Letter abstract

Nature Genetics 40, 83 - 89 (2008)
Published online: 2 December 2007 | doi:10.1038/ng.2007.47

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

Deborah S Cunninghame Graham1, Robert R Graham2, Harinder Manku1, Andrew K Wong1, John C Whittaker3, Patrick M Gaffney4,7, Kathy L Moser4,7, John D Rioux5,6, David Altshuler2, Timothy W Behrens4,7 & Timothy J Vyse1


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.

  1. Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
  2. Programme in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
  3. Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
  4. Center of Immunology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
  5. University of Montreal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.
  6. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
  7. 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.).

Correspondence to: Timothy J Vyse1 e-mail: t.vyse@imperial.ac.uk