Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10−8, odds ratio = 1.70) and Korean (P = 8.33 × 10−10, odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

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  1. 1.

    , , & A20 zinc finger protein inhibits TNF and IL-1 signaling. J. Immunol. 156, 1166–1173 (1996).

  2. 2.

    et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).

  3. 3.

    et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).

  4. 4.

    et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28, 381–390 (2008).

  5. 5.

    et al. The ubiquitin modifying enzyme A20 restricts B-cell survival and prevents autoimmunity. Immunity 33, 181–191 (2010).

  6. 6.

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

  7. 7.

    et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).

  8. 8.

    et al. Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population. Ann. Rheum. Dis. 69, 1958–1964 (2010).

  9. 9.

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

  10. 10.

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

  11. 11.

    et al. Meta-analysis and imputation identifies a 109-kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations. Genes Immun. 10, 470–477 (2009).

  12. 12.

    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).

  13. 13.

    et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005).

  14. 14.

    et al. Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences. Genome Res. 15, 1051–1060 (2005).

  15. 15.

    et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

  16. 16.

    et al. Variation in transcription factor binding among humans. Science 328, 232–235 (2010).

  17. 17.

    et al. Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina. Am. J. Phys. Anthropol. 114, 18–29 (2001).

  18. 18.

    et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

  19. 19.

    et al. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J. Immunol. 184, 7001–7009 (2010).

  20. 20.

    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).

  21. 21.

    et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

  22. 22.

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

  23. 23.

    et al. A high-density admixture map for disease gene discovery in African Americans. Am. J. Hum. Genet. 74, 1001–1013 (2004).

  24. 24.

    , , , & A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications. Hum. Mutat. 29, 648–658 (2008).

  25. 25.

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

  26. 26.

    et al. Control of confounding of genetic associations in stratified populations. Am. J. Hum. Genet. 72, 1492–1504 (2003).

  27. 27.

    , , , & Design and analysis of admixture mapping studies. Am. J. Hum. Genet. 74, 965–978 (2004).

  28. 28.

    1000 Genomes Project Consortium et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  29. 29.

    et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  30. 30.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  31. 31.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  32. 32.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

  33. 33.

    et al. The genetic structure and history of Africans and African Americans. Science 324, 1035–1044 (2009).

  34. 34.

    , , , & Admixture in Hispanics: distribution of ancestral population contributions in the continental United States. Hum. Biol. 75, 1–11 (2003).

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We are thankful to all the individuals with SLE and to the controls that participated in this study. We are grateful to the research assistants, coordinators and physicians that helped in the recruitment of subjects. We would like to thank the following individuals for contributing samples genotyped in this study: S. D'Alfonso (Italy), R. Scorza (Italy), P. Junker and H. Laustrup (Denmark), M. Bijl (Holland), E. Endreffy (Hungary), C. Vasconcelos and B.M. da Silva (Portugal), A. Suarez and C. Gutierrez (Spain), I. Rúa-Figueroa (Spain) and C. Garcilazo (Argentina). For the Asociación Andaluza de Enfermedades Autoimmunes (AADEA) collaboration: N. Ortego-Centeno (Spain), J. Jimenez-Alonso (Spain), E. de Ramon (Spain) and J. Sanchez-Roman (Spain). For the collaboration on Hispanic populations enriched for Amerindian-European admixture: M. Cardiel (Mexico), I.G. de la Torre (Mexico), M. Maradiaga (Mexico), J.F. Moctezuma (Mexico), E. Acevedo (Peru), C. Castel and M. Busajm (Argentina), and J. Musuruana (Argentina). Other participants from the Argentine Collaborative Group are: H.R. Scherbarth, P.C. Marino, E.L. Motta, S. Gamron, C. Drenkard, E. Menso, A. Allievi, G.A. Tate, J.L. Presas, S.A. Palatnik, M. Abdala, M. Bearzotti, A. Alvarellos, F. Caeiro, A. Bertoli, S. Paira, S. Roverano, C.E. Graf, E. Bertero, C. Guillerón, S. Grimaudo, J. Manni, L.J. Catoggio, E.R. Soriano, C.D. Santos, C. Prigione, F.A. Ramos, S.M. Navarro, G.A. Berbotto, M. Jorfen, E.J. Romero, M.A. Garcia, J.C. Marcos, A.I. Marcos, C.E. Perandones, A. Eimon and C.G. Battagliotti.

We thank M.C. Comeau, M.C. Marion, P.S. Ramos, A. Williams, J. Zigler, A. Adler, S. Frank, S. Glenn and M.L. Zhu for their assistance in genotyping, quality control analyses and clinical data management; R. Lu and N. Dominguez for their assistance with EMSA; J.D. Capra for his critical reading of the manuscript; and the staff of the Lupus Family Registry and Repository (LFRR) for collecting and maintaining SLE samples. Support for this work was obtained from the US National Institutes of Health grants R01 AI063274 and R01 AR056360 (P.M.G.); R01 AR043274 (K.L.M.); N01 AR62277, R37 24717, R01 AR042460, P01 AI083194, P20 RR020143, R01 DE018209 (J.B.H.); P01 AR49084 (R.P.K. and E.E.B); R01 AR33062 (R.P.K.); P30 AR055385 (E.E.B); K08 AI083790, LRP AI071651, UL1 RR024999 (T.B.N.); R01CA141700, RC1 AR058621 (M.E.A.-R.); R01AR051545-01A2, ULI RR025014-02 (A.M.S.); P30 AR053483, N01 AI50026 (J.A.J. and J.M.G.); P20 RR015577 (J.A.J.); R21 AI070304, R01 AI070983 (S.A.B.); R01 AR43814 (B.P.T.); P60 AR053308, M01 RR-00079 (L.A.C.); R01 AR043727, UL1 RR025005 (M.A.P.). A portion of this study was supported by a grant of the Korea Healthcare Technology Research and Development Project, Ministry for Health and Welfare, Republic of Korea (A010252, A080588; S.-C.B.). Additional support was granted from the Alliance for Lupus Research (K.L.M.); Merit Award from the US Department of Veterans Affairs (J.B.H. and G.S.G.); the Swedish Research Council for Medicine, Gustaf Vth-80th Jubilee Fund and Swedish Association Against Rheumatism, Instituto de Salud Carlos III, Oklahoma Center for Advancement of Science and Technology (OCAST) HR09-106 (M.E.A.-R.); the European Science Foundation funds the BIOLUPUS network (M.E.A.-R. coordinator); the Barrett Scholarship Fund Oklahoma Medical Research Foundation (OMRF) (C.J.L.); Lupus Research Institute (T.B.N.); The Alliance for Lupus Research (T.B.N., L.A.C. and C.O.J.); the Arthritis National Research Foundation Eng Tan Scholar Award (T.B.N.); Arthritis Foundation (P.M.G. and A.M.S.); the Lupus Foundation of Minnesota (P.M.G. and K.L.M.); the Wellcome Trust (T.J.V.); Arthritis Research UK (T.J.V.); Kirkland Scholar Award (L.A.C.); and Wake Forest University Health Sciences Center for Public Health Genomics (C.D.L.). The work reported on in this publication has been in part financially supported by the European Science Foundation (ESF), in the framework of the Research Networking Programme European Science Foundation-The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) 07-RNP-083.

Author information

Author notes

    • Mary Beth Humphrey
    • , Courtney Gray Montgomery
    •  & Patrick M Gaffney

    These authors jointly directed this work.


  1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Indra Adrianto
    • , Feng Wen
    • , Graham Wiley
    • , Christopher J Lessard
    • , Jared S Bates
    • , Jennifer A Kelly
    • , Kenneth M Kaufman
    • , Joel M Guthridge
    • , Marta E Alarcón-Riquelme
    • , Judith A James
    • , R Hal Scofield
    • , Kathy L Moser
    • , Courtney Gray Montgomery
    •  & Patrick M Gaffney
  2. College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Amanda Templeton
    • , Jarrod B King
    • , Christopher J Lessard
    • , Yanqing Hu
    • , Kenneth M Kaufman
    • , Judith A James
    • , R Hal Scofield
    • , Kathy L Moser
    •  & Mary Beth Humphrey
  3. US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.

    • Kenneth M Kaufman
    •  & John B Harley
  4. Center for Genomics and Oncological Research (GENyO), Granada, Spain.

    • Marta E Alarcón-Riquelme
  5. Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.

    • Juan-Manuel Anaya
  6. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.

    • Sang-Cheol Bae
    • , So-Young Bang
    •  & So-Yeon Park
  7. Division of Rheumatology, University of Colorado Denver, Aurora, Colorado, USA.

    • Susan A Boackle
  8. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Elizabeth E Brown
  9. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Michelle A Petri
  10. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

    • Caroline Gallant
  11. Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Rosalind Ramsey-Goldman
  12. Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • John D Reveille
  13. Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.

    • Luis M Vila
  14. Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, California, USA.

    • Lindsey A Criswell
  15. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Jeffrey C Edberg
    •  & Robert P Kimberly
  16. Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

    • Barry I Freedman
  17. The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore Long Island Jewish (LIJ) Health System, Manhasset, New York, USA.

    • Peter K Gregersen
  18. Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Gary S Gilkeson
    •  & Diane L Kamen
  19. Department of Medicine, University of Southern California, Los Angeles, California, USA.

    • Chaim O Jacob
  20. Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.

    • Javier Martin
  21. Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Joan T Merrill
  22. Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.

    • Timothy B Niewold
  23. Sanatorio Parque, Rosario, Argentina.

    • Bernardo A Pons-Estel
  24. Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Anne M Stevens
  25. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Anne M Stevens
  26. Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, California, USA.

    • Betty P Tsao
  27. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Timothy J Vyse
  28. Division of Immunology, Infection and Inflammatory Diseases, Kings College London, London, UK.

    • Timothy J Vyse
  29. Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

    • Carl D Langefeld
  30. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • John B Harley
  31. Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Carol F Webb


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P.M.G., C.G.M., K.L.M., C.J.L., J.A.K., K.M.K., C.D.L. and J.B.H. selected SNPs and were responsible for the study design. J.M.G., M.E.A.-R., J.-M.A., S.-C.B., S.-Y.B., S.A.B., E.E.B., M.A.P., C.G., R.R.-G., J.D.R., L.M.V., L.A.C., J.C.E., B.I.F., P.K.G., G.S.G., C.O.J., J.A.J., D.L.K., R.P.K., J.M., J.T.M., T.B.N., S.-Y.P., B.A.P.-E., R.H.S., A.M.S., B.P.T., L.M.V., T.J.V., J.B.H., K.L.M. and P.M.G. assisted in the collection and characterization of the SLE cases and controls. K.M.K. and P.M.G. performed the genotyping. K.M.K. and C.D.L. performed quality control analyses. I.A. and J.S.B. performed association analyses and imputation under the guidance of C.G.M. and P.M.G. F.W., G.W. and P.M.G. performed the sequencing. F.W., A.T., J.B.K., Y.H., C.F.W., M.B.H. and P.M.G. performed functional studies. I.A., C.G.M. and P.M.G. prepared the manuscript. All authors approved the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Patrick M Gaffney.

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    Supplementary Table 4

    Genotyping results of all observed and imputed markers

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