Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Abstract

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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Figure 1: Variants in the TNFAIP3 region associated with SLE.
Figure 2: TNFAIP3 haplotype and conditional association analyses.
Figure 3: Functional characterization of the TT>A polymorphic dinucleotide and TNFAIP3 risk haplotype.

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Acknowledgements

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.

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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.

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Correspondence to Patrick M Gaffney.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 and 5–8 (PDF 6722 kb)

Supplementary Table 4

Genotyping results of all observed and imputed markers (XLS 647 kb)

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Adrianto, I., Wen, F., Templeton, A. et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet 43, 253–258 (2011). https://doi.org/10.1038/ng.766

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