts for approximately one-third of the overall genetic component of RA risk (34). There are approximately 10 million common single-nucleotide polymorphisms (SNPs) in the human genome, which makes the identification of RA susceptibility genes that lie outside the MHC region more challenging. After the discovery of HLA associations, a long period of genetic investigation during the 1990s and early 2000s has yielded evidence for additional genetic regions linked to RA susceptibility; however, with a few exceptions, no definitive risk alleles have been identified. Advances in human genetics, especially the substantial progress in genome-wide association study (GWAS), have greatly promoted the discovery and independent replication of a growing number of RA-associated gene variants. One of the most convincing non-HLA loci associated with RA is PTPN22, a negative regulator of T-cell activation on chromosome 1, identified in 2004 (7). A missense C-to-T substitution at nucleotide

position 1856 of this gene (rs2476601 [(R620W)]) leads to substitution of tryptophan (W) for arginine (R) at residue 620 of the protein product, resulting in increased risk of RA by 40-80% in Caucasians (40, 41). However, this genetic association has not been found in Asian populations (7, 65, 113). Interestingly, PADI4, a member of peptidyl arginine deiminases family genes encoding enzymes that are responsible for the post-translational modification of arginine to citrullin, has been consistently associated in Asian populations (23, 47, 51), but has yielded conflicting association results in Caucasian populations (13, 27, 104). The strikingly feature after 2007 is that unprecedented international collaborations, large patient collections as well as growing genome-wide association studies, have made genetic study a revolution. A large-scale genetic association study has identified the risk allele in STAT4 (rs7574865) is common in individuals of Asian, African, and European ancestries (1624 cases and 2635 controls), providing a significant contribution to RA susceptibility (40). Subsequently, a similar strong association signal of this SNP has been replicated in another large casecontrol study of the British population (6400 cases and 6422 controls) (5). To date, 5 genome-wide association studies in RA have been performed, uncovering many new genes or loci associated robustly with susceptibility for RA (26, 49, 87, 102, 113). The landmark study of GWAS is reported by Trust Case Control Consortium (WTCCC), which performed an genome-wide analysis on 7 common diseases including RA in the UK population (113). In this study, the two well-known genes, HLADRB1 and PTPN22, and nine additional variants were identified for association with RA. The replication study was performed in a large independent UK cohort (5063 cases and 3849 controls) by genotyping these 9 variants resulting in the discovery of a novel RA risk locus, TNFAIP3 at 6q23 (rs6920220) (109). Subsequently, many additional RA-associated genes were revealed by GWAS including TRAF1-C5, REL, CTLA4, BLK, KLF12, CCR6, CD40, CD28, PRDM1, CD2/CD58, L6ST, SPRED2, RBPJ, IRF5, PXK, C5orf30, UBE2L3, TAGAP, SH2B3, 8q24.2, DDX6, CD247 and UBASH3A (17, 31, 49, 58, 85, 98, 99, 102, 121). Interestingly, the previously identified RA-susceptibility R620W PTPN22 allele has been replicated in almost all GWAS using European populations, highlighting its pivotal role in the RA pathogenesis, especially in European populations. As of April, 2011, more than 30 new non-HLA loci contributing to RA have been discovered and confirmed (Table 1). The latest GWAS study in Koreans found that a number of the established Caucasian risk loci, including, STAT4, AFF3, CCR6,

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Table 1. Confirmed non-HLA loci associated with RA susceptibility Gene PADI4 PTPN22 CTLA4 FCRL3 TNFAIP Location 1p36 1p13 2q33 1q23 6q23 SNP rs2240340 rs2476601 rs3087243 rs7528684 rs6920220 rs10499194 rs5029937 rs1953126 rs7574865 rs6822844 rs3761847 rs7021049 rs10760130 rs10818488 rs1953126 rs4810485 rs3890745 rs2812378 rs4750316 rs3890745 rs1678542 rs42041 rs3218253 rs3766379 rs6682654 rs1980422 rs548234 rs11586238 rs13031237 rs10865035 rs934734 rs6859219 rs262321 rs13315591 rs874040 rs3093023 rs3093024 rs10488631 rs2736340 rs5754217 rs2298428 rs212389 rs653178 rs975730 rs10892279 rs864537 rs11203203 OR 1.4 1.65 1.14 2.15 1.33 1.22 1.34 1.1 1.32 1.39 1.32 1.39 1.09 1.28 1.1 0.91 0.92 1.1 0.86 0.86 0.92 1.15 1.11 1.37 1.34 1.13 1.11 1.13 1.21 1.12 1.13 0.78 0.88 1.29 1.14 1.13 1.19 1.19 1.14 1.14 1.11 0.87 1.07 0.93 0.87 0.9 1.11 Population Japanese North American Swedish, North American Japanese UK North America (BRASS), Swedish UK European North American Dutch Swedish, North American Dutch, North American UK Dutch, Swedish, North American European UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American UK, Dutch, Swedish, North American Japanese Japanese European and North American European and North American European and North American North American UK European European European European European European Japanese European European European European European European European European European European Reference Suzuki 2003 (104) Begovich 2004 (7) Plenge 2005 (96) Kochi 2005 (59) Thomson 2007 (109) Plenge 2007 (95) Orozco 2009 (86) Zhernakova 2011 (121) Remmers 2007 (100) Zhernakova 2011 (121) Zhernakova 2007 (120) Plenge 2007 (97) Chang 2008 (15) Barton 2008 (5) Kurreeman 2007 (61) Zhernakova 2011 (121) Raychaudhuri 2008 (98) Raychaudhuri 2008 (98) Raychaudhuri 2008 (98) Raychaudhuri 2008 (98) Barton 2008 (6) Raychaudhuri 2008 (98) Raychaudhuri 2008 (98) Barton 2008 (6) Raychaudhuri 2008 (98) Barton 2008 (6) Suzuki 2008 (105) Suzuki 2008 (105) Raychaudhuri 2009 (99) Raychaudhuri 2009 (99) Raychaudhuri 2009 (99) Gregersen 2009 (31) Barton 2009 (4) Stahl 2010 (102) Stahl 2010 (102) Stahl 2010 (102) Stahl 2010 (102) Stahl 2010 (102) Stahl 2010 (102) Kochi 2010 (58) Stahl 2010 (102) Orozco 2011 (85) Orozco 2011 (85) Zhernakova 2011 (121) Chen 2011 (17) Zhernakova 2011 (121) Zhernakova 2011 (121) Zhernakova 2011 (121) Zhernakova 2011 (121) Zhernakova 2011 (121)

STAT4 IL2/IL21 TRAF1/C5

2q32 4q27 9q33

CD40 TNFSF30 CCL21 PRKCQ MMEL1 KIF5A CDK6 IL2RB CD244 CD28 PRDM1 CD2/CD58 REL AFF3 SPRED2 ANKRD55 C5orf30 PXK RBPJ CCR6 IRF5 BLK UBE2L3 TAGAP SH2B3 8q24.2 DDX6 CD247 UBASH3A

20q13 1p36.2 9p13 10p15 1p36 12q13 7q21 22q13 1q23 2q33 6q 2q33 2p16 2q11 2p30 5q11 5q21 3p14 4p15 6q27 7q32 8p22 22q11 6q25 12q24 8q24 11q23 1q24 21q22

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CCL21, and BLK exhibiting evidence for association (26). They also discovered 10 novel loci (rs1600249, rs2736340 in BLK; rs2009094 in AFF3; rs12831974 in TRHDE; rs7024727 in CCL21; rs657555 in PTPN2; rs2062583 in ARHGEF3; rs7537965 in GPR137B; rs4867947 in LCP2/C5orf; rs4547623 in GGA1/LGALS2; rs4936059 in FLI1/ ETS1) associated with RA susceptibility. However, none of these associations reach genome-wide significance (P = 5 10 -8). It is estimated that these known non-MHC risk alleles contribute between 35% of the genetic burden of RA (102) suggesting additional risk alleles remain to be identified. It is clear that the development of RA is dependent on inputs from multiple loci. Given that the relative risks for these common variants are generally modest, it is hypothesized that rare genetic variants (with population frequency <1%) and/or copy number variants (CNV) may be the major contributors to disease susceptibility (1, 35). Uddin et al. reported genome-wide CNV burden is 2-fold higher in patients with RA compared with controls (114). They identified rare copy number variable regions including TNFAIP3, TNIP1, IRF1, ALOX5AP, LCP2, B2M and PRKCH by using the WTCCC highdensity SNP genotype data. The challenge now is to identify the remaining, genetic effects and their functional roles of these RA-associated variants in the pathogenesis of RA, and to explore how they interact with each other as well as environmental factors to induce the development of RA. In summary, the most convincing evidence for RA association is the HLA-DRB1 alleles expressing the share epitope, which has been consistently demonstrated in ethnically diverse populations (26, 31, 49, 58, 95, 97-99, 102, 113). STAT4, CCR6, AFF3, CCL21 and BLK are also important genetic risk factors in Asians, European and African derived populations (26, 31, 58, 100, 121). PADI4, FCRL3 and CD244 are specific risk factors in Asian populations (59, 104, 105) while TNFSF14, MMEL1, CDK6, PRKCQ, KIF5A, SPRED2, ANKRD55, PTPN22, TNFAIP3, TRAF1-C5, CTLA4, REL, CD40, CD28, PRDM1, CD2/ CD58, C5orf30, PXK, RBPJ, IRF5, UBE2L3, TAGAP, SH2B3, 8q24.2, DDX6, CD247, UBASH3A, IL2/IL21, IL2RB, AFF3, are shown to be significantly associated with RA in European-derived populations (5, 7, 17, 31, 61, 85, 87, 95, 97-99, 102, 109, 121). Taken together, it is important to consider ethnic differences in RA genetic predisposition.

Genetic Risk in Immune Pathways

T Cell Pathways It is well established that T cells, B cells, macrophages,

neutrophils and synovial fibroblasts play central roles in the pathogenesis of joint inflammation and disease progression in RA. The strong genetic association of HLA-DR and RA implies that the disease is, at least in part, driven by T cells. Studies from crystal structure of HLA-DR molecules showed that the RA-associated QKRAA region primarily faces away from the antigenbinding cleft of the DR molecule. Citrullination of peptides triggers a stronger immune response in human HLA-DR4 transgenic mice via increasing the affinity to HLA-DR molecule and activating CD4+ T cells (39), suggesting HLA-DR molecules were involved in antigen presentation. Accordingly, prevailing hypotheses postulate that specific HLA-DR alleles confer susceptibility to RA through 1) their involvement in presenting arthritogenic self-peptides to CD4+ T cell (110), 2) molecular mimicry with foreign Ags (48), and/or 3) T cell repertoire selection (98). In addition to antigen presentation, most recent studies suggested that the SE functions as an allele-specific signaltransducing ligand that can polarize T cell differentiation toward Th17 cells, facilitating autoimmunity in mice (20). In additional to class II MHC region, risk alleles highlight genes involved in T cell activation by antigen presenting cells including PTPN22, STAT4, IL2/IL21, IL2RB, CD28, and CTLA4. A missense C-to-T substitution at nucleotide position 1856 of PTPN22 leads to substitution of tryptophan (W) for arginine (R) at residue 620 of the protein product, resulting in enhanced regulation of T-cell receptor (TCR) signaling during thymic selection, permits autoantigen-specific T cells to escape clonal deletion. STAT4, a signal transducer and activator of transcription 4, encodes a transcription factor that transduces interleukin-12 (IL-12), interleukin-23 (IL-23), and type I interferon cytokine signals in T cells and monocytes, leading to T-helper type 1 (Th1) and T-helper type 17 (Th17) differentiation, and production of interferon- (73, 82), suggesting the critical role in the development of a Th1 and Th17 type T-cell response. STAT4-deficient mice are generally resistant to models of autoimmune disease, including arthritis (24), highlighting its role in RA pathogenesis. Although previous studies did not find an allele-specific role of STAT4 in gene expression, it is quite possible that variants located in STAT4 introns could influence its gene transcription rate of its alternatively spliced forms by altering a transcription factor binding site or a binding site for modified histone proteins (60). Recent associations have also clearly implicated the interleukin-2 (IL-2) signaling pathway, a critical cytokine involved in T cell activation and proliferation. The IL2RB, encodes the beta unit of the interleukin2 receptor (IL2R) present in the moderate and high affinity forms of the receptor required for signal

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transduction from IL-2 (55), was validated for genetic association with RA in European ancestries (6). The implicated SNP of the IL2/IL21 locus was associated with RA and type 1 diabetes, supporting a general risk locus for multiple autoimmune diseases (120). Functional connections between IL2/IL21 and IL2RB loci are clearly highlighted genetic factor involved in IL-2 signaling pathway. T cells activation derived from nave T cell upon interaction of the TCR with specific peptides presented by MHC molecules are regulated by a delicate balance between costimulatory signals that activate T cells, and inhibitory signals that attenuate harmful inflammatory responses (19). Simultaneous recognition of the cognate MHC-peptide complex by the TCR (signal 1) and B7 costimulatory family members (CD80/ CD86) by CD28 (signal 2) results in T cell activation, proliferation, and differentiation. The association between variants with costimulatory receptors CD28 (99) and its inhibitory receptors CTLA4 (96) predisposing to RA highlighted the critical role of costimulatory pathways in RA pathogenesis. A newly identified subset of CD4 effector T helper that produces interleukin-17 (IL-17), termed Th17 cells, have been implicated as the pivotal driving force of autoimmune inflammation in collagen or adjuvant-induced arthritis (28, 63, 78). In RA, clinical data suggested that IL-17 is mainly involved in the progression of joint damage (115) and might be a future therapeutic target for RA. Polymorphism in CCR6 (rs3093024), the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells), was identified and validated with RA susceptibility in Japanese (58) and Caucasians (102). Interestingly, a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that could affect levels of CCR6 transcription, was associated with the levels of IL-17 in serum samples of RA patients, suggesting that CCR6 is critically involved in IL-17 driven autoimmunity (58). In the development of Th17 cells, IL-23 plays an important role in cells expansion and maintenance (89). Case-control studies in 3 Caucasian cohorts and 1 Korean cohort have been conducted to investigate the association of IL-23 receptor (IL-23R) polymorphism and RA susceptibility (42, 90, 113, 118). However, these studies yielded either no evidence for association or identified SNPs of one study that were not evaluated in other independent panels. This apparent discrepancy may due to different candidate SNPs genotyped in each study, inadequate power to detect association, and ethnic variations in allele frequencies and linkage disequilibrium patterns. Therefore, further studies are needed to evaluate a comprehensive set of informative markers of IL-23R in large collections of RA case-control panels to

address the role of IL-23 variants in RA susceptibility. B Cell Pathways B cells have long been considered playing an important role in RA since the discovery of autoantibody in serum samples from RA patients. Several autoantibodies have been described in RA. Among them, RF exhibits 70-80% sensitivity and has been widely used in clinical settings traditionally. ACPA, which is more specific for RA compared to RF, can be detected years before the first clinical manifestations and is associated with a more severe, erosive arthritis compared to ACPA negative RA patients, implying a putative role as a predictor for the development of RA. Though citrullinated peptides are present in the rheumatoid synovium, suggesting a possible pathogenic role of this autoantibody (51), there are no direct evidence for their contribution to the pathogenesis of RA. HLADRB1, PTPN22, TRAF1C5, CD40, FCGR3A, STAT4, REL and PADI4 have been identified and validated in ACPA positive RA patients (14, 97, 100, 106, 108, 116). However, none of these loci achieved genomewide significant in ACPA negative RA patients. Recently, one GWAS study in Sweden found that one SNP close to the RPS12P4 locus in chromosome 2 might be considered as a candidate locus for APCA negative RA (87). SE+ RA patients with co-occurrence of ACPA positive at baseline had a significantly higher rate of joint destruction than did other RA patients (117). Intriguingly, the histology study demonstrated that ACPA positive synoviums appeared to be characterized by denser lymphocyte infiltrations and a higher rate of joint destruction, whereas more extensive fibrotic changes were apparent in ACPA negative tissue (98). Taken together, RA is probably a clinical syndrome consisting of at least two distinct disease subsets defined by the presence or absence of ACPA. FCRL3 is a member of the Fc receptor-like family and its precise function of FCRL3 is unknown. A RA-associated FCRL3 promoter SNP could alters the binding affinity of NF-B and FCRL3. Interestingly, RA patients carrying the FCRL3 risk allele conferred higher FCRL3 expression on B cell surfaces and augmented autoantibody production compared with non-carriers, suggesting that FCRL3 might influence the fate of B cells and augment the emergence of self-reactive B cells in RA patients. NF-B Signaling Pathway The NF-B family, consists of p50 (NF-B1), p52 (NF-B2), p65 (RelA), RELB, and REL (c-Rel). Upon to stimuli, a dimer of NF-B proteins acts as a transcription factor binds to a B site in the promoter or enhancer of a target gene, controlling immune re-

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IL2/21 STAT4
B7-CD28

IL2RB CCR6

Th1/Th17 differentiation

CD28
MHCII-TCR

HLA-DRB1 PTPN22

T cell activation

B7-CTLA4

CTLA4
NFB activation

CD40 TRAF1
APC

PRKCQ TNFRSF14
T cell

TNFAIP3 REL

PADI4 FCGR3A STAT4

B cell Autoantibody

PTPN22 REL CD40

HLA-DRB1 TRAF1-C5

ACPA positive

Fig. 1. Gene loci associated with RA susceptibility and their potential roles in RA pathogenesis.

sponses and autoimmunity (36). Several RA risk loci containing genes that are involved in NF-B signaling, including CD40, TRAF1, TNFAIP3, PRKCQ, TNFRSF14 and the recent report of REL. CD40, expressed on the cell surfaces of APCs, is a TNF receptor family member (TNFRSF5). This receptor is essential in mediating a variety of B-cell responses, including B-cell proliferation and differentiation, with predominant activation through NF-B pathways (76). A common variant at the CD40 locus showed very strong evidence for association with RA (P = 8.2 10 -9) in a large GWAS meta-analysis study, including a total of >7300 autoantibody positive RA cases and >18000 matched control individuals (97). REL, encoding cRel, have recently identified as a new risk locus for rheumatoid arthritis (31). A variety of genes in T cells are regulated by c-Rel, including CD40 and other accepted RA susceptibility loci TNFAIP3 (95), suggesting an important role of CD40/NF-B signaling pathways in RA pathogenesis. Recent genetic discoveries have indentified many RA risk loci involved in autoimmune and inflammatory pathways (Fig. 1). Thus, it is not surprising that many of these loci predispose to more than one autoimmune diseases including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), inflammatory bowel disease, and multiple sclerosis in addition to RA (6, 46, 77, 94, 100), suggesting shared autoimmune pathways affected by genes and environment factors. On the other hand, physiological functions of some associated genes, such as ANKRD55 and C5orf30, are not clear yet, suggesting additional

pathophysiological pathways other than those currently known. Much more work remains before a complete understanding in the function of the causal variants and their roles in autoimmune pathway of RA is needed for the eventual improvement of patient care.

Interaction of Genetic, Immunity and Environment Factor

Although several potential environmental factors have been linked to RA susceptibility or disease severity including coffee consumption, in particular decaffeinated coffee, cigarette smoking history, exposure to air pollution, and environmental exposure to silicacontaining dust (21). To date, smoking and periodontitis are the mostly well-established environmental risk factors. The role for smoking is first reported more than 15 years ago, and its role in RA has been highlighted recently by new evidence of interactions among smoking, the presence of shared epitope, and the presence of ACPA (38). The landmark study of gene-environment interaction was described by Klareskog and colleagues (57, 88). This work demonstrated that patients with RA onset within the previous year, smokers without HLA-DRB1*SE alleles (SE negative) were 1.5 times more likely to develop ACPA positive RA compared to SE negative nonsmokers. The risk of developing ACPA positive RA is increased 21-fold in individuals who have smoking history and the presence of double copies of HLA-DR SE compared to SE-negative nonsmokers (57). Subsequently, this

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Genetic

En vir on me nt

Smoking

HLA-DRB1 PTPN22

AT CG CG AT TA CG CG CG

Autoimmunity

AutoantigenCitrullination production

RA

Fig. 2. Schematic diagram of the interaction between genetic, immune and environment factors.

interaction was confirmed in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls) (50). Interestingly, although no interaction is seen between smoking and PTPN22, combinations of HLA-DRB1, PTPN22 and smoking confer a high odds ratio (OR = 23-25) to the development ACPA positive RA, highlighting that MHC class II-dependent T-cell activation is of central pathogenic importance for the subset of ACPA positive RA (50). A study using three large US cohorts (64) failed to demonstrate the interaction among ever smoking, SE-positivity, and the presence of ACPA in RA patients. However, another prospective case-control study in US observed strong smoking-SE interaction by stratifying pack-year rather than by ever (52). These results suggest that smoking has a cumulative effect on RA development in SE-positive individuals. Recently, antibodies to the immunodominant citrullinated -enolase CEP-1 epitope, a subset of the ACPA response with specific autoimmunity to citrullinated -enolase, were detected in 43-63% of the ACPA positive RA patients. In a 1,000 case- 872 control analysis, HLA-DRB1-SE, PTPN22 and smoking showed the strongest association with the anti-CEP1positive subset (OR = 37, compared to OR = 2 for the corresponding anti-CEP-1negative, anti-CCP positive subset). These results imply that citrullinatedenolase is a specific citrullinated autoantigen which links smoking to genetic risk factors in the development of RA (71). The possible explanation for the strong interaction between smoking, HLA-DRB1 and ACPA is that long-term exposure to cigarette tobacco would accelerate the presence of citrullinated

autoantigens in the lungs; thus, immune activation against such posttranslationally modified proteins would be preferentially induced in individuals carrying HLA-DRB1 SE alleles (50) (Fig. 2). Another interesting environmental risk factor in the pathogenesis of RA is periodontitis. The prevalence and severity of periodontitis is increased in RA (18, 33, 37, 93) and this phenomenon cannot be attributed to secondary Sjgren syndrome (37, 62, 92). On the other hand, RA disease severity, including numbers of swollen joints, serum C-reactive protein levels and erythrocyte sedimentation rate are associated with the severity of periodontitis (74). There is also a significant correlation between the presence of ACPA and the presence of periodontitis in RA patients (79). There is a link in important inflammatory cytokines between RA and periodontitis. Elevated serum levels of TNF, IL-1 and IL-17 are correlated with the degree of tissue destruction in periodontitis (30, 112, 119). Evidence also showed that RANKRANKL plays an important role in inducing alveolar bone loss in aggressive periodontitis (8, 11, 12, 68, 105, 107, 110), which is also a crucial mechanism in RA bone erosion. Emerging data has revealed DNA of Porphyromonas gingivalis, the major bacterial cause of periodontitis, is often found in gingiva from gingivalis patients (9) and synovium from RA patients (72). P. gingivitis could induce citrullination of human fibrinogen and -enolase by endogeouns peptidylaginine deiminase (111) which may also lead to the citrullination of fibrin in the synovium (66). Presence of gp39, cartilage antigen targeted by the autoimmune response in rheumatoid synovitis, was also found in gingival tissue from periodontitis patients (80). Interestingly, HLA-DRB1, the most relevant

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genetic risk factor of RA, has been associated with development of severe and rapidly progressive periodontal disease (10). Therefore, the production of auto-antigens in gingival and synovium may predispose to the loss of tolerance in susceptible individuals. Furthermore, animal studies showed that introducing heat-killed P. gingivalis in rats could accelerate the occurrence of adjuvant-induced arthritis (3). However, it is unclear at present whether the presence of P. gingivalis DNA in the synovium is an epiphenomenon related to DNA trapping by the synovial filter, and whether there is a causal relation between P. gingivalis and ACPA production. Another possible environmental risk factor of RA is insecticide usage. Early studies have shown association between farming and RA in men (83, 84) that active components of insecticides and/or their interaction with other environmental agents (including microbial products) may affect the immune system (22, 44, 69). However, specific environmental triggers for RA are yet to be identified (83, 84). Recently, one observational study shows the hazard ratio of RA incidence increased in post-menopausal women who were exposed to greater frequency ( 6 times per year) or greater duration ( 20 years) of insecticides (91). These findings suggest a possible interaction between environmental exposure to particular chemicals and the risk for RA development, which awaits further replication studies.

Conclusion
Gene-immunity-environment interactions are key features in the development of RA. Inheritance of multiple gene variants involved in T-cell, B-cell, and NF-B signaling pathways predisposes an individual to have broken immune tolerance upon environmental triggers, leading to the development of RA. To date, a growing number of gene variants have been identified predisposing to RA in multiple ethnic groups including HLA-DRB1, STAT4, TNFAIP3, CCR6, TRAF1, and BLK. Patients carrying the HLA-DRB1 shared epitope may be more vulnerable to environmental factors, including smoking and periodontitis. The identification of environmental factors that modify disease risk may impact on risk reduction in disease susceptibility as well as in modulating the clinical course of the disease. Understand functional consequences of disease-associated gene variants and gene-immunity-environment interactions are likely to lead to the development of novel therapies and/or prevention strategies for RA.

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