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Clinical implications of shared genetics and pathogenesis in autoimmune diseases

Nature Reviews Endocrinology volume 9, pages 646–659 (2013)Cite this article

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Abstract

Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the presence of autoreactive T cells. They are caused by a complex genetic predisposition that is attributable to multiple genetic variants, each with a moderate-to-low effect size. Most of the genetic variants associated with a particular autoimmune endocrine disease are shared between other systemic and organ-specific autoimmune and inflammatory diseases, such as rheumatoid arthritis, coeliac disease, systemic lupus erythematosus and psoriasis. Here, we review the shared and specific genetic background of autoimmune diseases, summarize their treatment options and discuss how identifying the genetic and environmental factors that predispose patients to an autoimmune disease can help in the diagnosis and monitoring of patients, as well as the design of new treatments.

Key Points

  • Autoimmune diseases share a large proportion of their genetic background; shared genes and pathways might serve as common drug targets across diseases

  • Genetic studies are discovering new pathways relevant to autoimmune diseases

  • Determining genetic profiles for common autoimmune diseases could improve understanding of the underlying pathways and help identify novel drug targets for less common and rare autoimmune diseases

  • Genetic profiling will help identify individuals at risk of autoimmune diseases, which is important for timely diagnosis and treatment

  • Genetic, microRNA, metabolomic, microbiome and autoimmune profiles can serve as biomarkers for monitoring disease progression and response to treatment

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Figure 1: An overview of the common, less common and rare autoimmune and/or endocrine diseases and their affected organs that are discussed in this article.
Figure 2: Genes associated with common autoimmune and/or endocrine diseases that are current or potential drug targets.
Figure 3: Extracellular and intracellular molecules as drug targets.
Figure 4: Prediction of autoimmune diseases on different pathogenetic levels.

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References

  1. Qiao, S.-W., Iversen, R., Ráki, M. & Sollid, L. M. The adaptive immune response in celiac disease. Semin. Immunopathol. 34, 523–540 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Van Lummel, M., Zaldumbide, A. & Roep, B. O. Changing faces, unmasking the β-cell: post-translational modification of antigens in type 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 20, 299–306 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Weetman, A. P. Cellular immune responses in autoimmune thyroid disease. Clin. Endocrinol. 61, 405–413 (2004).

    Article  CAS  Google Scholar 

  4. Richard-Miceli, C. & Criswell, L. A. Emerging patterns of genetic overlap across autoimmune disorders. Genome Med. 4, 6 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M. & Smoller, J. W. Pleiotropy in complex traits: challenges and strategies. Nat. Rev. Genet. 14, 483–495 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cooper, J. D. et al. Seven newly identified loci for autoimmune thyroid disease. Hum. Mol. Genet. 21, 5202–5208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Trynka, G. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193–1201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsoi, L. C. et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat. Genet. 44, 1341–1348 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhernakova, A. et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 7, e1002004 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smyth, D. J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hsu, L. N. & Armstrong, A. W. Psoriasis and autoimmune disorders: a review of the literature. J. Am. Acad. Dermatol. 67, 1076–1079 (2012).

    Article  PubMed  Google Scholar 

  14. Hemminki, K., Li, X., Sundquist, K. & Sundquist, J. Shared familial aggregation of susceptibility to autoimmune diseases. Arthritis Rheum. 60, 2845–2847 (2009).

    Article  PubMed  Google Scholar 

  15. Skinningsrud, B. et al. Multiple loci in the HLA complex are associated with Addison's disease. J. Clin. Endocrinol. Metab. 96, E1703–E1708 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Zurawek, M. et al. A coding variant in NLRP1 is associated with autoimmune Addison's disease. Hum. Immunol. 71, 530–534 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Magitta, N. F. et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun. 10, 120–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Skinningsrud, B. et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease. Eur. J. Hum. Genet. 16, 977–982 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Criswell, L. A. et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vaidya, B. et al. Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison's disease. J. Clin. Endocrinol. Metab. 85, 688–691 (2000).

    CAS  PubMed  Google Scholar 

  21. Brozzetti, A. et al. Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies. Eur. J. Endocrinol. 162, 361–369 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Owen, C. J. et al. Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders suggests a complex pattern of disease association. J. Clin. Endocrinol. Metab. 92, 1106–1111 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Skinningsrud, B. et al. Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. J. Clin. Endocrinol. Metab. 93, 3310–3317 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Husebye, E. S. & Anderson, M. S. Review autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 32, 479–487 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gan, E. H., Mitchell, A. L., Macarthur, K. & Pearce, S. H. S. The role of a nonsynonymous CD226 (DNAX-accessory molecule-1) variant (Gly 307Ser) in isolated Addison's disease and autoimmune polyendocrinopathy type 2 pathogenesis. Clin. Endocrinol. 75, 165–168 (2011).

    Article  CAS  Google Scholar 

  26. Song, G., Bae, S.-C., Choi, S., Ji, J. & Lee, Y. Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 21, 1522–1530 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Plagnol, V. et al. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet. 7, e1002216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2008).

    Article  CAS  Google Scholar 

  29. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gallo, V. et al. Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model. Expert. Rev. Clin. Immunol. 9, 43–51 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Pearce, S. H. et al. A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Am. J. Hum. Genet. 63, 1675–1684 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Terao, C. et al. The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to rheumatoid arthritis in Japanese population. Hum. Mol. Genet. 20, 2680–2685 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    Article  CAS  Google Scholar 

  37. McGovern, D. P. B. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332–337 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 

  39. 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 

  40. Ricaño-Ponce, I. & Wijmenga, C. Mapping of immune-mediated disease genes. Annu. Rev. Genomics Hum. Genet. http://dx.doi.org/10.1146/annurev-genom-091212-153450.

  41. Pettigrew, H. D., Teuber, S. S. & Gershwin, M. E. Clinical significance of complement deficiencies. Ann. NY Acad. Sci. 1173, 108–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Pickering, M. C. & Walport, M. J. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology 39, 133–141 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Namjou, B. et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 12, 270–279 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Betterle, C. & Morlin, L. Autoimmune Addison's disease. Endocr. Dev. 20, 161–172 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Maahs, D. M., West, N. A., Lawrence, J. M. & Mayer-Davis, E. J. Epidemiology of type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39, 481–497 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Schön, M. P. & Boehncke, W.-H. Psoriasis. N. Engl. J. Med. 352, 1899–1912 (2005).

    Article  PubMed  Google Scholar 

  49. Kahaly, G. J. Polyglandular autoimmune syndromes. Eur. J. Endocrinol. 161, 11–20 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Li, M., Li, C. & Guan, W. Evaluation of coverage variation of SNP chips for genome-wide association studies. Eur. J. Hum. Genet. 16, 635–643 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. 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 

  52. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  53. Wacklin, P. et al. The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease. Inflamm. Bowel Dis. 19, 934–941 (2013).

    Article  PubMed  Google Scholar 

  54. Ogrendik, M. Rheumatoid arthritis is linked to oral bacteria: etiological association. Mod. Rheumatol. 19, 453–456 (2009).

    Article  PubMed  Google Scholar 

  55. Fahlén, A., Engstrand, L., Baker, B. S., Powles, A. & Fry, L. Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin. Arch. Dermatol. Res. 304, 15–22 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Brown, C. T. et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE 6, e25792 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Knip, M. & Simell, O. Environmental triggers of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2, a007690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rausch, P. et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc. Natl Acad. Sci. USA 108, 19030–19035 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Markle, J. G. M. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Liu, Y. et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 31, 142–147 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Park, S.-H. et al. Hypermethylation of EBF3 and IRX1 genes in synovial fibroblasts of patients with rheumatoid arthritis. Mol. Cells 35, 298–304 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Klareskog, L., Catrina, A. I. & Paget, S. Rheumatoid arthritis. Lancet 373, 659–672 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Kiyohara, C. et al. Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population. Scand. J. Rheumatol. 41, 103–109 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Badenhoop, K. et al. MHC-environment interactions leading to type 1 diabetes: feasibility of an analysis of HLA DR-DQ alleles in relation to manifestation periods and dates of birth. Diabetes Obes. Metab. 11 (Suppl. 1), 88–91 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Scott, D. L., Wolfe, F. & Huizinga, T. W. J. Rheumatoid arthritis. Lancet 376, 1094–1108 (2010).

    Article  PubMed  Google Scholar 

  67. Faustman, D. & Davis, M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov. 9, 482–493 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. van Schouwenburg, P. A., Rispens, T. & Wolbink, G. J. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 164–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Fernando, M. M. A. et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 4, e1000024 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pan, H.-F. et al. Association of TNF-α promoter-308 A/G polymorphism with susceptibility to systemic lupus erythematosus: a meta-analysis. Rheumatol. Int. 32, 2083–2092 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Li, N. et al. Association of tumour necrosis factor α (TNF-α) polymorphisms with Graves' disease: A meta-analysis. Clin. Biochem. 41, 881–886 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Shin, H. D., Yang, S. W., Kim, D. H. & Park, Y. Independent association of tumor necrosis factor polymorphism with type 1 diabetes susceptibility. Ann. NY Acad. Sci. 1150, 76–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Science Signaling Database of Cell Signaling. NF-κB pathway [online], (2013).

  74. Ibrahim, I., Owen, S.-A. & Barton, A. Genetics and the impact on treatment protocols in patients with rheumatoid arthritis. Expert Rev. Clin. Immunol. 8, 509–511 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Wijbrandts, C. A. et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium. Ann. Rheum. Dis. 67, 1139–1144 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Gómez-Reino, J. J., Carmona, L., Valverde, V. R., Mola, E. M. & Montero, M. D. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 48, 2122–2127 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Cui, J. et al. Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet. 9, e1003394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gregory, A. P. et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508–511 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. & Karin, M. Immunosuppression by glucocorticoids: inhibition of NF-κB activity through induction of IκB synthesis. Science 270, 286–290 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S. Role of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995).

    Article  CAS  PubMed  Google Scholar 

  81. Tegeder, I., Pfeilschifter, J. & Geisslinger, G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 15, 2057–2072 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Dasgupta, S. et al. Antineuroinflammatory effect of NF-κB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis. J. Immunol. 173, 1344–1354 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Sullivan, B. O., Thompson, A. & Thomas, R. NF-κB as a therapeutic target in autoimmune disease. Expert Opin. Ther. Targets 11, 111–122 (2007).

    Article  Google Scholar 

  84. McIntyre, K. W. et al. A highly selective inhibitor of IκB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum. 48, 2652–2659 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Palombella, V. J. et al. Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis. Proc. Natl Acad. Sci. USA 95, 15671–15676 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li, G. et al. Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. PLoS Genet. 9, e1003487 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miossec, P. & Kolls, J. K. Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov. 11, 763–776 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Watanabe, N. & Nakajima, H. Coinhibitory molecules in autoimmune diseases. Clin. Dev. Immunol. 2012, 269756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chu, X. et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat. Genet. 43, 897–901 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. 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 

  91. Yang, W. et al. Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am. J. Hum. Genet. 92, 41–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nakamura, M. et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am. J. Hum. Genet. 91, 721–728 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dubois, P. C. A. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat. Genet. 42, 295–302 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Emery, P. et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann. Rheum. Dis. 69, 510–516 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cui, Y., Sheng, Y. & Zhang, X. Genetic susceptibility to SLE: recent progress from GWAS. J. Autoimmun. 41, 25–33 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Harley, I. T. W., Kaufman, K. M., Langefeld, C. D., Harley, J. B. & Kelly, J. A. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat. Rev. Genet. 10, 285–290 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Flesher, D. L. T., Sun, X., Behrens, T. W., Graham, R. R. & Criswell, L. A. Recent advances in the genetics of systemic lupus erythematosus. Expert Rev. Clin. Immunol. 6, 461–479 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bezalel, S., Asher, I., Elbirt, D. & Sthoeger, Z. M. Novel biological treatments for systemic lupus erythematosus: current and future modalities. Isr. Med. Assoc. J. 14, 508–514 (2012).

    PubMed  Google Scholar 

  100. Kozyrev, S. V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat. Genet. 40, 211–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dall'era, M. & Chakravarty, E. F. Treatment of mild, moderate, and severe lupus erythematosus: focus on new therapies. Curr. Rheumatol. Rep. 13, 308–316 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bronson, P. G., Chaivorapol, C., Ortmann, W., Behrens, T. W. & Graham, R. R. The genetics of type I interferon in systemic lupus erythematosus. Curr. Opin. Immunol. 24, 530–537 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  106. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  107. Burmester, G. R., Panaccione, R., Gordon, K. B., McIlraith, M. J. & Lacerda, A. P. M. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann. Rheum. Dis. 72, 517–524 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Cleynen, I. & Vermeire, S. Paradoxical inflammation induced by anti-TNF agents in patients with IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 496–503 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Kopf, M., Bachmann, M. F. & Marsland, B. J. Averting inflammation by targeting the cytokine environment. Nat. Rev. Drug Discov. 9, 703–718 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Sildorf, S. M., Fredheim, S., Svensson, J. & Buschard, K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. http://dx.doi.org/10.1136/bcr.02.2012.5878.

  111. Cosnes, J. et al. Incidence of autoimmune diseases in celiac disease: protective effect of the gluten-free diet. Clin. Gastroenterol. Hepatol. 6, 753–758 (2008).

    Article  PubMed  Google Scholar 

  112. Zhang, T. et al. Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition. PLoS ONE 7, e30044 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pozo-Rubio, T. et al. Immune development and intestinal microbiota in celiac disease. Clin. Dev. Immunol. 2012, 654143 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Murri, M. et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case–control study. BMC Med. 11, 46 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kriegel, M. A. et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 108, 11548–11553 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Anderson, J. L., Edney, R. J. & Whelan, K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment. Pharmacol. Ther. 36, 503–516 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Csizmadia, C. G., Mearin, M. L., Von Blomberg, B. M., Brand, R. & Verloove-Vanhorick, S. P. An iceberg of childhood coeliac disease in the Netherlands. Lancet 353, 813–814 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Herold, K. C., Vignali, D. A., Cooke, A. & Bluestone, J. A. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat. Rev. Immunol. 13, 243–256 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rantapää-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Nielen, M. M. J. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).

    Article  PubMed  Google Scholar 

  122. Shepshelovich, D. & Shoenfeld, Y. Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus 15, 183–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Hutfless, S., Matos, P., Talor, M. V, Caturegli, P. & Rose, N. R. Significance of prediagnostic thyroid antibodies in women with autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 96, E1466–E1471 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Husby, S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 54, 136–160 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Chatterjee, N. et al. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat. Genet. 45, 400–405 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pasquinelli, A. E. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat. Rev. Genet. 13, 271–282 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Cortez, M. A. et al. MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat. Rev. Clin. Oncol. 8, 467–477 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Weber, J. A. et al. The microRNA spectrum in 12 body fluids. Clin. Chem. 56, 1733–1741 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zibert, J. R. et al. MicroRNAs and potential target interactions in psoriasis. J. Dermatol. Sci. 58, 177–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Sonkoly, E. et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS ONE 2, e610 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zahm, A. M. et al. Circulating microRNA is a biomarker of pediatric Crohn disease. J. Pediatr. Gastroenterol. Nutr. 53, 26–33 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Zhou, Q., Souba, W. W., Croce, C. M. & Verne, G. N. MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome. Gut 59, 775–784 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Liu, G. & Abraham, E. MicroRNAs in immune response and macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 33, 170–177 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bernecker, C. et al. MicroRNAs miR-146a1, miR-155_2, and miR-200a1 are regulated in autoimmune thyroid diseases. Thyroid 22, 1294–1295 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Kumar, V., Wijmenga, C. & Withoff, S. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Semin. Immunopathol. 34, 567–580 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Xia, J., Joyce, C. E., Bowcock, A. M. & Zhang, W. Noncanonical microRNAs and endogenous siRNAs in normal and psoriatic human skin. Hum. Mol. Genet. 22, 737–748 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Carlsen, A. L. et al. Circulating microRNA expression profiles associated with systemic lupus erythematosus. Arthritis Rheum. 65, 1324–1334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Seeger, K. Metabolic changes in autoimmune diseases. Curr. Drug Discov. Technol. 6, 256–261 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Bernini, P. et al. Are patients with potential celiac disease really potential? The answer of metabolomics. J. Proteome Res. 10, 714–721 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. El-Hini, S. H. et al. Visfatin and adiponectin as novel markers for evaluation of metabolic disturbance in recently diagnosed rheumatoid arthritis patients. Rheumatol. Int. http://dx.doi.org/10.1007/s00296-013-2714-2713.

  141. Wu, T. et al. Metabolic disturbances associated with systemic lupus erythematosus. PLoS ONE 7, e37210 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wang, Z. et al. (1)H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis. Exp. Ther. Med. 4, 165–171 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. McCulloch, M. et al. Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Integr. Cancer Ther. 5, 30–39 (2006).

    Article  PubMed  Google Scholar 

  144. Robroeks, C. M. et al. Metabolomics of volatile organic compounds in cystic fibrosis patients and controls. Pediatr. Res. 68, 75–80 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Van Berkel, J. J. et al. A profile of volatile organic compounds in breath discriminates COPD patients from controls. Respir. Med. 104, 557–563 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Verdam, F. J. et al. Non-alcoholic steatohepatitis: A non-invasive diagnosis by analysis of exhaled breath. J. Hepatol. 58, 543–548 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Baranska, A. et al. Profile of volatile organic compounds in exhaled breath changes as a result of gluten-free diet. J. Breath Res. 7, 037104 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Kamada, N., Seo, S.-U., Chen, G. Y. & Núñez, G. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13, 321–335 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Zeeuwen, P. L. et al. Microbiome dynamics of human epidermis following skin barrier disruption. Genome Biol. 13, R101 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sellitto, M. et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE 7, e33387 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mori, K., Nakagawa, Y. & Ozaki, H. Does the gut microbiota trigger Hashimoto's thyroiditis? Discov. Med. 14, 321–326 (2012).

    PubMed  Google Scholar 

  152. Hogen Esch, C. E. et al. The PreventCD Study design: towards new strategies for the prevention of coeliac disease. Eur. J. Gastroenterol. Hepatol. 22, 1424–1430 (2010).

    PubMed  Google Scholar 

  153. Romanos, J. et al. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants. Gut http://dx.doi.org/10.1136/gutjnl-2012-304110.

  154. Manolio, T. A., Bailey-Wilson, J. E. & Collins, F. S. Genes, environment and the value of prospective cohort studies. Nat. Rev. Genet. 7, 812–820 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Bluestone, J. A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to acknowledge grants from Top Institute Food and Nutrition, the Netherlands (TiFN GH001 to C. Wijmenga and A. Zhernakova) and from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 2012- 322698 to C. Wijmenga, the Dutch Digestive Diseases Foundation (MLDS, WO11-30 to C. Wijmenga), and the Dutch MS Foundation (11-752 MS) to S. Withoff. A. Zhernakova holds a Rosalind Franklin Fellowship from the University of Groningen and a grant from the Dutch Reumafonds (11-1-101).

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  1. Department of Genetics, University of Groningen, University Medical Centre Groningen, PO Box 30001, Groningen, 9700 RB, Netherlands

    Alexandra Zhernakova, Sebo Withoff & Cisca Wijmenga

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  1. Alexandra Zhernakova
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  2. Sebo Withoff
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All authors contributed equally to all aspects of this manuscript.

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Correspondence to Cisca Wijmenga.

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Supplementary information

Supplementary Figure 1

An overview of the common, less common and rare autoimmune and/or endocrine diseases and their affected organs. (PDF 1305 kb)

Supplementary Table 1

GWAS studies in this Review (XLS 49 kb)

Supplementary Table 2

Ichip studies in this Review (XLS 26 kb)

Supplementary Table 3

Associated loci in disease (XLS 72 kb)

Supplementary Table 4

Selected genes and drug targets (XLS 70 kb)

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Zhernakova, A., Withoff, S. & Wijmenga, C. Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Nat Rev Endocrinol 9, 646–659 (2013). https://doi.org/10.1038/nrendo.2013.161

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