Research Article2009 Joint Meeting of Spondyloarthritis Research and Therapy Network (SPARTAN) and International Genetics of Ankylosing Spondylitis (IGAS)

The Genetic Basis of Spondyloarthritis: SPARTAN/IGAS 2009

DAVID M. EVANS, JOHN D. REVEILLE, MATTHEW A. BROWN, VINOD CHANDRAN, DAFNA D. GLADMAN, TAMMY M. MARTIN, DERMOT McGOVERN, PAUL WORDSWORTH and ROBERT D. INMAN
The Journal of Rheumatology December 2010, 37 (12) 2626-2631; DOI: https://doi.org/10.3899/jrheum.100892

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Abstract

A joint meeting was held in July 2009 in Houston, Texas, of members of the Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), and members of International Genetics of AS (IGAS), founded in 2003 to encourage and coordinate studies internationally in the genetics of AS. The general topic was the genetic basis of SpA, with presentations on the future of human genetic studies; microbes, SpA, and innate immunity; susceptibility of AS to the major histocompatibility complex (MHC) and non-MHC; and individual discussions of the genetics of psoriasis and psoriatic arthritis, uveitis, inflammatory bowel disease, and enteropathic arthritis. Summaries of those discussions are presented.

A joint meeting was held in July 2009 in Houston, Texas, USA, of members of the Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), and members of International Genetics of AS (IGAS), founded in 2002 to encourage and coordinate studies internationally in the genetics of AS. The general topic was the genetic basis of SpA, with presentations on the future of human genetic studies; microbes, SpA, and innate immunity; susceptibility of AS to the major histocompatibility complex (MHC) and non-MHC; and individual discussions of the genetics of psoriasis and psoriatic arthritis (PsA), uveitis, inflammatory bowel disease (IBD) and enteropathic arthritis.

Future of Human Genetic Studies

David M. Evans, PhD (University of Bristol, Bristol, UK) first explained that genetic mapping studies of complex diseases had not met with success until very recently, generally because sample sizes were insufficient and coverage of common genetic variation in the genome was inadequate1. Then 3 developments made genome-wide association studies (GWAS) a reality: large cohorts, high throughput genotyping, and the haplotype map (HapMap; International HapMap Project)2. Dr. Evans briefly reviewed current knowledge of the genetics of AS, and suggested that important next steps would be fine mapping to better localize the variants involved, as well as in vitro and animal studies to identify the functional variants involved.

Dr. Evans discussed the possibility of genetic testing in complex diseases, noting difficulty because the effects of individual variants were so small; however, if several predisposing genetic and environmental factors were considered, it might be possible to predict disease risk in conditions like AS where there exists a variant of large effect (i.e., HLA-B27).

He noted that although the current paradigm in diagnostic testing was to test only variants known to affect disease risk, extra information might be gathered by genotyping individuals across their genome and constructing a risk score based on thousands of putative genetic variants. He showed that constructing a genome-wide score did increase the degree to which individuals with and without disease could be discriminated3.

Dr. Evans briefly discussed how new findings from GWAS could be used to inform classical observational epidemiology through a technique called Mendelian randomization. Because randomized clinical trials are not always possible or ethical, Mendelian randomization could be used as an alternative to investigate whether an exposure-disease association reflects an underlying causal relationship. The approach is based on Mendel’s law of independent assortment (i.e., inheritance of a trait is independent with respect to other traits) so that individuals are in essence randomized into 3 “exposures” according to their genotype, and that their genotype at this locus should be random (under certain assumptions) with respect to other confounding factors. As an example, he showed how a variant in the nicotinic receptor could be used as a proxy for smoking status (a modifiable environmental exposure) and how this could then be related to functional impairment on the Bath AS Functional Index (BASFI). If the variant in the nicotinic receptor was associated with functional impairment, then it suggests that smoking affects severity of AS, whereas if there was no correlation between the variant and BASFI, then it would suggest that the relationship between smoking and severity is correlational only.

The MHC and AS Susceptibility

John D. Reveille, MD (University of Texas, Houston, TX, USA) displayed a schematic of the MHC, which contains over 220 genes divided into 3 classes of molecules and which has the greatest single effect on susceptibility to AS — particularly HLA-B27. The arthritogenic peptide hypothesis suggests that disease results from the ability of HLA-B27 to bind a unique peptide or a set of antigenic peptides, and HLA-B27 misfolding generates the proinflammatory unfolded protein response. Over 62 HLA-B27 subtypes have evolved and migrated along ethnogeographic lines, with HLA-B*2705, the parent subtype, being the most common throughout the world, and small numbers of most other subtypes centered in particular areas of the globe (such as B*2703 in Africa; B*2707 in the Middle East; B*2702 in Europe; B*2704 in East Asia; and B*2706 in Southeast Asia).

Although numerous HLA-B27 subtypes exist, only HLA-B*2705, B*2702, B*2704, and B*2707 have been definitely shown to be associated with AS. HLA-B*2706 and B*2709 are not associated with AS, and in fact may be protective, which some have attributed to the last Asp at position 116. However, AS-associated HLA-B*2707 also lacks Asp116 and shows preference for peptides with non-polar C-terminal residues. Examination of the relationships between the peptide specificity of B*2707 and those of the disease-associated B*2705 and the non-associated subtypes found that the B*2707-bound repertoire was as different from that of B*2705 as from those of B*2706, B*2709, or the 2 latter subtypes from each other4.

HLA-B27 can adopt novel conformations, resulting in differential accessibility of cysteine residues, which can explain the propensity to homodimerize. The cysteine exposure in the HLA-B27 heavy chain is also affected by residues within the 114 and 116 regions, thereby possibly providing a potential biochemical basis for the association of HLA-B27 subtypes with AS5.

Dr. Reveille reminded the group that while less than 5% of HLA-B27-positive people develop SpA, 20% of HLA-B27-positive relatives of AS patients will develop SpA. And although family studies suggest that HLA-B27 forms only about 16%–40% of the overall risk for SpA, the entire effect of the MHC is about 50%. Other HLA-B alleles that have been implicated in AS susceptibility include B*4001 (B60; White and Asian cohorts)6 and B*1403 (West Africa)7.

Non-MHC and AS Susceptibility

Matthew Brown, MBBS, MD, FRACP (Diamantina Institute, University of Queensland, Brisbane, Australia) began with an update of the Australo-Anglo-American Spondylitis Consortium (TASC) GWAS, introduced briefly elsewhere in this supplement8. In the study in question, several previously unknown loci were newly identified. Three markers for the 2p15 “gene desert” achieved genome-wide significance in the discovery set [rs10865331 (p = 6.1 x 10−15), rs10865332 (p = 3.5 x 10−10), and rs4672503 (p = 9.3 x 10−10)] and 2 were genotyped in the confirmation set [rs4672495 (p = 8.4 x 10−4), rs10865331 (p = 5.5 x 10−6)]; the combined association was very strong for rs4672495 (p = 3.2 x 10−9) and rs10865331 (p = 1.9 x 10−19). Of note, 2p15 has not been associated previously with any disease.

Three markers for the 21q22 gene desert also achieved genome-wide significance in the discovery set [rs2242944 (p = 2.7 x 10−14), rs2836878 (p = 4.9 x 10−12), rs378108 (p = 6.1 x 10−11)] and one was genotyped in the confirmation set [rs2242944 (p = 5.6 x 10−7)], with a strong combined association for rs2242944 (p = 8.3 x 10−20). 21q22 had been associated previously with pediatric IBD9; however, the association did not change with exclusion of IBD cases in our study [n = 1159 cases; rs2242944 (p = 1.3 x 10−9)].

The peak association for the known loci ERAP1 (endoplasmic reticulum aminopeptidase) lies in a 4.6 kb region between rs27529 to rs469758, achieving p < 10−11. Two noncoding single-nucleotide polymorphisms (SNP) also lie in this region, including rs31087. ERAP1 has 2 known functions: it cleaves cytokine receptors (e.g., TNFR1, IL1R2, IL6Rα) from the cell surface; and it trims peptides before presentation by HLA Class 1 molecules.

The strongest associated SNP for the known locus IL23R is rs11209026 (p = 9.1 x 10−14). Strong association also was observed with rs11465817 (p = 1.2 x 10−10), compared with rs11209026 (p = 2.3 x 10−9). Among East Asians, IL23R is not associated with Crohn’s disease (CD) in Japanese10, nor with psoriasis in Han Chinese11 or AS in Koreans12 or Han Chinese13.

The strongest associations for IL1R2 were with genotyped markers at rs2310173 (p = 8.3 x 10−6) and imputed markers at rs10185424 (p = 5.4 x 10−6); rs2310173 also was associated with AS in the replication study (p = 0.018) and overall (p = 4.8 x 10−7). For ANTXR2, rs4333130 was associated with AS in both the discovery cohort (p = 7.5 x 10−7) and replication cohort (p = 0.029), and overall (p = 9.3 x 10−8).

Several other genes (TNFR1, TRADD, CARD9, STAT3, TNFSF15) have shown moderate associations that have not been fully established. In most GWAS studies, study power remains limited and further work must be done.

Genetics of Psoriasis and Psoriatic Arthritis

Vinod Chandran, MBBS, MD, DM, on behalf of Dafna D. Gladman, MD, FRCPC (University of Toronto, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Canada), outlined the systematic approach to identifying genetic factors in disease14; showed that the recurrence risk ratio is increased in psoriasis and psoriatic arthritis (PsA)15,16; and presented a summary of results from linkage studies in psoriasis that have identified 10 psoriasis susceptibility loci, as well as the result of a single linkage study in PsA17,18. He summarized association studies in psoriasis and PsA and described the largest GWAS survey in psoriasis that revealed an association with Th17 and nuclear factor-κB (NF-κB) pathways, in addition to confirming the strong association with HLA-Cw619. Associations of genomic copy number variants with psoriasis (ß-defensin, late cornified envelope LCE3B and LCE3C genes) were discussed.

Among several environmental factors that appear to affect development of disease, smoking reportedly has a major effect: the time to development of PsA decreases with smoking prior to psoriasis onset, but increases with smoking after psoriasis onset20. Also, the association between IL13 polymorphisms and PsA is modified by smoking21.

Moreover, the risk allele, HLA-Cw*0602, is reportedly associated with early onset psoriasis, higher incidence of guttate or streptococcal-induced flares, koebnerization, and a more severe disease course22. In PsA, HLA alleles associated with patterns of joint involvement as well as joint damage progression and protection were discussed23.

Dr. Chandran concluded by suggesting that genetic studies have the potential to help us understand disease pathogenesis and identify pharmacologic targets, and may help predict disease course and response to therapy.

Genetics of Uveitis

Tammy M. Martin, PhD (Department of Ophthalmology, Oregon Health and Science University, Portland, OR, USA) began with a discussion of Mendelian uveitic disease: studying the genotype/phenotype relationships of rare autosomal dominant forms of uveitis can provide insights into the disease, and different variations in the same gene can lead to dominant as well as complex disease phenotypes. She noted that several NOD-like receptors (nucleotide-binding oligomerization domain) have been implicated in diseases such as IBD, asthma, CD, and Blau syndrome, and said that in a cohort of Blau syndrome patients with NOD2 mutation, ocular involvement was the most relevant morbidity24. The discovery of NOD2 mutations in Blau syndrome has led to ongoing studies in animal models.

Dr. Martin reviewed several strong MHC Class I associations [HLA-A29, birdshot retinochoroidopathy; HLA-B15 and HLA-B51, Behçet’s disease; HLA-B27, acute anterior uveitis (AAU)] before discussing the challenges of uveitis genetic studies: clinical descriptors are variably used; subjects are not followed longitudinally; and the same uveitis phenotype may be present in the absence or presence of systemic disease, and may be episodic. Uveitis nomenclature for reporting clinical trial data was standardized following an international workshop in 200525.

Linkage mapping was used in the first genome-wide scan for AAU26, in which regions with linkage to AAU [chromosomes 6p (MHC) and 1q] also were found to have linkage to AS; a gene on chromosome 9q may be uniquely implicated in AAU. In a candidate-gene analysis, the relationship of IL23R SNP to genetic risk in uveitis was studied because of the well established clinical association of uveitis with IBD, psoriasis, and AS; 6 of 11 IL23R SNP were associated with AAU. Two ERAP1 SNP, previously identified for AS susceptibility, have also been associated with AAU; however, a larger cohort is needed to verify this finding.

Dr. Martin presented interesting work with KIR, which are expressed on natural killer cells and some T cells and transmit activating (aKIR) or inhibitory (iKIR) signals to these cells. In a study of 143 AAU patients and 429 controls, there were no differences in KIR gene frequencies or genotypes between AAU and controls; however, a trend was noted toward decreased aKIR genes in AAU with SpA compared to controls27.

In a GWAS survey of uveitis patients versus AS patients with/without uveitis, no differences were noted at known AS loci (MHC, IL23R, ERAP1, 2p15, 21q22, IL1R2, ANTXR2); however, some positive associations indicate that we can detect uveitis-specific genetic factors. Alternative comparisons and further research is needed.

Genetics of Inflammatory Bowel Disease

Dermot McGovern, MD, PhD, MRCP (Cedars-Sinai Medical Center, Los Angeles, CA, USA) summarized the recent advances in IBD, CD, and ulcerative colitis (UC) genetics and how these novel insights help us not only to better understand the pathogenesis of IBD but also may lead to a more sophisticated molecular classification of the heterogeneous conditions within IBD as well as highlighting novel pathways for future therapeutic intervention in IBD.

Variants of the NOD2 gene and the 5q31 cytokine cluster were associated with CD in the pre-GWAS era28,29, and after several GWAS studies and a metaanalysis, a total of 32 loci had been confirmed as CD susceptibility regions30,31,32,33. These findings highlighted novel pathogenic pathways including autophagy and the IL23R/Th17 pathway32. Dr. McGovern also discussed a GWAS in patients with UC, where UC loci were identified at chromosomes 1p36 and 12q1534.

After summarizing IBD-associated genetic findings organized by cellular immune mechanisms, Dr. McGovern emphasized that additional studies are required following identification of loci in GWAS studies. These include both more detailed haplotypic analysis of the individual loci as well as appropriate pathway analyses such as have been performed with IL23R itself33 and the extended IL23/IL17 pathway35. Further, “functional” studies are also necessary to determine how these loci alter disease susceptibility; one recent example of such a study demonstrated that TL1A (encoded by the IBD gene TNFSF15) is expressed differentially by haplotype, ethnic background, and antibody response36.

Future genetic work in IBD should include characterizing the complete extent and causative SNP of loci, conducting larger and smarter GWAS studies, and analyzing both gene-environment and gene-gene interactions.

Genetics of Enteropathic Arthritis

Paul Wordsworth, MA, MB, FRCP (University of Oxford, Headington, UK) reminded the group that the presentation of AS is highly variable and often insidious, which contributes to diagnostic delay. Unsurprisingly, where coexistent active IBD is observed, involvement of the axial skeleton may be missed. In his series of over 3000 subjects with AS, about 6% also have IBD, and many patients with IBD have peripheral and/or axial arthritis37. The prevalence of peripheral arthritis was reviewed among patients with IBD (n = 976 with UC, and n = 483 with CD) attending the Oxford (UK) IBD clinic. Type 1 arthropathy (typically oligoarticular and self-limiting) affects about 3.6% of those with UC and 6% of those with CD; Type 2 arthropathy (typically polyarticular and persistent) affects about 2.5% of those with UC and 4% of those with CD38. Further, these 2 clinically distinct forms of arthropathy had distinctive immunogenetic associations (Type 1 with HLA-B27, -B35, and –DRB1*0103; Type 2 with HLA-B4439). In a subgroup of patients with CD of at least 5 years’ duration, suggestive magnetic resonance image (MRI) evidence of sacroiliitis was observed in over one-third of patients. HLA-B27 correlated better with the presence of clinical AS than with MRI sacroiliitis alone40. The relevance of these findings should be tested in longitudinal studies.

Prof. Wordsworth reviewed results from the Wellcome Trust Case-Control Consortium (WTCCC) GWAS, particularly the involvement of ERAP1 (also know as ARTS 1) and IL23R with AS41. The Oxford Spondyloarthropathy Research Group extended the WTCCC study of IL23R to 730 further AS cases and combined their results in a meta-analysis, which confirmed the association with AS (rs11209026; OR = 0.61, p < 10−10)42. This association is robust to stratification on the presence of IBD and/or psoriasis, indicating that the association with this coding SNP is likely to be the primary association with AS42. Other genes that are associated with both IBD and AS include CARD9, an important component of the innate immune system, linking infection and NF-κB activation43. The number of genetic associations common to both IBD and AS is likely to increase with the imminent release of further GWAS data in both conditions, highlighting the likely common genetic background to these disorders, which also show substantial clinical overlap.

Microbes, Spondyloarthritis, and Innate Immunity

Robert D. Inman, MD, FRCPC, FACP, FRCP (Toronto Western Hospital, Toronto, Canada) spoke of SpA as an interplay of genes and germs, citing 2 studies: target-tissue injury in the postinfectious sequelae of Salmonella in reactive arthritis (ReA) that suggested a pathogen-host interaction44; and a study of host determinants of severity in experimental Chlamydia-induced arthritis45. Further, a genetically defined early host immune response to an arthritogenic pathogen may result in either transient inflammation or chronic joint injury, showing results from a study of interferon-γ dysregulation in patients with AS46. In a study of the Rac gene in neutrophils and Toll-like receptor 4 (TLR4) in mice, Rac deficiency was associated with a decrease in severity of acute Chlamydia-induced arthritis and an increase in severity of chronic Chlamydia-induced arthritis, indicating that innate immunity, the first line of host defense against pathogens, sets the stage for ReA. The data also demonstrated that Chlamydia upregulation of TLR4 in neutrophils depends on Rac47.

Two separate studies in mice were discussed: one where pathogen-derived TLR2 ligands promoted proliferation of dysfunctional Tregs (regulatory T lymphocytes) paralleled by temporarily abrogated suppression, thus failing to suppress an immune response to acute infection48; and a second where TLR2 deficiency was associated with increased arthritis severity and a TLR4 deficiency with decreased arthritis severity49. He also discussed a study of 592 people who developed acute gastroenteritis following an outbreak of Salmonella in Ontario in 2005: of 104 people who responded to the survey, 62 reported extraintestinal symptoms consistent with ReA. Genotyping of patients and controls demonstrated that TRL2 polymorphisms are associated with acute ReA50.

Recognizing the plasticity of the immune response (genetically defined or not) is important because environmental exposure can reverse an inherent resistance to ReA, resulting in a susceptible phenotype51. In an individual who is B27-positive, or who has certain allelic variants of the ERAP1 or IL23R genes, the immune stage is set for the development of SpA. Ongoing research into gene-environment interactions in SpA should look broadly at genetic susceptibility and at potential environmental factors.

Future Plans of SPARTAN and IGAS

SPARTAN and IGAS will continue to support clinical research projects in SpA. SPARTAN’s next Annual Research and Education meeting will be held July 23–24, 2010, in Houston, TX (see www.spartangroup.org). The next meeting of IGAS will be held in Shanghai in March 2011, to be organized by Prof. Huji Xu.

Acknowledgment

The authors thank Amanda Pacia, SPARTAN Association Manager, San Francisco, CA, for her help in the organization of this meeting, and Linda Melvin for writing assistance.

REFERENCES

  1. 1.↵
    1. Glazier AM,
    2. Nadeau JH,
    3. Aitman TJ
    . Finding genes that underlie complex traits. Science 2002;298:2345–9.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Manolio TA,
    2. Brooks LD,
    3. Collins FS
    . A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008;118:1590–605.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Evans DM,
    2. Visscher PM,
    3. Wray NR
    . Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet 2009;18:3525–31.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Gomez P,
    2. Montserrat V,
    3. Marcilla M,
    4. Paradela A,
    5. de Castro JA
    . B*2707 differs in peptide specificity from B*2705 and B*2704 as much as from HLA-B27 subtypes not associated to spondyloarthritis. Eur J Immunol 2006;36:1867–81.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Fussell H,
    2. Nesbeth D,
    3. Lenart I,
    4. Campbell EC,
    5. Lynch S,
    6. Santos S,
    7. et al.
    Novel detection of in vivo HLA-B27 conformations correlates with ankylosing spondylitis association. Arthritis Rheum 2008;58:3419–24.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Robinson WP,
    2. van der Linden SM,
    3. Khan MA,
    4. Rentsch HU,
    5. Cats A,
    6. Russell A,
    7. et al.
    HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum 1989;32:1135–41.
    OpenUrlPubMed
  7. 7.↵
    1. Lopez-Larrea C,
    2. Mijiyawa M,
    3. Gonzalez S,
    4. Fernandez-Morera JL,
    5. Blanco-Gelaz MA,
    6. Martinez-Borra J,
    7. et al.
    Association of ankylosing spondylitis with HLA-B*1403 in a West African population. Arthritis Rheum 2002;46:2968–71.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Weisman M,
    2. Learch TJ,
    3. Baraliakos X,
    4. Chandran V,
    5. Gladman DD,
    6. Raychaudhuri SP,
    7. et al.
    Current controversies in spondyloarthritis: SPARTAN. J Rheumatol 2010;37:2617–23.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Kugathasan S,
    2. Baldassano RN,
    3. Bradfield JP,
    4. Sleiman PM,
    5. Imielinski M,
    6. Guthery SL,
    7. et al.
    Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 2008;40:1211–5.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Yamazaki K,
    2. Onouchi Y,
    3. Takazoe M,
    4. Kubo M,
    5. Nakamura Y,
    6. Hata A
    . Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet 2007;52:575–83.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Zhang Y,
    2. Goss AM,
    3. Cohen ED,
    4. Kadzik R,
    5. Lepore JJ,
    6. Muthukumaraswamy K,
    7. et al.
    A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat Genet 2008;40:862–70.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Sung IH,
    2. Kim TH,
    3. Bang SY,
    4. Kim TJ,
    5. Lee B,
    6. Peddle L,
    7. et al.
    IL-23R polymorphisms in patients with ankylosing spondylitis in Korea. J Rheumatol 2009;36:1003–5.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Davidson SI,
    2. Wu X,
    3. Liu Y,
    4. Wei M,
    5. Danoy PA,
    6. Thomas G,
    7. et al.
    Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum 2009;60:3263–8.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Burton PR,
    2. Tobin MD,
    3. Hopper JL
    . Key concepts in genetic epidemiology. Lancet 2005;366:941–51.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Rahman P,
    2. Elder JT
    . Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005;64 Suppl 2:ii37–9; discussion ii40–1.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Chandran V,
    2. Schentag CT,
    3. Brockbank JE,
    4. Pellett FJ,
    5. Shanmugarajah S,
    6. Toloza SM,
    7. et al.
    Familial aggregation of psoriatic arthritis. Ann Rheum Dis 2009;68:664–7.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Duffin KC,
    2. Chandran V,
    3. Gladman DD,
    4. Krueger GG,
    5. Elder JT,
    6. Rahman P
    . Genetics of psoriasis and psoriatic arthritis: update and future direction. J Rheumatol 2008;35:1449–53.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Karason A,
    2. Gudjonsson JE,
    3. Upmanyu R,
    4. Antonsdottir AA,
    5. Hauksson VB,
    6. Runasdottir EH,
    7. et al.
    A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. Am J Hum Genet 2003;72:125–31.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Nair RP,
    2. Duffin KC,
    3. Helms C,
    4. Ding J,
    5. Stuart PE,
    6. Goldgar D,
    7. et al.
    Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappa B pathways. Nat Genet 2009;41:199–204.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Rakkhit T,
    2. Wong B,
    3. Nelson TS,
    4. Hansen CB,
    5. Papenfuss JS,
    6. Panko J,
    7. et al.
    Time to development of psoriatic arthritis decreases with smoking prior to psoriasis onset and increases with smoking after psoriasis onset [abstract]. J Invest Dermatol 2007;127 S52:310.
    OpenUrl
  21. 21.↵
    1. Duffin KC,
    2. Freeny IC,
    3. Schrodi SJ,
    4. Wong B,
    5. Feng BJ,
    6. Soltani-Arabshahi R,
    7. et al.
    Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking. J Invest Dermatol 2009;129:2777–83.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Gudjonsson JE,
    2. Karason A,
    3. Runarsdottir EH,
    4. Antonsdottir AA,
    5. Hauksson VB,
    6. Jonsson HH,
    7. et al.
    Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients — an analysis of 1019 HLA-C- and HLA-B-typed patients. J Invest Dermatol 2006;126:740–5.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Gladman DD,
    2. Farewell VT,
    3. Kopciuk KA,
    4. Cook RJ
    . HLA markers and progression in psoriatic arthritis. J Rheumatol 1998;25:730–3.
    OpenUrlPubMed
  24. 24.↵
    1. Rose CD,
    2. Wouters CH,
    3. Meiorin S,
    4. Doyle TM,
    5. Davey MP,
    6. Rosenbaum JT,
    7. et al.
    Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 2006;54:3337–44.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Jabs DA,
    2. Nussenblatt RB,
    3. Rosenbaum JT
    . Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005;140:509–16.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Levinson RD,
    2. Martin TM,
    3. Luo L,
    4. Ashouri E,
    5. Rosenbaum JT,
    6. Smith JR,
    7. et al.
    Genomewide scan in acute anterior uveitis: similarities and differences with genes associated with ankylosing spondylitis [abstract]. Arthritis Rheum 2009;60 Suppl:1231.
    OpenUrl
  27. 27.↵
    1. Austin CR,
    2. Lutt JR,
    3. Rajalingam R
    . Killer cell immunoglobulin-like receptors in HLA-B27-associated acute anterior uveitis, with and without axial spondyloarthropathy. Invest Ophthalmol Vis Sci 2010;51:1505–10.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Hugot JP,
    2. Chamaillard M,
    3. Zouali H,
    4. Lesage S,
    5. Cezard JP,
    6. Belaiche J,
    7. et al.
    Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599–603.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Rioux JD,
    2. Daly MJ,
    3. Silverberg MS,
    4. Lindblad K,
    5. Steinhart H,
    6. Cohen Z,
    7. et al.
    Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001;29:223–8.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Yamazaki K,
    2. McGovern D,
    3. Ragoussis J,
    4. Paolucci M,
    5. Butler H,
    6. Jewell D,
    7. et al.
    Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 2005;14:3499–506.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Rioux JD,
    2. Xavier RJ,
    3. Taylor KD,
    4. Silverberg MS,
    5. Goyette P,
    6. Huett A,
    7. et al.
    Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007;39:596–604.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Parkes M,
    2. Barrett JC,
    3. Prescott NJ,
    4. Tremelling M,
    5. Anderson CA,
    6. Fisher SA,
    7. et al.
    Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 2007;39:830–2.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Barrett JC,
    2. Hansoul S,
    3. Nicolae DL,
    4. Cho JH,
    5. Duerr RH,
    6. Rioux JD,
    7. et al.
    Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 2008;40:955–62.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Silverberg MS,
    2. Cho JH,
    3. Rioux JD,
    4. McGovern DP,
    5. Wu J,
    6. Annese V,
    7. et al.
    Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 2009;41:216–20.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. McGovern DP,
    2. Rotter JI,
    3. Mei L,
    4. Haritunians T,
    5. Landers C,
    6. Derkowski C,
    7. et al.
    Genetic epistasis of IL23/IL17 pathway genes in Crohn’s disease. Inflamm Bowel Dis 2009;15:883–9.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Michelsen KS,
    2. Thomas LS,
    3. Taylor KD,
    4. Yu QT,
    5. Mei L,
    6. Landers CJ,
    7. et al.
    IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One 2009;4:e4719.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Holden W,
    2. Orchard T,
    3. Wordsworth P
    . Enteropathic arthritis. Rheum Dis Clin North Am 2003;29:513–30.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Orchard TR,
    2. Wordsworth BP,
    3. Jewell DP
    . Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998;42:387–91.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Orchard TR,
    2. Thiyagaraja S,
    3. Welsh KI,
    4. Wordsworth BP,
    5. Hill Gaston JS,
    6. Jewell DP
    . Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology 2000;118:274–8.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Orchard TR,
    2. Holt H,
    3. Bradbury L,
    4. Hammersma J,
    5. McNally E,
    6. Jewell DP,
    7. et al.
    The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn’s disease. Aliment Pharmacol Ther 2009;29:193–7.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Burton PR,
    2. Clayton DG,
    3. Cardon LR,
    4. Craddock N,
    5. Deloukas P,
    6. Duncanson A,
    7. et al.
    Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39:1329–37.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Karaderi T,
    2. Harvey D,
    3. Farrar C,
    4. Appleton LH,
    5. Stone MA,
    6. Sturrock RD,
    7. et al.
    Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series. Rheumatology 2009;48:386–9.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Pointon JJ,
    2. Harvey D,
    3. Karaderi T,
    4. Appleton LH,
    5. Farrar C,
    6. Stone MA,
    7. et al.
    Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes Immun 2010;11:490–6.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Thomson GT,
    2. DeRubeis DA,
    3. Hodge MA,
    4. Rajanayagam C,
    5. Inman RD
    . Post-Salmonella reactive arthritis: late clinical sequelae in a point source cohort. Am J Med 1995;98:13–21.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Tse SM,
    2. Mason D,
    3. Botelho RJ,
    4. Chiu B,
    5. Reyland M,
    6. Hanada K,
    7. et al.
    Accumulation of diacylglycerol in the Chlamydia inclusion vacuole: possible role in the inhibition of host cell apoptosis. J Biol Chem 2005;280:25210–5.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Smith JA,
    2. Barnes MD,
    3. Hong D,
    4. DeLay ML,
    5. Inman RD,
    6. Colbert RA
    . Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferon-gamma dysregulation. Arthritis Rheum 2008;58:1640–9.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Zhang X,
    2. Glogauer M,
    3. Zhu F,
    4. Kim TH,
    5. Chiu B,
    6. Inman RD
    . Innate immunity and arthritis: neutrophil Rac and toll-like receptor 4 expression define outcomes in infection-triggered arthritis. Arthritis Rheum 2005;52:1297–304.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Sutmuller RP,
    2. den Brok MH,
    3. Kramer M,
    4. Bennink EJ,
    5. Toonen LW,
    6. Kullberg BJ,
    7. et al.
    Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006;116:485–94.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Horai R,
    2. Saijo S,
    3. Tanioka H,
    4. Nakae S,
    5. Sudo K,
    6. Okahara A,
    7. et al.
    Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 2000;191:313–20.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Tsui FW,
    2. Xi N,
    3. Rohekar S,
    4. Riarh R,
    5. Bilotta R,
    6. Tsui HW,
    7. et al.
    Toll-like receptor 2 variants are associated with acute reactive arthritis. Arthritis Rheum 2008;58:3436–8.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Inman RD,
    2. Chiu B
    . Heavy metal exposure reverses genetic resistance to Chlamydia-induced arthritis. Arthritis Res Ther 2009;11:R19.
    OpenUrlCrossRefPubMed
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