Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of experimental design.
Figure 2: Newly discovered genome-wide significant associations in SLE.
Figure 3

Similar content being viewed by others

References

  1. Rönnblom, L. & Pascual, V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17, 394–399 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vyse, T.J. & Todd, J.A. Genetic analysis of autoimmune disease. Cell 85, 311–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. Graham, R.R. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat. Genet. 40, 1059–1061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. Sawalha, A.H. et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3, e1727 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Musone, S.L. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. Diveu, C., McGeachy, M.J. & Cua, D.J. Cytokines that regulate autoimmunity. Curr. Opin. Immunol. 20, 663–668 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hirschhorn, J.N. & Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hochberg, M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tian, C. et al. Analysis and application of European genetic substructure using 300 K SNP information. PLoS Genet. 4, e4 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, Y. & Mach Abecasis, G. Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  45. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

V.G. and J.K.S. performed the primary statistical analyses and contributed to initial manuscript preparation; J.K.S managed DNA samples and performed genotyping. G.H. contributed to the statistical analyses and experimental design. K.E.T. and S.A.C. performed statistical analyses and contributed to manuscript preparation. X.S., W.O. and R.C.F. managed DNA samples and contributed to experimental design. G.N., I.G., E.S., L.P., G.S., A.J., A.A.B., S.R.-D., E.C.B, E.E.B., G.S.A., J.C.E., R.R.-G., G.M. Jr., J.D.R., L.M.V., R.P.K., S.M. and M.A.P. provided samples and phenotype information. A.L. managed samples and oversaw genotyping efforts. P.K.G. provided samples and contributed to the initial manuscript preparation. M.F.S. and R.K. contributed statistical analyses and contributed to the selection of the ancestry-informative markers. L.R., L.A.C. and A.-C.S. contributed samples, input into experimental design, data interpretation and initial manuscript preparation; A.-C.S. oversaw genotyping efforts. R.R.G. and T.W.B. contributed to experimental design and interpretation, statistical analyses and initial manuscript preparation. All authors contributed to the final paper.

Corresponding author

Correspondence to Robert R Graham.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–4 (PDF 401 kb)

Rights and permissions

Reprints and permissions

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.468

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing