1. Adaptive Medicine 3(2): 73-84, 2011 73
DOI: 10.4247/AM.2011.ABB005
Review
Rheumatoid Arthritis: An Orchestra of Genetic, Autoimmune
and Environmental Factors
Wenfeng Tan 1, Weiting Hung 2, and Betty P. Tsao 1
1
Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
2
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 Introduction
be the results of a combination of genetic and environ-
mental risk factors resulting in a prominent autoimmune Rheumatoid arthritis (RA) (MIM180300) is the most
component. Evidence from case-control studies, either common inflammatory arthritis affecting 0.5-1% of
using the candidate gene or genome-wide association
populations worldwide, and is approximately 2 to 3
approaches, have revealed more than 30 loci that are as-
sociated with RA susceptibility. Many RA-associated times higher in women than men. RA is characterized
gene variants are involved in pathways of T-cell, B-cell by inflammatory polyarthritis, destruction of cartilage
and NF-κB signaling. HLA-DRB1 shared epitope is a and underlying bone as well as the presence of autoanti-
major determinant of genetic predisposition to RA de- bodies (rheumatoid factor [RF] and antibodies to cyclic
velopment in different ethnic groups, which is involved citrullinated peptide [ACPA]). Although the etiology
in T-cell antigen presentation and the production of is not fully understood, the puzzle of RA pathogenesis
anti-cyclic citrullinated peptides antibodies (ACPA). is slowly fitting together during the past decades. It is
The presence or absence of ACPA appears to stratify RA known that a combination of genetic and environmen-
patients into two distinct subsets with different genetic
tal risk factors contributes to breaching of the immune
profiles, clinical courses and histological findings. In
addition to the shared epitope, a growing number of tolerance, leading to autoimmune manifestations of
gene variants is associated with RA in multiple ethnic RA (25,103). In this article, we will outline the key
groups, including STAT4, AFF3, CCR6, CCL21, and findings regarding the pathogenesis of RA, focusing
BLK. Some of the RA-associated gene variants may be on the interactions between genetic, autoimmunity and
particularly important in a specific ethnic group; for environment in the development of RA.
example, PTPN22 in populations of European ancestry
and PADI4 in Asians. Emerging evidence has shown Genetic Risk in RA
that many disease-associated loci are shared among
multiple autoimmune diseases, including type 1 diabetes,
Major Histocompatibility Complex (MHC)-Region
systemic lupus erythematosus, inflammatory bowel disease
and multiple sclerosis, suggesting the presence of common
pathways in the pathophysiology of these diseases. In Cumulative evidence from the twin studies (70), family
addition to genetic risk factors, recent data have impli- studies (2, 48), and genome-wide linkage scans (31,
cated cigarette smoking and infection of P. ginivitis as 49, 58, 95, 97-99, 102, 113) has strongly indicated
environmental risk factors that may potentiate disease that genetic contribution to RA susceptibility. The
risk in genetically susceptible individuals. Frequent most robust risk factor that has been reproducibly
and long-term exposure to insecticides also may increase identified in multiple populations is HLA-DRB1 vari-
risks for RA development. Further studies to understand ants located in the short arm of chromosome 6 (6p21.3)
functional consequences of disease-associated gene vari-
encoding the MHC class II molecules.
ants and gene-environment interactions that impact on
the immune system are likely to lead to the development A genetic link between HLA-DR and RA was
of novel therapies and/or prevention strategies for RA. initially described in the 1970s, showing HLA-DR4
occurred in 70% of RA patients but only present in
Key Words: genetic epidemiology, GWAS, autoimmune, 30% of controls (103). In the 1980s, Gregersen et
smoking, periodontal disease, rheumatoid al. proposed the ‘shared epitope’ hypothesis (32).
arthritis 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: +1-310-825-
6903, 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

2. 74 Tan, Hung and Tsao
conserved amino acid sequence (QKRAA, QRRAA, position 1856 of this gene (rs2476601 [(R620W)])
or RRRAA) at positions 70-74 in the third hyper- leads to substitution of tryptophan (W) for arginine
variable region of the DRB1 chain show an increased (R) at residue 620 of the protein product, resulting in
risk for disease. Subsequently, numerous studies increased risk of RA by 40-80% in Caucasians (40,
have confirmed the association between RA and allelic 41). However, this genetic association has not been
variants at HLA-DRB1 including HLA-DRB1 *04 allele found in Asian populations (7, 65, 113). Interestingly,
group (e.g. *04:01, *04:04, *04:05 and *04:08), HLA- PADI4, a member of peptidyl arginine deiminases
DRB1 *01:01 or *01:02, HLA-DRB1*14:02 and HLA- family genes encoding enzymes that are responsible
DRB1*10:01 (46). The risk alleles with the greatest for the post-translational modification of arginine to
association with RA are *04:01, *04:04, *01:01, and citrullin, has been consistently associated in Asian
*14:02. The HLA-DRB1 may also predict the earlier populations (23, 47, 51), but has yielded conflicting
age of RA onset and more severe disease. RA patients association results in Caucasian populations (13, 27,
who carry two copies of risk alleles tend to have a 104).
greater prevalence of extra-articular disease and bone The strikingly feature after 2007 is that unprece-
erosions than patients who carry a single copy of the dented international collaborations, large patient
risk allele (16, 29). More recently, studies have collections as well as growing genome-wide associa-
shown that HLA-DRB1 shared epitope alleles only tion studies, have made genetic study a revolution. A
influence the development of seropositive RA, and large-scale genetic association study has identified
more specifically for ACPA positive RA (45, 57). the risk allele in STAT4 (rs7574865) is common in
The MHC region spans 3.6 megabases (Mb) and individuals of Asian, African, and European ances-
contains a wide range of other immunologically re- tries (1624 cases and 2635 controls), providing a
levant genes. Several candidate genes within the MHC significant contribution to RA susceptibility (40).
have been implicated contributing to the susceptibility Subsequently, a similar strong association signal of
of RA, including MHC I chain related gene A (MICA) this SNP has been replicated in another large case-
(56), the MHC class II gene HLA-DQB1*03:01 (81), control study of the British population (6400 cases
the MHC class III genes tumor necrosis factor alpha and 6422 controls) (5).
(TNFA) and nuclear factor inhibitor of kappa B-like To date, 5 genome-wide association studies in
(NFKBIL1) (54). However, these genes have not been RA have been performed, uncovering many new genes
comprehensively tested in large case-control popula- or loci associated robustly with susceptibility for RA
tions, and conflicting reports in different ethnicities (26, 49, 87, 102, 113). The landmark study of GWAS
make them inconclusive (67, 75). Thus, it will need is reported by Trust Case Control Consortium (WTCCC),
further work to provide additional insight into these which performed an genome-wide analysis on 7
MHC genes. common diseases including RA in the UK population
(113). In this study, the two well-known genes, HLA-
Non-MHC Genes DRB1 and PTPN22, and nine additional variants were
identified for association with RA. The replication
HLA-DRB1 gene has been estimated accounts for study was performed in a large independent UK cohort
approximately one-third of the overall genetic com- (5063 cases and 3849 controls) by genotyping these
ponent of RA risk (34). There are approximately 10 9 variants resulting in the discovery of a novel RA
million common single-nucleotide polymorphisms risk locus, TNFAIP3 at 6q23 (rs6920220) (109).
(SNPs) in the human genome, which makes the identi- Subsequently, many additional RA-associated genes
fication of RA susceptibility genes that lie outside the were revealed by GWAS including TRAF1-C5, REL,
MHC region more challenging. After the discovery of CTLA4, BLK, KLF12, CCR6, CD40, CD28, PRDM1,
HLA associations, a long period of genetic investi- CD2/CD58, L6ST, SPRED2, RBPJ, IRF5, PXK,
gation during the 1990s and early 2000s has yielded C5orf30, UBE2L3, TAGAP, SH2B3, 8q24.2, DDX6,
evidence for additional genetic regions linked to RA CD247 and UBASH3A (17, 31, 49, 58, 85, 98, 99,
susceptibility; however, with a few exceptions, no de- 102, 121). Interestingly, the previously identified
finitive risk alleles have been identified. Advances in RA-susceptibility R620W PTPN22 allele has been
human genetics, especially the substantial progress in replicated in almost all GWAS using European
genome-wide association study (GWAS), have greatly populations, highlighting its pivotal role in the RA
promoted the discovery and independent replication pathogenesis, especially in European populations.
of a growing number of RA-associated gene variants. As of April, 2011, more than 30 new non-HLA
One of the most convincing non-HLA loci as- loci contributing to RA have been discovered and
sociated with RA is PTPN22, a negative regulator of confirmed (Table 1). The latest GWAS study in
T-cell activation on chromosome 1, identified in 2004 Koreans found that a number of the established
(7). A missense C-to-T substitution at nucleotide Caucasian risk loci, including, STAT4, AFF3, CCR6,

3. Genetic and Environmental Risk Factors in Rheumatoid Arthritis 75
Table 1. Confirmed non-HLA loci associated with RA susceptibility
Gene Location SNP OR Population Reference
PADI4 1p36 rs2240340 1.4 Japanese Suzuki 2003 (104)
PTPN22 1p13 rs2476601 1.65 North American Begovich 2004 (7)
CTLA4 2q33 rs3087243 1.14 Swedish, North American Plenge 2005 (96)
FCRL3 1q23 rs7528684 2.15 Japanese Kochi 2005 (59)
TNFAIP 6q23 rs6920220 1.33 UK Thomson 2007 (109)
rs10499194 1.22 North America (BRASS), Swedish Plenge 2007 (95)
rs5029937 1.34 UK Orozco 2009 (86)
rs1953126 1.1 European Zhernakova 2011 (121)
STAT4 2q32 rs7574865 1.32 North American Remmers 2007 (100)
Zhernakova 2011 (121)
IL2/IL21 4q27 rs6822844 1.39 Dutch Zhernakova 2007 (120)
TRAF1/C5 9q33 rs3761847 1.32 Swedish, North American Plenge 2007 (97)
rs7021049 1.39 Dutch, North American Chang 2008 (15)
rs10760130 1.09 UK Barton 2008 (5)
rs10818488 1.28 Dutch, Swedish, North American Kurreeman 2007 (61)
rs1953126 1.1 European Zhernakova 2011 (121)
CD40 20q13 rs4810485 0.91 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
TNFSF30 1p36.2 rs3890745 0.92 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
CCL21 9p13 rs2812378 1.1 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
PRKCQ 10p15 rs4750316 0.86 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
Barton 2008 (6)
MMEL1 1p36 rs3890745 0.86 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
KIF5A 12q13 rs1678542 0.92 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
Barton 2008 (6)
CDK6 7q21 rs42041 1.15 UK, Dutch, Swedish, North American Raychaudhuri 2008 (98)
IL2RB 22q13 rs3218253 1.11 UK, Dutch, Swedish, North American Barton 2008 (6)
CD244 1q23 rs3766379 1.37 Japanese Suzuki 2008 (105)
rs6682654 1.34 Japanese Suzuki 2008 (105)
CD28 2q33 rs1980422 1.13 European and North American Raychaudhuri 2009 (99)
PRDM1 6q rs548234 1.11 European and North American Raychaudhuri 2009 (99)
CD2/CD58 2q33 rs11586238 1.13 European and North American Raychaudhuri 2009 (99)
REL 2p16 rs13031237 1.21 North American Gregersen 2009 (31)
AFF3 2q11 rs10865035 1.12 UK Barton 2009 (4)
SPRED2 2p30 rs934734 1.13 European Stahl 2010 (102)
ANKRD55 5q11 rs6859219 0.78 European Stahl 2010 (102)
C5orf30 5q21 rs262321 0.88 European Stahl 2010 (102)
PXK 3p14 rs13315591 1.29 European Stahl 2010 (102)
RBPJ 4p15 rs874040 1.14 European Stahl 2010 (102)
CCR6 6q27 rs3093023 1.13 European Stahl 2010 (102)
rs3093024 1.19 Japanese Kochi 2010 (58)
IRF5 7q32 rs10488631 1.19 European Stahl 2010 (102)
BLK 8p22 rs2736340 1.14 European Orozco 2011 (85)
UBE2L3 22q11 rs5754217 1.14 European Orozco 2011 (85)
rs2298428 1.11 European Zhernakova 2011 (121)
TAGAP 6q25 rs212389 0.87 European Chen 2011 (17)
SH2B3 12q24 rs653178 1.07 European Zhernakova 2011 (121)
8q24.2 8q24 rs975730 0.93 European Zhernakova 2011 (121)
DDX6 11q23 rs10892279 0.87 European Zhernakova 2011 (121)
CD247 1q24 rs864537 0.9 European Zhernakova 2011 (121)
UBASH3A 21q22 rs11203203 1.11 European Zhernakova 2011 (121)

4. 76 Tan, Hung and Tsao
CCL21, and BLK exhibiting evidence for associa- neutrophils and synovial fibroblasts play central roles
tion (26). They also discovered 10 novel loci in the pathogenesis of joint inflammation and disease
(rs1600249, rs2736340 in BLK; rs2009094 in AFF3; progression in RA. The strong genetic association of
rs12831974 in TRHDE; rs7024727 in CCL21; HLA-DR and RA implies that the disease is, at least
rs657555 in PTPN2; rs2062583 in ARHGEF3; in part, driven by T cells. Studies from crystal structure
rs7537965 in GPR137B; rs4867947 in LCP2/C5orf; of HLA-DR molecules showed that the RA-associated
rs4547623 in GGA1/LGALS2; rs4936059 in FLI1/ QKRAA region primarily faces away from the antigen-
ETS1) associated with RA susceptibility. However, binding cleft of the DR molecule. Citrullination of
none of these associations reach genome-wide peptides triggers a stronger immune response in human
significance (P = 5 × 10 -8). It is estimated that these HLA-DR4 transgenic mice via increasing the affinity
known non-MHC risk alleles contribute between 3- to HLA-DR molecule and activating CD4+ T cells
5% of the genetic burden of RA (102) suggesting (39), suggesting HLA-DR molecules were involved
additional risk alleles remain to be identified. It is in antigen presentation. Accordingly, prevailing hy-
clear that the development of RA is dependent on potheses postulate that specific HLA-DR alleles confer
inputs from multiple loci. susceptibility to RA through 1) their involvement in
Given that the relative risks for these common presenting arthritogenic self-peptides to CD4+ T cell
variants are generally modest, it is hypothesized that (110), 2) molecular mimicry with foreign Ags (48),
rare genetic variants (with population frequency <1%) and/or 3) T cell repertoire selection (98). In addition
and/or copy number variants (CNV) may be the major to antigen presentation, most recent studies suggested
contributors to disease susceptibility (1, 35). Uddin that the SE functions as an allele-specific signal-
et al. reported genome-wide CNV burden is 2-fold transducing ligand that can polarize T cell differentia-
higher in patients with RA compared with controls tion toward Th17 cells, facilitating autoimmunity in
(114). They identified rare copy number variable mice (20).
regions including TNFAIP3, TNIP1, IRF1, ALOX5AP, In additional to class II MHC region, risk alleles
LCP2, B2M and PRKCH by using the WTCCC high- highlight genes involved in T cell activation by antigen
density SNP genotype data. The challenge now is to presenting cells including PTPN22, STAT4, IL2/IL21,
identify the remaining, genetic effects and their func- IL2RB, CD28, and CTLA4. A missense C-to-T sub-
tional roles of these RA-associated variants in the stitution at nucleotide position 1856 of PTPN22 leads
pathogenesis of RA, and to explore how they interact to substitution of tryptophan (W) for arginine (R) at
with each other as well as environmental factors to in- residue 620 of the protein product, resulting in en-
duce the development of RA. hanced regulation of T-cell receptor (TCR) signaling
In summary, the most convincing evidence for during thymic selection, permits autoantigen-specific
RA association is the HLA-DRB1 alleles expressing T cells to escape clonal deletion. STAT4, a signal
the share epitope, which has been consistently de- transducer and activator of transcription 4, encodes
monstrated in ethnically diverse populations (26, 31, a transcription factor that transduces interleukin-12
49, 58, 95, 97-99, 102, 113). STAT4, CCR6, AFF3, (IL-12), interleukin-23 (IL-23), and type I interferon
CCL21 and BLK are also important genetic risk factors cytokine signals in T cells and monocytes, leading
in Asians, European and African derived populations to T-helper type 1 (Th1) and T-helper type 17 (Th17)
(26, 31, 58, 100, 121). PADI4, FCRL3 and CD244 are differentiation, and production of interferon-γ (73,
specific risk factors in Asian populations (59, 104, 82), suggesting the critical role in the development of
105) while TNFSF14, MMEL1, CDK6, PRKCQ, a Th1 and Th17 type T-cell response. STAT4-deficient
KIF5A, SPRED2, ANKRD55, PTPN22, TNFAIP3, mice are generally resistant to models of autoimmune
TRAF1-C5, CTLA4, REL, CD40, CD28, PRDM1, CD2/ disease, including arthritis (24), highlighting its role
CD58, C5orf30, PXK, RBPJ, IRF5, UBE2L3, TAGAP, in RA pathogenesis. Although previous studies did
SH2B3, 8q24.2, DDX6, CD247, UBASH3A, IL2/IL21, not find an allele-specific role of STAT4 in gene ex-
IL2RB, AFF3, are shown to be significantly associated pression, it is quite possible that variants located in
with RA in European-derived populations (5, 7, 17, STAT4 introns could influence its gene transcription
31, 61, 85, 87, 95, 97-99, 102, 109, 121). Taken rate of its alternatively spliced forms by altering a
together, it is important to consider ethnic differences transcription factor binding site or a binding site for
in RA genetic predisposition. modified histone proteins (60).
Recent associations have also clearly implicated
Genetic Risk in Immune Pathways the interleukin-2 (IL-2) signaling pathway, a critical
cytokine involved in T cell activation and proliferation.
T Cell Pathways The IL2RB, encodes the beta unit of the interleukin-
2 receptor (IL2R) present in the moderate and high
It is well established that T cells, B cells, macrophages, affinity forms of the receptor required for signal

5. Genetic and Environmental Risk Factors in Rheumatoid Arthritis 77
transduction from IL-2 (55), was validated for genetic address the role of IL-23 variants in RA susceptibility.
association with RA in European ancestries (6). The
implicated SNP of the IL2/IL21 locus was associated B Cell Pathways
with RA and type 1 diabetes, supporting a general risk
locus for multiple autoimmune diseases (120). Func- B cells have long been considered playing an important
tional connections between IL2/IL21 and IL2RB loci role in RA since the discovery of autoantibody in se-
are clearly highlighted genetic factor involved in rum samples from RA patients. Several autoantibodies
IL-2 signaling pathway. have been described in RA. Among them, RF exhibits
T cells activation derived from naïve T cell upon 70-80% sensitivity and has been widely used in clinical
interaction of the TCR with specific peptides presented settings traditionally. ACPA, which is more specific
by MHC molecules are regulated by a delicate balance for RA compared to RF, can be detected years before
between costimulatory signals that activate T cells, the first clinical manifestations and is associated with
and inhibitory signals that attenuate harmful inflam- a more severe, erosive arthritis compared to ACPA
matory responses (19). Simultaneous recognition of negative RA patients, implying a putative role as a
the cognate MHC-peptide complex by the TCR (signal predictor for the development of RA. Though citrul-
1) and B7 costimulatory family members (CD80/ linated peptides are present in the rheumatoid syn-
CD86) by CD28 (signal 2) results in T cell activation, ovium, suggesting a possible pathogenic role of this
proliferation, and differentiation. The association autoantibody (51), there are no direct evidence for
between variants with costimulatory receptors CD28 their contribution to the pathogenesis of RA. HLA-
(99) and its inhibitory receptors CTLA4 (96) predispos- DRB1, PTPN22, TRAF1–C5, CD40, FCGR3A, STAT4,
ing to RA highlighted the critical role of costimulatory REL and PADI4 have been identified and validated in
pathways in RA pathogenesis. ACPA positive RA patients (14, 97, 100, 106, 108,
A newly identified subset of CD4 effector T 116). However, none of these loci achieved genome-
helper that produces interleukin-17 (IL-17), termed wide significant in ACPA negative RA patients. Re-
Th17 cells, have been implicated as the pivotal driving cently, one GWAS study in Sweden found that one
force of autoimmune inflammation in collagen or SNP close to the RPS12P4 locus in chromosome 2
adjuvant-induced arthritis (28, 63, 78). In RA, clinical might be considered as a candidate locus for APCA
data suggested that IL-17 is mainly involved in the negative RA (87). SE+ RA patients with co-occurrence
progression of joint damage (115) and might be a of ACPA positive at baseline had a significantly higher
future therapeutic target for RA. Polymorphism in rate of joint destruction than did other RA patients
CCR6 (rs3093024), the gene encoding chemokine (117). Intriguingly, the histology study demonstrated
(C-C motif) receptor 6 (a surface marker for Th17 that ACPA positive synoviums appeared to be char-
cells), was identified and validated with RA susce- acterized by denser lymphocyte infiltrations and a
ptibility in Japanese (58) and Caucasians (102). In- higher rate of joint destruction, whereas more exten-
terestingly, a triallelic dinucleotide polymorphism of sive fibrotic changes were apparent in ACPA negative
CCR6 (CCR6DNP) in strong linkage disequilibrium tissue (98). Taken together, RA is probably a clinical
with rs3093024 that could affect levels of CCR6 tran- syndrome consisting of at least two distinct disease
scription, was associated with the levels of IL-17 in subsets defined by the presence or absence of ACPA.
serum samples of RA patients, suggesting that CCR6 FCRL3 is a member of the Fc receptor-like
is critically involved in IL-17 driven autoimmunity family and its precise function of FCRL3 is unknown.
(58). In the development of Th17 cells, IL-23 plays A RA-associated FCRL3 promoter SNP could alters
an important role in cells expansion and maintenance the binding affinity of NF-κB and FCRL3. Inter-
(89). Case-control studies in 3 Caucasian cohorts and estingly, RA patients carrying the FCRL3 risk allele
1 Korean cohort have been conducted to investigate conferred higher FCRL3 expression on B cell surfaces
the association of IL-23 receptor (IL-23R) poly- and augmented autoantibody production compared
morphism and RA susceptibility (42, 90, 113, 118). with non-carriers, suggesting that FCRL3 might in-
However, these studies yielded either no evidence fluence the fate of B cells and augment the emergence
for association or identified SNPs of one study that of self-reactive B cells in RA patients.
were not evaluated in other independent panels. This
apparent discrepancy may due to different candidate NF-κB Signaling Pathway
SNPs genotyped in each study, inadequate power to
detect association, and ethnic variations in allele The NF-κB family, consists of p50 (NF-κB1), p52
frequencies and linkage disequilibrium patterns. (NF-κB2), p65 (RelA), RELB, and REL (c-Rel). Upon
Therefore, further studies are needed to evaluate a to stimuli, a dimer of NF-κB proteins acts as a tran-
comprehensive set of informative markers of IL-23R scription factor binds to a κB site in the promoter or
in large collections of RA case-control panels to enhancer of a target gene, controlling immune re-

6. 78 Tan, Hung and Tsao
IL2/21 IL2RB
STAT4 CCR6
B7-CD28 Th1/Th17 differentiation
CD28
MHCII-TCR
HLA-DRB1
T cell activation
PTPN22
B7-CTLA4
CTLA4
NFκB activation
CD40 PRKCQ TNFAIP3
TRAF1 TNFRSF14 REL
APC
T cell
PADI4 PTPN22 HLA-DRB1
FCGR3A REL TRAF1-C5
STAT4 CD40
B cell Autoantibody 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 pathophysiological pathways other than those current-
containing genes that are involved in NF-κB signal- ly known. Much more work remains before a complete
ing, including CD40, TRAF1, TNFAIP3, PRKCQ, understanding in the function of the causal variants
TNFRSF14 and the recent report of REL. CD40, ex- and their roles in autoimmune pathway of RA is
pressed on the cell surfaces of APCs, is a TNF receptor needed for the eventual improvement of patient care.
family member (TNFRSF5). This receptor is essential
in mediating a variety of B-cell responses, including Interaction of Genetic, Immunity and
B-cell proliferation and differentiation, with predom- Environment Factor
inant activation through NF-κB pathways (76). A
common variant at the CD40 locus showed very strong Although several potential environmental factors have
evidence for association with RA (P = 8.2 × 10 -9) in been linked to RA susceptibility or disease severity
a large GWAS meta-analysis study, including a total including coffee consumption, in particular decaf-
of >7300 autoantibody positive RA cases and >18000 feinated coffee, cigarette smoking history, exposure
matched control individuals (97). REL, encoding c- to air pollution, and environmental exposure to silica-
Rel, have recently identified as a new risk locus for containing dust (21). To date, smoking and periodon-
rheumatoid arthritis (31). A variety of genes in T cells titis are the mostly well-established environmental
are regulated by c-Rel, including CD40 and other ac- risk factors.
cepted RA susceptibility loci TNFAIP3 (95), sug- The role for smoking is first reported more than
gesting an important role of CD40/NF-κB signaling 15 years ago, and its role in RA has been highlighted
pathways in RA pathogenesis. recently by new evidence of interactions among smok-
Recent genetic discoveries have indentified ing, the presence of shared epitope, and the presence
many RA risk loci involved in autoimmune and in- of ACPA (38). The landmark study of gene-environ-
flammatory pathways (Fig. 1). Thus, it is not surpris- ment interaction was described by Klareskog and
ing that many of these loci predispose to more than colleagues (57, 88). This work demonstrated that
one autoimmune diseases including type 1 diabetes patients with RA onset within the previous year, smokers
(T1D), systemic lupus erythematosus (SLE), inflam- without HLA-DRB1*SE alleles (SE negative) were
matory bowel disease, and multiple sclerosis in 1.5 times more likely to develop ACPA positive RA
addition to RA (6, 46, 77, 94, 100), suggesting shared compared to SE negative nonsmokers. The risk of
autoimmune pathways affected by genes and en- developing ACPA positive RA is increased 21-fold in
vironment factors. On the other hand, physiological individuals who have smoking history and the pres-
functions of some associated genes, such as ANKRD55 ence of double copies of HLA-DR SE compared to
and C5orf30, are not clear yet, suggesting additional SE-negative nonsmokers (57). Subsequently, this

7. Genetic and Environmental Risk Factors in Rheumatoid Arthritis 79
AT
HLA-DRB1 CG
CG
Genetic PTPN22 AT
Smoking TA
nt
CG
CG
me
CG
on
vir
En
Autoimmunity
Autoantigen-
Citrullination
production
RA
Fig. 2. Schematic diagram of the interaction between genetic, immune and environment factors.
interaction was confirmed in three large case-control autoantigens in the lungs; thus, immune activation
studies: the Swedish Epidemiological Investigation against such posttranslationally modified proteins
of Rheumatoid Arthritis (EIRA) study, the North would be preferentially induced in individuals carrying
American RA Consortium (NARAC) study, and the HLA-DRB1 SE alleles (50) (Fig. 2).
Dutch Leiden Early Arthritis Clinic study (in total, Another interesting environmental risk factor in
1,977 cases and 2,405 controls) (50). Interestingly, the pathogenesis of RA is periodontitis. The preva-
although no interaction is seen between smoking and lence and severity of periodontitis is increased in RA
PTPN22, combinations of HLA-DRB1, PTPN22 and (18, 33, 37, 93) and this phenomenon cannot be at-
smoking confer a high odds ratio (OR = 23-25) to the tributed to secondary Sjögren syndrome (37, 62, 92).
development ACPA positive RA, highlighting that MHC On the other hand, RA disease severity, including
class II-dependent T-cell activation is of central numbers of swollen joints, serum C-reactive protein
pathogenic importance for the subset of ACPA positive levels and erythrocyte sedimentation rate are as-
RA (50). A study using three large US cohorts (64) sociated with the severity of periodontitis (74). There
failed to demonstrate the interaction among ever is also a significant correlation between the presence
smoking, SE-positivity, and the presence of ACPA in of ACPA and the presence of periodontitis in RA pa-
RA patients. However, another prospective case-control tients (79). There is a link in important inflammatory
study in US observed strong smoking-SE interaction cytokines between RA and periodontitis. Elevated
by stratifying pack-year rather than by ever (52). These serum levels of TNF, IL-1 and IL-17 are correlated
results suggest that smoking has a cumulative effect with the degree of tissue destruction in periodontitis
on RA development in SE-positive individuals. (30, 112, 119). Evidence also showed that RANK-
Recently, antibodies to the immunodominant RANKL plays an important role in inducing alveolar
citrullinated α-enolase CEP-1 epitope, a subset of the bone loss in aggressive periodontitis (8, 11, 12, 68,
ACPA response with specific autoimmunity to citrul- 105, 107, 110), which is also a crucial mechanism in
linated α-enolase, were detected in 43-63% of the RA bone erosion.
ACPA positive RA patients. In a 1,000 case- 872 con- Emerging data has revealed DNA of Porphy-
trol analysis, HLA-DRB1-SE, PTPN22 and smoking romonas gingivalis, the major bacterial cause of peri-
showed the strongest association with the anti-CEP- odontitis, is often found in gingiva from gingivalis
1–positive subset (OR = 37, compared to OR = 2 for patients (9) and synovium from RA patients (72). P.
the corresponding anti-CEP-1–negative, anti-CCP– gingivitis could induce citrullination of human fibrin-
positive subset). These results imply that citrullinated- ogen and α-enolase by endogeouns peptidylaginine
enolase is a specific citrullinated autoantigen which deiminase (111) which may also lead to the citrullina-
links smoking to genetic risk factors in the develop- tion of fibrin in the synovium (66). Presence of gp-
ment of RA (71). The possible explanation for the 39, cartilage antigen targeted by the autoimmune
strong interaction between smoking, HLA-DRB1 and response in rheumatoid synovitis, was also found in
ACPA is that long-term exposure to cigarette to- gingival tissue from periodontitis patients (80).
bacco would accelerate the presence of citrullinated Interestingly, HLA-DRB1, the most relevant

8. 80 Tan, Hung and Tsao
genetic risk factor of RA, has been associated with 2. Bali, D., Gourley, S., Kostyu, D.D., Goel, N., Bruce, I., Bell, A.,
development of severe and rapidly progressive peri- Walker, D.J., Tran, K., Zhu, D.K., Costello, T.J., Amos, C.I. and
Seldin, M.F. Genetic analysis of multiplex rheumatoid arthritis
odontal disease (10). Therefore, the production of families. Genes Immun. 1: 28-36, 1999.
auto-antigens in gingival and synovium may predis- 3. Bartold, P.M., Marino, V., Cantley, M. and Haynes, D.R. Effect of
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Furthermore, animal studies showed that introducing ment of rheumatoid arthritis. J. Clin. Periodontol. 37: 405-411,
2010.
heat-killed P. gingivalis in rats could accelerate the 4. Barton, A., Eyre, S., Ke, X., Hinks, A., Bowes, J., Flynn, E., Martin,
occurrence of adjuvant-induced arthritis (3). However, P., YEAR Consortium, BIRAC Consortium, Wilson, A.G., Morgan,
it is unclear at present whether the presence of P. A.W., Emery, P., Steer, S., Hocking, L.J., Reid, D.M., Harrison, P.,
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and ACPA production. 2522, 2009.
Another possible environmental risk factor of 5. Barton, A., Thomson, W., Ke, X., Eyre, S., Hinks, A., Bowes, J.,
RA is insecticide usage. Early studies have shown Gibbons, L., Plant, D., Wellcome Trust Case Control Consortium,
Wilson, A.G., Marinou, I., Morgan, A., Emery, P., YEAR consortium,
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that active components of insecticides and/or their Worthington, J. Re-evaluation of putative rheumtoid arthritis
interaction with other environmental agents (including susceptibility genes in the post-genome wide assocition study era
microbial products) may affect the immune system and hypothesis of a key pathway underlying susceptibility. Hum.
Mol. Genet. 17: 2274-2279, 2008.
(22, 44, 69). However, specific environmental triggers
6. Barton, A., Thomson, W., Ke, X., Eyre, S., Hinks, A., Bowes, J.,
for RA are yet to be identified (83, 84). Recently, one Plant, D., Gibbons, L.J., Wellcome Trust Case Control Consortium,
observational study shows the hazard ratio of RA in- YEAR Consortium, BIRAC Consortium, Wilson, A.G., Bax, D.E.,
cidence increased in post-menopausal women who Morgan, A.W., Emery, P., Steer, S., Hocking, L., Reid, D.M.,
were exposed to greater frequency (≥ 6 times per Wordsworth, P., Harrison, P. and Worthington, J. Rheumatoid
arthritis susceptibility loci at chromosomes 10p15, 12q13 and
year) or greater duration (≥ 20 years) of insecticides 22q13. Nat. Genet. 40: 1156-1159, 2008.
(91). These findings suggest a possible interaction 7. Begovich, A.B., Carlton, V.E., Honigberg, L.A., Schrodi, S.J.,
between environmental exposure to particular chemi- Chokkalingam, A.P., Alexander, H.C., Ardlie, K.G., Huang, Q.,
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further replication studies. Saiki, R.K., Catanese, J.J., Leong, D.U., Garcia, V.E., McAllister,
L.B., Jeffery, D.A., Lee, A.T., Batliwalla, F., Remmers, E., Criswell,
L.A., Seldin, M.F., Kastner, D.L., Amos, C.I., Sninsky, J.J. and
Conclusion Gregersen, P.K. A missense single-nucleotide polymorphism in a
gene encoding a protein tyrosine phosphatase (PTPN22) is associ-
Gene-immunity-environment interactions are key ated with rheumatoid arthritis. Am. J. Hum. Genet. 75: 330-337,
2004.
features in the development of RA. Inheritance of
8. Belibasakis, G.N., Emingil, G., Saygan, B., Turkoglu, O., Atilla, G.
multiple gene variants involved in T-cell, B-cell, and and Bostanci, N. Gene expression of transcription factor NFATc1
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to have broken immune tolerance upon environmental 9. Berglundh, T. and Donatim, M. Aspects of adaptive host response
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10. Bonfil, J.J., Dillier, F.L., Mercier, P., Reviron, D., Foti, B., Sambuc,
a growing number of gene variants have been identified R., Brodeur, J.M. and Sedarat, C. A case control study on the role
predisposing to RA in multiple ethnic groups including of HLADR4 in severe periodontitis and rapidly progressive peri-
HLA-DRB1, STAT4, TNFAIP3, CCR6, TRAF1, and odontitis. J. Clin. Periodontol. 26: 77-84, 1999.
BLK. Patients carrying the HLA-DRB1 shared epitope 11. Bostanci, N., Ilgenli, T. and Emingil, G. Gingival crevicular fluid
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cluding smoking and periodontitis. The identification 12. Bostanci, N., Ilgenli, T., Emingil, G., Afacan, B., Han, B., Töz, H.,
of environmental factors that modify disease risk may Berdeli, A., Atilla, G., McKay, I.J., Hughes, F.J. and Belibasakis,
impact on risk reduction in disease susceptibility as G.N. Differential expression of receptor activator of nuclear factor-
well as in modulating the clinical course of the disease. κB ligand and osteoprotegerin mRNA in periodontal diseases. J.
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Understand functional consequences of disease-as-
13. Burr, M.L., Naseem, H., Hinks, A., Eyre, S., Gibbons, L.J., Bowes,
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