Abstract
Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case–control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. Most SLE-associated gene products participate in key pathogenic pathways, including Toll-like receptor and type I interferon signaling pathways, immune regulation pathways and those that control the clearance of immune complexes. Disease-associated loci that have not yet been demonstrated to have important functions in the immune system might provide new clues to the underlying molecular mechanisms that contribute to the pathogenesis or progression of SLE. Of note, genetic risk factors that are shared between SLE and other immune-related diseases highlight common pathways in the pathophysiology of these diseases, and might provide innovative molecular targets for therapeutic interventions.
Key Points
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Innovations in genotyping technology such as candidate gene studies and genome-wide association studies (GWAS) have advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE)
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GWAS and candidate gene studies using both European and Asian populations identified and confirmed more than 30 robust SLE susceptibility loci
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Genetic associations identified in various ethnic groups not only highlight major SLE susceptibility genes that are common to multiple ethnic populations, but also indicate those loci with population-specific effects
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Most SLE-associated gene products participate in key pathways involved in the disease pathogenesis and genetic risk factors that are shared between autoimmune diseases can help to identify common disease pathways
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Novel SLE risk loci can reveal new paradigms for the pathogenesis of the disease, and might provide new therapeutic targets for disease management
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References
Deapen, D. et al. A revised estimate of twin concordance in SLE. Arthritis Rheum. 35, 311–318 (1992).
Alarcón-Segovia, D. et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 52, 1138–1147 (2005).
Nath, S. K. et al. A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat. Genet. 40, 152–154 (2008).
Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).
Harley, J. B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).
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).
Graham, R. R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).
Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).
Han, J. W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).
Yang, W. et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 6, e1000841 (2010).
Moser, K. L., Kelly, J. A., Lessard, C. J. & Harley, J. B. Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun. 10, 373–379 (2009).
Harley, I. T., 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).
Rhodes, B. & Vyse, T. J. The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology (Oxford) 47, 1603–1611 (2008).
Crow, M. K. Collaboration, genetic associations, and lupus erythematosus. N. Engl. J. Med. 358, 956–961 (2008).
Vyse, T. J. & Todd, J. A. Genetic analysis of autoimmune disease. Cell 85, 311–318 (1996).
Goldberg, M. A., Arnett, F. C., Bias, W. B. & Shulman, L. E. Histocompatibility antigens in systemic lupus erythematosus. Arthritis Rheum. 19, 129–132 (1976).
The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923 (1999).
Tsao, B. P. in Dubois' Lupus Erythematosus, 6th edn (eds Wallace, D. J. & Hahn, B. H.) 97–120 (Lippincott Williams & Wilkins, Philadelphia, 2002).
Graham, R. R. et al. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am. J. Hum. Genet. 71, 543–553 (2002).
Doherty, D. G. et al. Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese. Arthritis Rheum. 35, 641–646 (1992).
Hong, G. H. et al. Association of complement C4 and HLA-DR alleles with systemic lupus erythematosus in Koreans. J. Rheumatol. 21, 442–447 (1994).
Lee, H. S. et al. Independent association of HLA-DR and Fcγ receptor polymorphisms in Korean patients with systemic lupus erythematosus. Rheumatology (Oxford) 42, 1501–1507 (2003).
Jiang, C. et al. Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens. J. Immunol. 184, 1085–1091 (2010).
Walport, M. J. Complement. Second of two parts. N. Engl. J. Med. 344, 1140–1144 (2001).
Wu, Y. L., Hauptmann, G., Viguier, M. & Yu, C. Y. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immun. 10, 433–445 (2009).
Truedsson, L., Bengtsson, A. A. & Sturfelt, G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40, 560–566 (2007).
Schifferli, J. A., Steiger, G., Paccaud, J. P., Sjöholm, A. G. & Hauptmann, G. Difference in the biological properties of the two forms of the fourth component of human complement (C4). Clin. Exp. Immunol. 63, 473–477 (1986).
Blanchong, C. A. et al. Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologs, Slp and C4. Int. Immunopharmacol. 1, 365–392 (2001).
Pickering, M. C. & Walport, M. J. Links between complement abnormalities and systemic lupus erythematosus. Rheumatology (Oxford) 39, 133–141 (2000).
Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).
Fernando, M. M. et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet. 3, e192 (2007).
Yang, Z., Shen, L., Dangel, A. W., Wu, L. C. & Yu, C. Y. Four ubiquitously expressed genes, RD(D6S45)–SKI2W(SKIV2L)–DOM3Z–RP1(D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 53, 338–347 (1998).
Barcellos, L. F. et al. High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet. 5, e1000696 (2009).
Graham, R. R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38, 550–555 (2006).
Graham, R. R. et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl Acad. Sci. USA 104, 6758–6763 (2007).
Sigurdsson, S. et al. Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. Hum. Mol. Genet. 17, 872–881 (2008).
Demirci, F. Y. et al. Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE). Ann. Hum. Genet. 71, 308–311 (2007).
Shin, H. D. et al. Replication of the genetic effects of IFN regulatory factor 5 (IRF5) on systemic lupus erythematosus in a Korean population. Arthritis Res. Ther. 9, R32 (2007).
Kawasaki, A. et al. Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms. Arthritis Rheum. 58, 826–834 (2008).
Siu, H. O. et al. Association of a haplotype of IRF5 gene with systemic lupus erythematosus in Chinese. J. Rheumatol. 35, 360–362 (2008).
Kelly, J. A. et al. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun. 9, 187–194 (2008).
Löfgren, S. E. et al. Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells. J. Rheumatol. 37, 574–578 (2010).
Niewold, T. B. et al. Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients. Arthritis Rheum. 58, 2481–2487 (2008).
Rullo, O. J. et al. Association of IRF5 polymorphisms with activation of the interferon-α pathway. Ann. Rheum. Dis. 69, 611–617 (2010).
Richez, C. et al. IFN regulatory factor 5 is required for disease development in the FcγRIIB−/−Yaa and FcγRIIB−/− mouse models of systemic lupus erythematosus. J. Immunol. 184, 796–806 (2010).
Remmers, E. F. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).
Taylor, K. E. et al. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 4, e1000084 (2008).
Palomino-Morales, R. J. et al. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians. Genes Immun. 9, 379–382 (2008).
Kawasaki, A. et al. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1–STAT4 region. Arthritis Res. Ther. 10, R113 (2008).
Sigurdsson, S. et al. A risk haplotype of STAT4 for systemic lupus erythematosus is overexpressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum. Mol. Genet. 17, 2868–2876 (2008).
Kariuki, S. N. et al. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-α in lupus patients in vivo. J. Immunol. 182, 34–38 (2009).
Abelson, A. K. et al. STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann. Rheum. Dis. 68, 1746–1753 (2009).
Namjou, B. et al. High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups. Arthritis Rheum. 60, 1085–1095 (2009).
Cohen, S., Dadi, H., Shaoul, E., Sharfe, N. & Roifman, C. M. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 93, 2013–2024 (1999).
Gregersen, P. K. & Olsson, L. M. Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27, 363–391 (2009).
Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).
Orrú, V. et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum. Mol. Genet. 18, 569–579 (2009).
Kariuki, S. N., Crow, M. K. & Niewold, T. B. The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-α activity and low tumor necrosis factor α levels in patients with lupus. Arthritis Rheum. 58, 2818–2823 (2008).
Bredius, R. G. et al. Phagocytosis of Staphylococcus aureus and Hemophilus influenzae type B opsonized with polyclonal human IgG1 and IgG2 antibodies. Functional hFcγ RIIa polymorphism to IgG2. J. Immunol. 151, 1463–1472 (1993).
Duits, A. J. et al. Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum. 38, 1832–1836 (1995).
Yap, S. N., Phipps, M. E., Manivasagar, M., Tan, S. Y. & Bosco, J. J. Human Fcγ receptor IIA (FcγRIIA) genotyping and association with systemic lupus erythematosus (SLE) in Chinese and Malays in Malaysia. Lupus 8, 305–310 (1999).
Chen, J. Y. et al. Fcγ receptor IIa, IIIa, and IIIb polymorphisms of systemic lupus erythematosus in Taiwan. Ann. Rheum. Dis. 63, 877–880 (2004).
Salmon, J. E. et al. Fcγ RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J. Clin. Invest. 97, 1348–1354 (1996).
Song, Y. W. et al. Abnormal distribution of Fcγ receptor type IIa polymorphisms in Korean patients with systemic lupus erythematosus. Arthritis Rheum. 41, 421–426 (1998).
Koene, H. R. et al. The FcγRIIIA-158F allele is a risk factor for systemic lupus erythematosus. Arthritis Rheum. 41, 1813–1818 (1998).
Alarcón, G. S. et al. Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort. PLoS Med. 3, e396 (2006).
Zuniga, R. et al. Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCγ receptor type IIA alleles. Arthritis Rheum. 48, 460–470 (2003).
Magnusson, V. et al. Both risk alleles for FcγRIIA and FcγRIIIA are susceptibility factors for SLE: a unifying hypothesis. Genes Immun. 5, 130–137 (2004).
Sullivan, K. E. et al. Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology (Oxford) 42, 446–452 (2003).
Kyogoku, C. et al. Fcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 46, 1242–1254 (2002).
Siriboonrit, U. et al. Association of Fcγ receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 61, 374–383 (2003).
Chu, Z. T. et al. Association of Fcγ receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 63, 21–27 (2004).
Li, X. et al. A novel polymorphism in the Fcγ receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum. 48, 3242–3252 (2003).
Kyogoku, C., Tsuchiya, N., Wu, H., Tsao, B. P. & Tokunaga, K. Association of Fcγ receptor IIA, but not IIB and IIIA, polymorphisms with systemic lupus erythematosus: a family-based association study in Caucasians. Arthritis Rheum. 50, 671–673 (2004).
Magnusson, V. et al. Polymorphisms of the Fcγ receptor type IIB gene are not associated with systemic lupus erythematosus in the Swedish population. Arthritis Rheum. 50, 1348–1350 (2004).
Floto, R. A. et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nat. Med. 11, 1056–1058 (2005).
Su, K. et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcγRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function. J. Immunol. 172, 7192–7199 (2004).
Salmon, J. E., Edberg, J. C. & Kimberly, R. P. Fcγ receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J. Clin. Invest. 85, 1287–1295 (1990).
Hatta, Y. et al. Association of Fcγ receptor IIIB, but not of Fcγ receptor IIA and IIIA polymorphisms with systemic lupus erythematosus in Japanese. Genes Immun. 1, 53–60 (1999).
Clark, M. R., Liu, L., Clarkson, S. B., Ory, P. A. & Goldstein, I. M. An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus. J. Clin. Invest. 86, 341–346 (1990).
Koene, H. R., Kleijer, M., Roos, D., de Hasse, M. & Von dem Borne, A. E. FcγRIIIB gene duplication: evidence for presence and expression of three distinct FcγRIIIB genes in NA(1+,2+)SH(+) individuals. Blood 91, 673–679 (1998).
Willcocks, L. C. et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J. Exp. Med. 205, 1573–1582 (2008).
Walport, M. J., Davies, K. A. & Botto, M. C1q and systemic lupus erythematosus. Immunobiology 199, 265–285 (1998).
Racila, D. M. et al. Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 12, 124–132 (2003).
Namjou, B. et al. Evaluation of C1q genomic region in minority racial groups of lupus. Genes Immun. 10, 517–524 (2009).
Yamada, M. et al. Complement C1q regulates LPS-induced cytokine production in bone marrow-derived dendritic cells. Eur. J. Immunol. 34, 221–230 (2004).
Lood, C. et al. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 60, 3081–3090 (2009).
Kollewe, C. et al. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adaptor in interleukin-1 signaling. J. Biol. Chem. 279, 5227–5236 (2004).
Jacob, C. O. et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 106, 6256–6261 (2009).
Sawalha, A. H. et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3, e1727 (2008).
Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
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).
Ramantani, G. et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi–Goutières syndrome. Arthritis Rheum. 62, 1469–1477 (2010).
Ito, T. et al. OX40 ligand shuts down IL-10-producing regulatory T cells. Proc. Natl Acad. Sci. USA 103, 13138–13143 (2006).
Stüber, E., Neurath, M., Calderhead, D., Fell, H. P. & Strober, W. Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity 2, 507–521 (1995).
Cunninghame Graham, D. S. et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat. Genet. 40, 83–89 (2008).
Delgado-Vega, A. M. et al. Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus. Genes Immun. 10, 248–253 (2009).
Hagiwara, E., Gourley, M. F., Lee, S. & Klinman, D. K. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-γ-secreting cells in the peripheral blood. Arthritis Rheum. 39, 379–385 (1996).
Eskdale, J. et al. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc. Natl Acad. Sci. USA 95, 9465–9470 (1998).
Eskdale, J., Wordsworth, P., Bowman, S., Field, M. & Gallagher, G. Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 49, 635–639 (1997).
Mehrian, R. et al. Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to SLE. Arthritis Rheum. 41, 596–602 (1998).
Chong, W. P. et al. Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus. Genes Immun. 5, 484–492 (2004).
Bengtsson, A. A. et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 9, 664–671 (2000).
Okamoto, T. NFκB and rheumatic diseases. Endocr. Metab. Immune Disord. Drug Targets 6, 359–372 (2006).
Beyaert, R., Heyninck, K. & Van Huffel, S. A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. Biochem. Pharmacol. 60, 1143–1151 (2000).
Shimane, K. et al. The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population. Arthritis Rheum. 62, 574–579 (2010).
Salloum, R. et al. Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients. Arthritis Rheum. 62, 553–561 (2010).
Reth, M. & Wienands, J. Initiation and processing of signals from the B cell antigen receptor. Annu. Rev. Immunol. 15, 453–479 (1997).
Zhang, Z. et al. The association of the BLK gene with SLE was replicated in Chinese Han. Arch. Dermatol. Res. 302, 619–624 (2010).
Ito, I. et al. Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis Rheum. 60, 553–558 (2009).
Yokoyama, K. et al. BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor. EMBO J. 21, 83–92 (2002).
Maier, H., Colbert, J., Fitzsimmons, D., Clark, D. R. & Hagman, J. Activation of the early B-cell-specific mb-1 (Ig-α) gene by Pax-5 is dependent on an unmethylated Ets binding site. Mol. Cell. Biol. 23, 1946–1960 (2003).
Moisan, J., Grenningloh, R., Bettelli, E., Oukka, M. & Ho, I. C. Ets-1 is a negative regulator of TH17 differentiation. J. Exp. Med. 204, 2825–2835 (2007).
Wang, D. et al. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int. Immunol. 17, 1179–1191 (2005).
Wojcik, H., Griffiths, E., Staggs, S., Hagman, J. & Winandy, S. Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis. Eur. J. Immunol. 37, 1022–1032 (2007).
Luo, B. H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).
Han, S. et al. Evaluation of imputation-based association in and around the integrin-αM (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum. Mol. Genet. 18, 1171–1180 (2009).
Yang, W. et al. ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum. Mol. Genet. 18, 2063–2070 (2009).
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Comparison of GWAS findings between European and Asian populations (DOC 162 kb)
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Deng, Y., Tsao, B. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6, 683–692 (2010). https://doi.org/10.1038/nrrheum.2010.176
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