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Genetics of susceptibility and treatment response in psoriatic arthritis

Nature Reviews Rheumatology volume 7, pages 718–732 (2011)Cite this article

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Abstract

Psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis, has a wide spectrum of disease severity. The clinical heterogeneity in PsA probably reflects substantial genetic heterogeneity. In recent years, many genes that contribute to the pathogenesis of psoriasis and PsA have been identified, especially in Western cohorts. Emerging evidence from functional studies of candidate genes identified by genome-wide association studies is suggestive of an integrated, multi-tiered pathogenic model, comprising distinct signaling networks that affect skin barrier function, innate immune responses (involving NFκB and interferon signaling), and adaptive immune responses (involving CD8+ T cells and type 17 T-helper-cell signaling). Although several genes—and variants thereof—within these pathways have been associated with susceptibility to psoriasis and PsA, replication in large multiethnic cohorts, fine mapping and resequencing efforts, together with functional studies of the variants, are warranted to better understand their role in disease susceptibility. With respect to pharmacogenetics, several candidate gene polymorphisms have been shown to influence responses to both traditional and biologic therapies in psoriasis and PsA, but confirmation in large prospective cohorts is required before the information can be used in the clinical setting.

Key Points

  • The strongest genetic association signal for psoriasis and PsA is with HLA-C, within the MHC region

  • Non-HLA genetic variants within the MHC region probably account for a substantial portion of the genetic risk associated with this locus, particularly in PsA

  • Genome-wide association studies have identified numerous genetic variants outside the MHC region, particularly in psoriasis, within genes important in skin barrier function as well as innate and adaptive immunity

  • The clinical utility of a sole genetic determinant is limited; however, combining known genetic variants into a genotype risk score might be of diagnostic or prognostic value

  • Few robust pharmacogenetic associations yet exist in psoriasis and PsA, in terms either of predicting response to therapy or the likelihood of adverse events

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Figure 1: A schematic representation of the MHC region, illustrating the chromosomal locations of genes and regions implicated in susceptibility to psoriasis and/or PsA.
Figure 2: Discovery timeline of genes of which variants are implicated in the pathogenesis of psoriasis.
Figure 3: Key signaling pathways in dermis that are affected by genetic variants that contribute to the pathogenesis of psoriasis, and, by analogy, PsA.
Figure 4: Key signaling pathways in joints that contribute to the pathogenesis of psoriasis, and, by analogy, PsA.

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References

  1. Rahman, P. & Elder, J. T. Genetic epidemiology of psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 64 (Suppl. 2), ii37–ii39; discussion ii40–ii41 (2005).

    PubMed  PubMed Central  Google Scholar 

  2. Ibrahim, G., Waxman, R. & Helliwell, P. S. The prevalence of psoriatic arthritis in people with psoriasis. Arthritis Rheum. 61, 1373–1378 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Taylor, W. et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54, 2665–2667 (2006).

    Article  PubMed  Google Scholar 

  4. Moll, J. M. & Wright, V. Psoriatic arthritis. Semin. Arthritis Rheum. 3, 55–78 (1973).

    Article  CAS  PubMed  Google Scholar 

  5. Gladman, D. D., Antoni, C., Mease, P., Clegg, D. O. & Nash, P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann. Rheum. Dis. 64 (Suppl. 2), ii14–ii47 (2005).

    PubMed  PubMed Central  Google Scholar 

  6. Saad, A. A., Symmons, D. P., Noyce, P. R. & Ashcroft, D. M. Risks and benefits of tumor necrosis factor-α inhibitors in the management of psoriatic arthritis: systematic review and metaanalysis of randomized controlled trials. J. Rheumatol. 35, 883–890 (2008).

    CAS  PubMed  Google Scholar 

  7. Saad, A. A. et al. Efficacy and safety of anti-TNF therapies in psoriatic arthritis: an observational study from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 49, 697–705 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kristensen, L. E., Gülfe, A., Saxne, T. & Geborek, P. Efficacy and tolerability of anti-tumour necrosis factor therapy in psoriatic arthritis patients: results from the South Swedish Arthritis Treatment Group register. Ann. Rheum. Dis. 67, 364–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Ritchlin, C. T. From skin to bone: translational perspectives on psoriatic disease. J. Rheumatol. 35, 1434–1437 (2008).

    PubMed  Google Scholar 

  10. Reece, R. J., Canete, J. D., Parsons, W. J., Emery, P. & Veale, D. J. Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum. 42, 1481–1484 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Fearon, U. et al. Angiopoietins, growth factors, and vascular morphology in early arthritis. J. Rheumatol. 30, 260–268 (2003).

    CAS  PubMed  Google Scholar 

  12. Ritchlin, C. T., Haas-Smith, S. A., Li, P., Hicks, D. G. & Schwarz, E. M. Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J. Clin. Invest. 111, 821–831 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moll, J. M. & Wright, V. Familial occurrence of psoriatic arthritis. Ann. Rheum. Dis. 32, 181–201 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chandran, V. et al. Familial aggregation of psoriatic arthritis. Ann. Rheum. Dis. 68, 664–667 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Gladman, D. D. Natural history of psoriatic arthritis. Baillieres Clin. Rheumatol. 8, 379–394 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Nair, R. P. et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jenisch, S. et al. Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region. Am. J. Hum. Genet. 63, 191–199 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Duffin, K. C. et al. Genetics of psoriasis and psoriatic arthritis: update and future direction. J. Rheumatol. 35, 1449–1453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Feng, B. J. et al. Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet. 5, e1000606 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Gladman, D. D, Anhorn, K. A., Schachter, R. K. & Mervart, H. HLA antigens in psoriatic arthritis. J. Rheumatol. 13, 586–592 (1986).

    CAS  PubMed  Google Scholar 

  21. Gerber, L. H. et al. Human lymphocyte antigens characterizing psoriatic arthritis and its subtypes. J. Rheumatol. 9, 703–707 (1982).

    CAS  PubMed  Google Scholar 

  22. Espinoza, L. R. et al. Histocompatibility typing in the seronegative spondyloarthropathies: a survey. Semin. Arthritis Rheum. 11, 375–381 (1982).

    Article  CAS  PubMed  Google Scholar 

  23. Kantor, S. M., Hsu, S. H., Bias, W. B. & Arnett, F. C. Clinical and immunologic subsets of psoriatic arthritis. Clin. Exp. Rheumatol. 2, 105–109 (1984).

    CAS  PubMed  Google Scholar 

  24. Gladman, D. D. & Farewell, V. T. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum. 38, 845–850 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Gladman, D. D. et al. HLA-DRB1*04 alleles in psoriatic arthritis: comparison with rheumatoid arthritis and healthy controls. Hum. Immunol. 62, 1239–1244 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Ho, P. Y. et al. Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis. Ann. Rheum. Dis. 67, 677–682 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Rahman, P. et al. TNFα polymorphisms and risk of psoriatic arthritis. Ann. Rheum. Dis. 65, 919–923 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Reich, K. et al. TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Arthritis Rheum. 56, 2056–2064 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Gonzalez, S. et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis. Arthritis Rheum. 42, 1010–1016 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Korendowych, E. et al. Disease-specific alleles of the MHC Class I related gene, MICA, are associated with type I psoriasis and psoriatic arthritis [abstract FC-10]. Br. J. Dermatol. 154, 4 (2006).

    Google Scholar 

  31. MacGregor, A. J. et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43, 30–37 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Rahman, P. et al. High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis. Ann. Rheum. Dis. 70, 690–694 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Boudreau, D. et al. Novel association of HCP5 gene in psoriatic arthritis [abstract]. Ann. Rheum. Dis. 69 (Suppl. 3), 114 (2010).

    Google Scholar 

  36. Nelson, G. W. et al. Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J. Immunol. 173, 4273–4276 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Martin, M. P. et al. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J. Immunol. 169, 2818–2822 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Sagoo, G. S., Cork, M. C., Patel, R. & Tazi-Ahnini, R. Genome-wide studies of psoriasis susceptibility loci: a review. J. Dermatol. Sci. 35, 171–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Karason, A. et al. A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. Am. J. Hum. Genet. 72, 125–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Karason, A. et al. Genetics of psoriasis in Iceland: evidence for linkage of subphenotypes to distinct loci. J. Invest. Dermatol. 124, 1177–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Nair, R. P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ellinghaus, E. et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat. Genet. 42, 991–995 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hüffmeier, U. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat. Genet. 42, 996–999 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, X. J. et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Sun, L. D. et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat. Genet. 42, 1005–1009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stuart, P. E. et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat. Genet. 42, 1000–1004 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Capon, F. et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum. Mol. Genet. 17, 1938–1945 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Filer, C. et al. Investigation of association of the IL12B and IL23R genes with psoriatic arthritis. Arthritis Rheum. 58, 3705–3709 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hüffmeier, U. et al. Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J. Invest. Dermatol. 129, 355–358 (2009).

    Article  PubMed  CAS  Google Scholar 

  52. Bowes, J. et al. Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis. Ann. Rheum. Dis. 69, 2199–2203 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat. Genet. 41, 211–215 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, M. et al. Deletion of the late cornified envelope genes LCE3C and LCE3B is associated with psoriasis in a Chinese population. J. Invest. Dermatol. 131, 1639–1643 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Coto, E. et al. Mutation analysis of the LCE3B/LCE3C genes in psoriasis. BMC Med. Genet. 11, 45 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Riveira-Munoz, E. et al. Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6. J. Invest. Dermatol. 131, 1105–1109 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Hüffmeier, U. et al. Replication of LCE3C–LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. J. Invest. Dermatol. 130, 979–984 (2009).

    Article  PubMed  CAS  Google Scholar 

  58. de Guzman Strong, C. et al. A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis. Hum. Mol. Genet. 19, 1453–1460 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Yang, D. et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Niyonsaba, F., Ogawa, H. & Nagaoka, I. Human β-defensin-2 functions as a chemotactic agent for tumour necrosis factor-α-treated human neutrophils. Immunology 111, 273–281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hollox, E. J. et al. Psoriasis is associated with increased β-defensin genomic copy number. Nat. Genet. 40, 23–25 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Varoga, D. et al. Expression and regulation of antimicrobial peptides in articular joints. Ann. Anat. 187, 499–508 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Labarthe, M. P., Bosco, D., Saurat, J. H., Meda, P. & Salomon, D. Upregulation of connexin 26 between keratinocytes of psoriatic lesions. J. Invest. Dermatol. 111, 72–76 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Djalilian, A. R. et al. Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response. J. Clin. Invest. 116, 1243–1253 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marino, A. A. et al. Increased intercellular communication through gap junctions may contribute to progression of osteoarthritis. Clin. Orthop. Relat. Res. 422, 224–232 (2004).

    Article  Google Scholar 

  66. Hayden, M. S. & Ghosh, S. NF-κB in immunobiology. Cell Res. 21, 223–244 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Vereecke, L., Beyaert, R. & van Loo, G. The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol. 30, 383–391 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Verstrepen, L., Carpentier, I., Verhelst, K. & Beyaert, R. ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling. Biochem. Pharmacol. 78, 105–114 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. De Molfetta, G. A. et al. Role of NFKB2 on the early myeloid differentiation of CD34+ hematopoietic stem/progenitor cells. Differentiation 80, 195–203 (2010).

    Article  PubMed  CAS  Google Scholar 

  70. Lu, T. et al. Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc. Natl Acad. Sci. USA 107, 46–51 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Zaba, L. C., Krueger, J. G. & Lowes, M. A. Resident and 'inflammatory' dendritic cells in human skin. J. Invest. Dermatol. 129, 302–208 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Enevold, C. et al. Polymorphisms of innate pattern recognition receptors, response to interferon-β and development of neutralizing antibodies in multiple sclerosis patients. Mult. Scler. 16, 942–949 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Strobl, B., Stoiber, D., Sexl, V. & Mueller, M. Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity. Front. Biosci. 17, 3224–3232 (2011).

    Article  Google Scholar 

  74. Miossec, P. IL-17 and TH17 cells in human inflammatory diseases. Microbes Infect. 11, 625–630 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Tsunemi, Y. et al. Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J. Dermatol. Sci. 30, 161–166 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Nair, R. P. et al. Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. J. Invest. Dermatol. 128, 1653–1661 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tesmer, L. A., Lundy, S. K., Sarkar, S. & Fox, D. A. TH17 cells in human disease. Immunol. Rev. 223, 87–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 8, 247–256 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Lowes, M. A. et al. Psoriasis vulgaris lesions contain discrete populations of TH1 and TH17 cells. J. Invest. Dermatol. 128, 1207–1211 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Hunter, C. A. Act1-ivating IL-17 inflammation. Nat. Immunol. 8, 232–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Zhou, Z. et al. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J. Virol. 81, 7749–7758 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Oyamada, A. et al. Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis. J. Immunol. 183, 7539–7546 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Serwold, T., Gaw, S. & Shastri, N. ER aminopeptidases generate a unique pool of peptides for MHC class 1 molecules. Nat. Immunol. 2, 644–651 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Chandran, V. & Rahman, P. Update on the genetics of spondyloarthritis—ankylosing spondylitis and psoriatic arthritis. Best Pract. Res. Clin. Rheumatol. 24, 579–588 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Bowes, J. et al. Evidence to support IL-13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris. Ann. Rheum. Dis. 70, 1016–1019 (2011).

    Article  PubMed  Google Scholar 

  87. Duffin, K. C. et al. Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking. J. Invest. Dermatol. 129, 2777–2783 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Chang, Y. T. et al. Cytokine gene polymorphisms in Chinese patients with psoriasis. Br. J. Dermatol. 156, 899–905 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Gregersen, P. K. et al. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat. Genet. 41, 820–823 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Reveille, J. D. et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhernakova, A., van Diemen, C. C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat. Rev. Genet. 10, 43–55 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Michel, S. et al. Unifying candidate gene and GWAS approaches in asthma. PLoS ONE 5, e13894 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Orozco, G. et al. Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus. Ann. Rheum. Dis. 70, 463–468 (2011).

    Article  PubMed  Google Scholar 

  95. Eyre, S. et al. Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Ann. Rheum. Dis. 70, 463–468 (2011).

    Article  PubMed  Google Scholar 

  96. Plenge, R. M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Graham, R. R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen, H. et al. A genetic risk score combining ten psoriasis risk loci improves disease prediction. PLoS ONE 6, e19454 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gladman, D. D. & Farewell, V. T. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum. 38, 845–850 (1995).

    Article  CAS  PubMed  Google Scholar 

  101. Ho, P. Y. et al. HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis. Ann. Rheum. Dis. 66, 807–811 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rahman, P. et al. A variant of the IL4 I50V single-nucleotide polymorphism is associated with erosive joint disease in psoriatic arthritis. Arthritis Rheum. 58, 2207–2208 (2008).

    Article  PubMed  Google Scholar 

  103. Menter, A. et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J. Am. Acad. Dermatol. 58, 826–850 (2008).

    Article  PubMed  Google Scholar 

  104. Cronstein, B. N. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol. Rev. 57, 163–172 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Zachariae, H. & Sogaard, H. Liver biopsy in psoriasis, a controlled study. Dermatologica 146, 149–155 (1973).

    Article  CAS  PubMed  Google Scholar 

  106. Warren, R. B. et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J. Invest. Dermatol. 128, 1925–1929 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Campalani, E. et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J. Invest. Dermatol. 127, 1860–1867 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Chandran, V. et al. Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis. J. Rheumatol. 37, 1508–1512 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. O'Rielly, D. D. & Rahman, P. Pharmacogenetics of rheumatoid arthritis: potential targets from susceptibility genes and present therapies. Pharmacogenomics and Personalized Medicine 3, 15–31 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Louis, E. et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-α production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin. Exp. Immunol. 113, 401–406 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cuchacovich, M. et al. Tumour necrosis factor (TNF)α -308 G/G promoter polymorphism and TNFα levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand. J. Rheumatol. 35, 435–440 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. O'Rielly, D. D., Roslin, N. M., Beyene, J., Pope, A. & Rahman, P. TNF-α-308 G/A polymorphism and responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis. Pharmacogenomics J. 9, 161–167 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Gottlieb, A. B. et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J. Immunol. 175, 2721–2729 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Zaba, L. C. et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J. Allergy Clin. Immunol. 124, 1022–10e1–395 (2009).

    Article  CAS  Google Scholar 

  115. Haider, A. S., Cardinale, I. R., Whynot, J. A. & Krueger, J. G. Effects of etanercept are distinct from infliximab in modulating proinflammatory genes in activated human leukocytes. J. Investig. Dermatol. Symp. Proc. 12, 9–15 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Baeten, D. et al. Infiltration of the synovial membrane with macrophage subsets and polymorphonuclear cells reflects global disease activity in spondyloarthropathy. Arthritis Res. Ther. 7, R359–R369 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Veale, D. J., Ritchlin, C. & FitzGerald, O. Immunopathology of psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 64 (Suppl. 2), ii26–ii29 (2005).

    PubMed  PubMed Central  Google Scholar 

  118. Mease, P. TNFα therapy in psoriatic arthritis and psoriasis. Ann. Rheum. Dis. 63, 755–758 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Duffin, K. C. et al. Association between IL13 polymorphisms and psoriatic arthritis is modified by smoking. J. Invest. Dermatol. 129, 2777–2783 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Eder, L. et al. IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients. Ann. Rheum. Dis. 70, 1594–1598 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The work of P. Rahman is funded by the National Research Initiative of the Arthritis Society of Canada, the Atlantic Innovation Foundation, and the Canadian Institute of Health Research Team Grant in Psoriatic Arthritis.

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Authors and Affiliations

  1. Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St John's, Newfoundland, A1B 3V6, Canada

    Darren D. O'Rielly

  2. St Clare's Mercy Hospital, 154 Le Marchant Road, St John's, Newfoundland, A1C 5B8, Canada

    Proton Rahman

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  1. Darren D. O'Rielly
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Both authors contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Proton Rahman.

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O'Rielly, D., Rahman, P. Genetics of susceptibility and treatment response in psoriatic arthritis. Nat Rev Rheumatol 7, 718–732 (2011). https://doi.org/10.1038/nrrheum.2011.169

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