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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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.
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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.
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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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DOI: https://doi.org/10.1038/ng.2007.47
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