Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rönnblom, L. & Pascual, V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17, 394–399 (2008).
Vyse, T.J. & Todd, J.A. Genetic analysis of autoimmune disease. Cell 85, 311–318 (1996).
Cunninghame Graham, D.S. et al. Polymorphism at the TNF superfamily gene OX40L confers susceptibility to systemic lupus erythematosus. Nat. Genet. 40, 83–89 (2008).
Graham, R.R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).
Graham, R.R., Hom, G., Ortmann, W. & Behrens, T.W. Review of recent genome-wide association scans in lupus. J. Intern. Med. 265, 680–688 (2009).
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).
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. Nat. Genet. 40, 211–216 (2008); erratum 40, 484 (2004).
Sawalha, A.H. et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3, e1727 (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).
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).
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).
Heyninck, K., Kreike, M.M. & Beyaert, R. Structure-function analysis of the A20-binding inhibitor of NF-κB activation, ABIN-1. FEBS Lett. 536, 135–140 (2003).
Musone, S.L. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).
Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).
Fung, E.Y. et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun. 10, 188–191 (2009).
Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).
Johansson, A. et al. Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum. Mol. Genet. 18, 373–380 (2009).
Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).
Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y. & Shirakawa, M. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455, 818–821 (2008).
Diveu, C., McGeachy, M.J. & Cua, D.J. Cytokines that regulate autoimmunity. Curr. Opin. Immunol. 20, 663–668 (2008).
Nath, S.K., Harley, J.B. & Lee, Y.H. Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum. Genet. 118, 225–234 (2005).
Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).
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).
Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
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).
Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617–619 (2006).
Sutherland, A. et al. Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves' disease susceptibility. J. Clin. Endocrinol. Metab. 92, 3338–3341 (2007).
Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462 (2006).
Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).
Hirschhorn, J.N. & Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).
Awata, T. et al. Association of type 1 diabetes with two loci on 12q13 and 16p13 and the influence of coexisting thyroid autoimmunity in Japanese. J. Clin. Endocrinol. Metab. 94, 231–235 (2009).
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).
Zoledziewska, M. et al. Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia. Genes Immun. 10, 15–17 (2009).
Fisher, S.A. et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat. Genet. 40, 710–712 (2008).
Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).
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).
Mitchell, M.K., Gregersen, P.K., Johnson, S., Parsons, R. & Vlahov, D. The New York Cancer Project: rationale, organization, design, and baseline characteristics. J. Urban Health 81, 301–310 (2004).
Plenge, R.M. et al. TRAF1–C5 as a risk locus for rheumatoid arthritis—a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).
Hochberg, M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).
Kosoy, R. et al. Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum. Mutat. 30, 69–78 (2009).
Tian, C. et al. Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet. 4, e4 (2008).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Li, Y. & Mach Abecasis, G. Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am. J. Hum. Genet. S79, 2290 (2006).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
We thank the many affected individuals and physicians who contributed DNA samples and clinical data for this study; M.I. Kamboh and P. Davies for the use of Alzheimer's disease samples as controls in our study; B. Neale for assistance in the percent of genetic variance explained calculation; and S. Sanna and C. Willer for assistance in generating regional association plots. Genotyping of the Swedish samples by the 12K chips was performed using equipment of the SNP technology platform in Uppsala. We thank C. Enström and A.-C. Wiman for assistance with genotyping. Financial support was obtained from the Swedish Research Council for Medicine, the Knut and Alice Wallenberg Foundation the Swedish Rheumatism Association, the King Gustaf V 80th Birthday Foundation, COMBINE, and a Target Identification in Lupus (TIL) grant from the Alliance for Lupus Research, US. This work was supported in part by R01 AR44804, K24 AR02175, the Mary Kirkland Center for Lupus Research, RO1 AR43727 and Institute for Clinical and Translational Research UL1RR025005. These studies were performed in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources, 5 M01 RR-00079, US Public Health Service.
The authors Robert R Graham, Timothy W Behrens, Geoff Hom, Vesela Gateva, Xin Sun, Ward Ortmann and Ricardo C Ferreira were fulltime employees of Genentech, Inc at the time of the work. Robert R Graham and Timothy W Behrens have applied for a patent based on this work.
About this article
Cite this article
Gateva, V., Sandling, J., Hom, G. 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). https://doi.org/10.1038/ng.468
Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases
Human Genetics (2020)
From genome-wide association studies to rational drug target prioritisation in inflammatory arthritis
The Lancet Rheumatology (2020)
Alterations in Circulating Fatty Acid Are Associated With Gut Microbiota Dysbiosis and Inflammation in Multiple Sclerosis
Frontiers in Immunology (2020)