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Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus

Nature Genetics volume 40, pages 83–89 (2008)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established1,2,3. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B6. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.

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Figure 1: Gene structure, haplotypic architecture and haplotype-TDT analysis in TNFSF4.
Figure 2: SLE susceptibility alleles are associated with an increase in TNFSF4 expression.

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Acknowledgements

This work was funded by the Wellcome Trust through a Senior Fellowship awarded to T.J.V. We acknowledge the work of P. Spencer in recruiting individuals and families into the study, and we would like to thank our clinical colleagues for helping us recruit study participants. Our thanks and appreciation is extended to all the study participants and their relatives for generously donating blood samples, and to all the general practitioners and practice nurses for collecting them. J.D.R. is funded by grants from the National Institutes of Allergy and Infectious Diseases (AI065687; AI067152) and from the National Institute of Diabetes and Digestive and Kidney Diseases (DK064869; DK062432). We appreciate the contribution to the genotyping from the Broad Institute Center for Genotyping and Analysis, which is supported by grant U54 RR020278-01 from the National Center for Research Resources. We gratefully acknowledge the work of D. Smyth at the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory for genotyping five variants from the diabetes collection. We also thank H. Stevens and the Diabetes and Inflammation Laboratory DNA team for sending EBV-transformed lymphoblastoid cell lines. We acknowledge use of DNA from the British 1958 Birth Cohort collection (D. Strachan, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02. We thank J. Todd for LCL lymphocytes and for critical reading of this manuscript.

Author information

Author notes

  1. Patrick M Gaffney, Kathy L Moser & Timothy W Behrens

    Present address: Present addresses: Arthritis and Immunology Research Programme, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA (P.M.G. and K.L.M.); Genentech Inc., South San Francisco, California 94080, USA (T.W.B.).,

Authors and Affiliations

  1. Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Deborah S Cunninghame Graham, Harinder Manku, Andrew K Wong & Timothy J Vyse

  2. Programme in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Robert R Graham & David Altshuler

  3. Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    John C Whittaker

  4. Center of Immunology, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Patrick M Gaffney, Kathy L Moser & Timothy W Behrens

  5. University of Montreal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, H1T 1C8, Quebec, Canada

    John D Rioux

  6. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    John D Rioux

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Contributions

D.S.C.G., T.J.V., H.M. and R.R.G. wrote the manuscript, A.K.W. managed the database, T.J.V. collected the UK samples, T.W.B., P.M.G. and K.L.M. provided access to the Minnesota samples, D.S.C.G. and J.D.R. performed the UK genotyping, R.R.G. and D.A. carried out the Minnesota genotyping, H.M. did the expression analysis, A.K.W. collected the lymphocytes, D.S.C.G., J.C.W. and J.D.R. did the data analysis in the UK samples and R.R.G. contributed to the analysis of the Minnesota samples.

Corresponding author

Correspondence to Timothy J Vyse.

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Graham, D., Graham, R., Manku, H. et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat Genet 40, 83–89 (2008). https://doi.org/10.1038/ng.2007.47

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