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Genetic and Functional Genetics of Autoimmune Diseases

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Genome-Wide Association Studies

Abstract

The majority of autoimmune diseases are multi-factorial diseases that develop through the interaction of several factors, such as genetic and environmental factors. A limited number of disease susceptibility genes, including those of the major histocompatibility complex have been known to exist for several decades. After these eras, genome-wide association studies have been used for more than 10 years to identify susceptibility genes for certain autoimmune diseases. These findings have contributed to our understanding of the pathogenesis of these diseases. As the analysis of susceptibility genes has progressed, it has become apparent that many disease susceptibility gene variants are involved at the expression level of genes. Furthermore, expression of genes related to disease pathogenesis is cell-specific, with involvement of epigenetic mechanisms. Genetic information exists before the onset of disease, and thus has a causal relationship to the disease. Therefore, the analysis of genomic function in human immunology research is essential, with regard to understanding the pathological mechanisms as well as having applications for drug discovery. In this article, we discuss these issues, with a particular focus on rheumatoid arthritis.

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References

  1. Silman AJ et al (1993) Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 32:903–907

    Article  CAS  Google Scholar 

  2. Gregersen PK et al (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30(11):1205–1213

    Article  CAS  Google Scholar 

  3. Raychaudhuri S et al (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44:291–296

    Article  CAS  Google Scholar 

  4. Scally SW et al (2013) A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med 210:2569–2582

    Article  CAS  Google Scholar 

  5. Okada Y et al (2016) Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. Am J Hum Genet 99:366–374

    Article  CAS  Google Scholar 

  6. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  Google Scholar 

  7. Hirschhorn JN et al (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108

    Article  CAS  Google Scholar 

  8. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

    Article  Google Scholar 

  9. Okada Y et al (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506:376–381

    Article  CAS  Google Scholar 

  10. Ram R et al (2017) Effects of type 1 diabetes risk alleles on immune cell gene expression. Genes 8:167

    Article  Google Scholar 

  11. Surolia I et al (2010) Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 466:243–247

    Article  CAS  Google Scholar 

  12. Gregersen PK et al (2006) Genetics of autoimmune diseases–disorders of immune homeostasis. Nat Rev Genet 7:917–928

    Article  CAS  Google Scholar 

  13. Ueda H et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511

    Article  CAS  Google Scholar 

  14. Kochi Y et al (2005) A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 37:478–485

    Article  CAS  Google Scholar 

  15. Kochi Y et al (2010) A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat Genet 42:515–519

    Article  CAS  Google Scholar 

  16. Suzuki A et al (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402

    Article  CAS  Google Scholar 

  17. Seri Y et al (2015) Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model. Sci Rep 5:13041

    Article  CAS  Google Scholar 

  18. Ishigaki K et al (2017) Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nat Genet 49:1120–1125

    Article  CAS  Google Scholar 

  19. Javirre BM et al (2010) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20:170–179

    Article  Google Scholar 

  20. Jeffries MA et al (2011) Genomewide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics 6:593–601

    Article  CAS  Google Scholar 

  21. Absher DM et al (2013) Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS Genet 9:e1003678

    Article  CAS  Google Scholar 

  22. Hu N et al (2008) Abnormal histone modification patterns in lupus CD4+ T cells. J Rheumatol 35:804–810

    CAS  PubMed  Google Scholar 

  23. Nakano K et al (2013) DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis 72:110–117

    Article  CAS  Google Scholar 

  24. Gillespie J et al (2012) Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum 64:418–442

    Article  CAS  Google Scholar 

  25. Karouzakis E et al (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60:3613–3622

    Article  CAS  Google Scholar 

  26. Dai R et al (2011) MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases. Transl Res 157:163–179

    Article  CAS  Google Scholar 

  27. Huang W et al (2015) DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature 528:517–522

    Article  CAS  Google Scholar 

  28. Trynka G et al (2013) Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat Genet 45:124–130

    Article  CAS  Google Scholar 

  29. Ye CJ et al (2014) Intersection of population variation and autoimmunity genetics in human T cell activation. Science 345:1254665

    Article  Google Scholar 

  30. Farh KK-H et al (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337–343

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Laboratory for Autoimmune Diseases, Riken Center for Integrative Medical Sciences, Yokohama, Japan

    Kazuhiko Yamamoto, Kazuyoshi Ishigaki, Akari Suzuki & Yuta Kochi

  2. Laboratory for Statistical Analysis, Riken Center for Integrative Medical Sciences, Yokohama, Japan

    Kazuyoshi Ishigaki

Authors
  1. Kazuhiko Yamamoto
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  2. Kazuyoshi Ishigaki
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  3. Akari Suzuki
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  4. Yuta Kochi
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Corresponding author

Correspondence to Kazuhiko Yamamoto .

Editor information

Editors and Affiliations

  1. Graduate School of Science, The University of Tokyo, Tokyo, Japan

    Tatsuhiko Tsunoda

  2. BioResource Research Center, Tokyo Medical and Dental University, Tokyo, Japan

    Toshihiro Tanaka

  3. Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Yusuke Nakamura

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© 2019 Springer Nature Singapore Pte Ltd.

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Yamamoto, K., Ishigaki, K., Suzuki, A., Kochi, Y. (2019). Genetic and Functional Genetics of Autoimmune Diseases. In: Tsunoda, T., Tanaka, T., Nakamura, Y. (eds) Genome-Wide Association Studies. Springer, Singapore. https://doi.org/10.1007/978-981-13-8177-5_3

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