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Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors. We carried out a genome-wide association scan and replication study and found an association between SLE and a variant in TNFAIP3 (rs5029939, meta-analysis P = 2.89 × 10−12, OR = 2.29). We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA). These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA.

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Figure 1: A genome-wide association scan in SLE identifies TNFAIP3 as a risk locus.

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Acknowledgements

Support for this work was obtained from the US National Institutes of Health (grants AI063274 (P.M.G.), AR052125 (P.M.G.) and AR043247 (K.L.M.)), NIH NSRA award (5F32AR50927-RRG), Lupus Foundation of Minnesota (P.M.G., K.L.M.) and the Arthritis Foundation (K.L.M.).

This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. Permission for use of these data was obtained from the oversight committees of the respective cohorts. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the “Molecular Genetics of Schizophrenia II” (MGS-2) collaboration. The investigators and co-investigators are as follows: ENH/Northwestern University, MH059571, P.V. Gejman (Collaboration Coordinator; PI), A.R. Sanders; Emory University School of Medicine, MH59587, F. Amin (PI); Louisiana State University Health Sciences Center, New Orleans, Louisiana, MH067257, N. Buccola (PI); University of California-Irvine, MH60870, W. Byerley (PI); Washington University, St. Louis, U01, MH060879, C.R. Cloninger (PI); University of Iowa, Iowa, MH59566, R. Crowe (PI), D. Black; University of Colorado, MH059565, R. Freedman (PI); University of Pennsylvania, MH061675, D. Levinson (PI); University of Queensland, MH059588, B. Mowry (PI); Mt. Sinai School of Medicine, MH59586, J. Silverman (PI). The samples were collected by V.L. Nimgaonkar's group at the University of Pittsburgh, as part of a multi-institutional collaborative research project with J. Smoller and P. Sklar (Massachusetts General Hospital) (grant MH 63420).

We thank T. Hudson for helpful discussions, T. McKenzie for coordinating the GenES study, J.O. Claudio for ensuring ethics approval of DNA sample sharing, J. Su for assistance with management of the GenES database and all the CaNIOS investigators that have contributed to GenES. GenES is funded by the Canadian Institute of Health Research (CIHR# 62840).

We thank S. Gabriel and the entire Affymetrix genotyping team at the Broad Institute of Harvard and MIT. We thank F. Kuruvilla, J. Korn and S. McCarroll for assistance with the Birdseed genotype-calling algorithm.

We would also like to acknowledge the research assistants and coordinators that recruited the individuals in the study. Most importantly, we thank the individuals who have participated in and contributed to these studies.

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R.R.G., C.C., C.J.L., J.M.L., D.A., K.L.M. and P.M.G. wrote the manuscript with input from coauthors. R.R.G., C.C. and R.M.P. performed the analyses under the supervision of D.A. and M.J.D. L.D., R.H., N.P.B., C. Guiducci, M.P. and C. Gates generated the genotype data. J.E.W., J.D.R., P.R.F., D.C.G., A.K.W., T.J.V. and T.W.B. assisted in the collection and characterization of SLE samples. R.R.G., C.C., D.A., M.J.D., K.L.M. and P.M.G. were responsible for the study design. D.A., K.L.M. and P.M.G. directed the project.

Corresponding author

Correspondence to Patrick M Gaffney.

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Supplementary Methods, Supplementary Figures 1–3, Supplementary Tables 1–3 (PDF 2742 kb)

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Graham, R., Cotsapas, C., Davies, L. et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40, 1059–1061 (2008). https://doi.org/10.1038/ng.200

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