Abstract
Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE). More than 20 robust associations have now been identified and confirmed, providing insights at the molecular level that refine our understanding of the involvement of host immune response processes. In addition, genes with unknown roles in SLE pathophysiology have been identified. These findings may provide new routes towards improved clinical management of this complex disease.
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References
Lau, C. S., Yin, G. & Mok, M. Y. Ethnic and geographical differences in systemic lupus erythematosus: an overview. Lupus 15, 713–714 (2006).
Lockshin, M. D. Sex differences in autoimmune disease. Lupus 15, 753–756 (2006).
Uribe, A. G., McGwin, G. Jr, Reveille, J. D. & Alarcon, G. S. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; nature vs. Nurture) cohort? Where are we heading? Autoimmun. Rev. 3, 321–329 (2004).
Hochberg, M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).
Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).
Alarcon-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).
Deapen, D. et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 35, 311–318 (1992).
Moser, K. L. et al. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc. Natl Acad. Sci. USA 95, 14869–14874 (1998).
Edberg, J. C. et al. Genetic linkage and association of Fcγ receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum. 46, 2132–2140 (2002).
Prokunina, L. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nature Genet. 32, 666–669 (2002).
The International HapMap Consoritum. The International HapMap Project. Nature 426, 789–796 (2003).
M. I. McCarthy et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 9, 356–369 (2008).
Cervino, A. C., Tsinoremas, N. F. & Hoffman, R. W. A genome-wide study of lupus: preliminary analysis and data release. Ann. N. Y Acad. Sci. 1110, 131–139 (2007).
International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nature Genet. 40, 204–210 (2008).
Hom, G. et al. Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. N. Engl. J. Med. 358, 900–909 (2008).
Kozyrev, S. V. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nature Genet. 40, 211–216 (2008).
Graham, R. R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nature Genet. 40, 1059–1061 (2008).
Nath, S. K. et al. A nonsynonymous functional variant in integrinαM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nature Genet. 40, 152–154 (2008).
Sachs, U. J. H. et al. Human alloantibody anti-Mart interferes with Mac 1-dependent leukocyte adhesion. Blood 104, 727–734 (2004).
Hooks, J. J. et al. Immune interferon in the circulation of patients with autoimmune disease. N. Engl. J. Med. 301, 5–8 (1979).
Niewold, T. B., Hua, J., Lehman, T. J., Harley, J. B. & Crow, M. K. High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 8, 492–502 (2007).
Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA 100, 2610–2615 (2003).
Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3′–5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nature Genet. 39, 1065–1067 (2007).
Musone, S. L. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nature Genet. 40, 1062–1064 (2008).
Sigurdsson, S. et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76, 528–537 (2005).
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).
Cunninghame Graham, D. S. et al. Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Hum. Mol. Genet. 16, 579–591 (2007).
Jacob, C. O. et al. Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform. Arthritis Rheum. 56, 4164–4173 (2007).
Ardoin, S. P. & Pisetsky, D. S. Developments of the scientific understanding of lupus. Arthritis Res. Ther. 10, 218 (2008).
Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genet. 37, 1317–1317 (2005).
Chung, S. A. & Criswell, L. A. PTPN22: its role in SLE and autoimmunity. Autoimmunity 40, 582–590 (2007).
Gregersen, P. K., Lee, H.-S., Batliwalla, F. & Begovich, A. B. PTPN22: Setting thresholds for autoimmunity. Sem. Immunol. 18, 214–223 (2006).
Orru, 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).
Giallourakis C. et al. A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligands. Genome Res. 16, 1056–1072 (2006).
Lawrie, C. H. et al. MicroRNA expression in lymphocyte development and malignancy. Leukemia 22, 1440–1446 (2008).
Deng L. et al. An unusual haplotype polymorphism on human chromosome 8p23 derived from the inversion polymorphism. Hum. Mutat. 10, 1209–1216 (2008).
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).
Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).
Thompson, I. M. et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 294, 66–70 (2005).
Botto, M. & Walport, M. J. C1q, autoimmunity and apoptosis. Immunobiology 205, 395–406 (2002).
Fielder, A. H. et al. Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. BMJ 286, 425–428 (1983).
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).
Sullivan, K. E. et al. Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. J. Rheumatol. 21, 1128–1133 (1994).
Taylor, K. E. et al. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 30, e1000084 (2008).
Kyogoku, C. et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75, 504–507 (2004).
Edberg, J. C. et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum. Mol. Genet. 17, 1147–1155 (2008).
Graham, D. S. et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nature Genet. 40, 83–89 (2008).
Sawalha, A. H. et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3, e1727 (2008).
Acknowledgements
This work has been supported by the National Institutes of Health (grants AI24717, AR62277, AR42460, AR49084, HD07463 and GM063483), the Mary Kirkland Scholarship, the Alliance for Lupus Research and the US Department of Veterans Affairs.
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Harley, I., Kaufman, K., Langefeld, C. et al. Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet 10, 285–290 (2009). https://doi.org/10.1038/nrg2571
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DOI: https://doi.org/10.1038/nrg2571
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