Genetics of autoimmune diseases: perspectives from genome-wide association studies

International Immunology - Tập 28 Số 4 - Trang 155-161 - 2016
Yuta Kochi1
1Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences , Tokyo 113–8655 , Japan

Tóm tắt

Abstract Genome-wide association studies (GWASs) for autoimmune diseases (ADs) have identified many risk loci and have provided insights into the etiology of each disease. Some of these loci, such as PTPN22 , IL23R and STAT4 , are shared among different ADs, and the combination of risk loci may determine an individual’s susceptibility for a disease. The majority of GWAS loci are expression quantitative trait loci (eQTLs), where disease-causing variants regulate expression of neighboring (or sometimes distant) genes. Because the eQTL effects are often cell type-specific, the incorporation of epigenetic data from disease-related cell types and tissues is expected to refine the identification of causal variants. The cumulative eQTL effects in multiple genes may influence the activity or fate of immune cells, which in turn may affect the function of the immune system in individuals. In this paper, I review the etiology of ADs by focusing on important immune cells (T h 1 cells, T h 17 cells and regulatory T cells), important pathways (antigen-receptor signaling and type I interferon signaling) and relevant genes identified in GWASs.

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Tài liệu tham khảo

Lleo, 2010, Definition of human autoimmunity--autoantibodies versus autoimmune disease, Autoimmun. Rev, 9, A259, 10.1016/j.autrev.2009.12.002

Hayter, 2012, Updated assessment of the prevalence, spectrum and case definition of autoimmune disease, Autoimmun. Rev, 11, 754, 10.1016/j.autrev.2012.02.001

Okada, 2014, Genetics of rheumatoid arthritis contributes to biology and drug discovery, Nature, 506, 376, 10.1038/nature12873

International Multiple Sclerosis Genetics Consortium, 2013, Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis, Nat. Genet, 45, 1353, 10.1038/ng.2770

Jostins, 2012, Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease, Nature, 491, 119, 10.1038/nature11582

Gusev, 2014, Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases, Am. J. Hum. Genet, 95, 535, 10.1016/j.ajhg.2014.10.004

Dubois, 2010, Multiple common variants for celiac disease influencing immune gene expression, Nat. Genet, 42, 295, 10.1038/ng.543

Okada, 2012, A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese, PLoS Genet, 8, e1002455, 10.1371/journal.pgen.1002455

Raj, 2014, Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes, Science, 344, 519, 10.1126/science.1249547

De Jager, 2015, ImmVar project: Insights and design considerations for future studies of “healthy” immune variation, Semin. Immunol, 27, 51, 10.1016/j.smim.2015.03.003

GTEx Consortium, 2015, Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans, Science, 348, 648, 10.1126/science.1262110

ENCODE Project Consortium, 2012, An integrated encyclopedia of DNA elements in the human genome, Nature, 489, 57, 10.1038/nature11247

Kundaje, 2015, Integrative analysis of 111 reference human epigenomes, Nature, 518, 317, 10.1038/nature14248

Farh, 2014, Genetic and epigenetic fine mapping of causal autoimmune disease variants, Nature

Witte, 2015, Super-enhancers: asset management in immune cell genomes, Trends Immunol, 36, 519, 10.1016/j.it.2015.07.005

Hnisz, 2013, Super-enhancers in the control of cell identity and disease, Cell, 155, 934, 10.1016/j.cell.2013.09.053

The 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, 10.1038/nature05911

Breban, 2015, Revisiting MHC genes in spondyloarthritis, Curr. Rheumatol. Rep, 17, 516, 10.1007/s11926-015-0516-1

Newton, 2004, A review of the MHC genetics of rheumatoid arthritis, Genes Immun, 5, 151, 10.1038/sj.gene.6364045

Gregersen P. K. Silver J. and WinchesterR. J . 1987 . The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis . Arthritis Rheum . 30 : 1205 .

Raychaudhuri, 2012, Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis, Nat. Genet, 44, 291, 10.1038/ng.1076

Han, 2014, Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity, Am. J. Hum. Genet, 94, 522, 10.1016/j.ajhg.2014.02.013

Nejentsev, 2007, Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A, Nature, 450, 887, 10.1038/nature06406

Hu, 2015, Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk, Nat. Genet, 47, 898, 10.1038/ng.3353

Moutsianas, 2015, Class II HLA interactions modulate genetic risk for multiple sclerosis, Nat. Genet, 47, 1107, 10.1038/ng.3395

Okada, 2015, Construction of a population-specific HLA imputation reference panel and its application to Graves’ disease risk in Japanese, Nat. Genet, 47, 798, 10.1038/ng.3310

Sakaguchi, 2003, Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice, Nature, 426, 454, 10.1038/nature02119

Kumar, 2006, Regulation of B cell tolerance by the lupus susceptibility gene Ly108, Science, 312, 1665, 10.1126/science.1125893

Gregersen, 2006, PTPN22: setting thresholds for autoimmunity, Semin. Immunol, 18, 214, 10.1016/j.smim.2006.03.009

Arechiga, 2009, Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling, J. Immunol, 182, 3343, 10.4049/jimmunol.0713370

Vang, 2005, Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant, Nat. Genet, 37, 1317, 10.1038/ng1673

Begovich, 2004, A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis, Am. J. Hum. Genet, 75, 330, 10.1086/422827

Zhang, 2011, The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness, Nat. Genet, 43, 902, 10.1038/ng.904

Dai, 2013, A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models, J. Clin. Invest, 123, 2024, 10.1172/JCI66963

Rawlings, 2015, The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human, J. Immunol, 194, 2977, 10.4049/jimmunol.1403034

Stanford, 2014, PTPN22: the archetypal non-HLA autoimmunity gene, Nat. Rev. Rheumatol, 10, 602, 10.1038/nrrheum.2014.109

Manjarrez-Orduño, 2012, CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation, Nat. Genet, 44, 1227, 10.1038/ng.2439

Simpfendorfer, 2015, Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells, Arthritis Rheumatol, 67, 2866, 10.1002/art.39301

Hom, 2008, Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX, N. Engl. J. Med, 358, 900, 10.1056/NEJMoa0707865

Dymecki, 1990, Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells, Science, 247, 332, 10.1126/science.2404338

Vahedi, 2015, Super-enhancers delineate disease-associated regulatory nodes in T cells, Nature, 10.1038/nature14154

Duerr, 2006, A genome-wide association study identifies IL23R as an inflammatory bowel disease gene, Science, 314, 1461, 10.1126/science.1135245

Nair, 2009, Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways, Nat. Genet, 41, 199, 10.1038/ng.311

Reveille, 2010, Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci, Nat. Genet, 42, 123, 10.1038/ng.513

Sarin, 2011, Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses, Proc. Natl Acad. Sci. USA, 108, 9560, 10.1073/pnas.1017854108

Remmers, 2010, Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease, Nat. Genet, 42, 698, 10.1038/ng.625

Mizuki, 2010, Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci, Nat. Genet, 42, 703, 10.1038/ng.624

Parkes, 2013, Genetic insights into common pathways and complex relationships among immune-mediated diseases, Nat. Rev. Genet, 14, 661, 10.1038/nrg3502

Hirschfield, 2009, Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants, N. Engl. J. Med, 360, 2544, 10.1056/NEJMoa0810440

Bossini-Castillo, 2012, A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations, Hum. Mol. Genet, 21, 926, 10.1093/hmg/ddr522

Mayes, 2014, Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis, Am. J. Hum. Genet, 94, 47, 10.1016/j.ajhg.2013.12.002

Jakkula, 2010, Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene, Am. J. Hum. Genet, 86, 285, 10.1016/j.ajhg.2010.01.017

Barrett, 2008, Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease, Nat. Genet, 40, 955, 10.1038/ng.175

Tsoi, 2012, Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity, Nat. Genet, 44, 1341, 10.1038/ng.2467

Westra, 2013, Systematic identification of trans eQTLs as putative drivers of known disease associations, Nat. Genet, 45, 1238, 10.1038/ng.2756

Remmers, 2007, STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus, N. Engl. J. Med, 357, 977, 10.1056/NEJMoa073003

Radstake, 2010, Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus, Nat. Genet, 42, 426, 10.1038/ng.565

Lessard, 2013, Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome, Nat. Genet, 45, 1284, 10.1038/ng.2792

Sigurdsson, 2008, A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5, Hum. Mol. Genet, 17, 2868, 10.1093/hmg/ddn184

Sakaguchi, 2008, Regulatory T cells and immune tolerance, Cell, 133, 775, 10.1016/j.cell.2008.05.009

Trynka, 2013, Chromatin marks identify critical cell types for fine mapping complex trait variants, Nat. Genet, 45, 124, 10.1038/ng.2504

Kochi, 2010, A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility, Nat. Genet, 42, 515, 10.1038/ng.583

Ferraro, 2014, Interindividual variation in human T regulatory cells, Proc. Natl Acad. Sci. USA, 111, E1111, 10.1073/pnas.1401343111

Kochi, 2005, A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities, Nat. Genet, 37, 478, 10.1038/ng1540

Kochi, 2009, FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-cell receptor-mediated signaling, J. Immunol, 183, 5502, 10.4049/jimmunol.0901982

Swainson, 2010, Expression of the autoimmune susceptibility gene FcRL3 on human regulatory T cells is associated with dysfunction and high levels of programmed cell death-1, J. Immunol, 184, 3639, 10.4049/jimmunol.0903943

Myouzen, 2012, Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese, PLoS Genet, 8, e1002949, 10.1371/journal.pgen.1002949

Schmidl, 2014, The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations, Blood, 123, e68, 10.1182/blood-2013-02-486944

Okamura, 2015, TGF-beta3-expressing CD4+CD25(-)LAG3+ regulatory T cells control humoral immune responses, Nat. Commun, 6, 6329, 10.1038/ncomms7329

Okamura, 2009, CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2, Proc. Natl Acad. Sci. USA, 106, 13974, 10.1073/pnas.0906872106

Yang, 2008, IL-21 and TGF-beta are required for differentiation of human T(H)17 cells, Nature, 454, 350, 10.1038/nature07021

Okada, 2012, Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population, Nat. Genet, 44, 511, 10.1038/ng.2231

Myouzen, 2010, Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus, Hum. Mol. Genet, 19, 2313, 10.1093/hmg/ddq092

Lopez de Padilla, 2016, The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases, Gene, 576, 14, 10.1016/j.gene.2015.09.058

Deng, 2014, Advances in lupus genetics and epigenetics, Curr. Opin. Rheumatol, 26, 482, 10.1097/BOR.0000000000000086

Liang, 2014, Therapeutic potential of STAT4 in autoimmunity, Expert Opin. Ther. Targets, 18, 945, 10.1517/14728222.2014.920325

Kariuki, 2009, Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo, J. Immunol, 182, 34, 10.4049/jimmunol.182.1.34

Salloum, 2010, Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients, Arthritis Rheum, 62, 553, 10.1002/art.27182

Wang, 2015, PTPN22 Variant R620W Is Associated With Reduced Toll-like Receptor 7-Induced Type I Interferon in Systemic Lupus Erythematosus, Arthritis Rheumatol, 67, 2403, 10.1002/art.39211

Cho, 2015, Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies, Nat. Med, 21, 730, 10.1038/nm.3897