1. ¹Unit of Medical Genetics, Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden
2. ²Instituto de Biomedicina 'López-Neyra', CSIC, Granada, Spain
3. ³Department of Medicine, Medical School Hannover, Hannover, Germany
4. ⁴Department of Medical Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy
5. ⁵Rheumatology Unit, Department of Clinical Medicine, Siena University, Siena, Italy
6. ⁶Servicio Medicina Interna, Hospital Virgen de las Nieves, Granada, Spain
7. ⁷Sanatorio Parque, Rosario, Argentina
8. ⁸Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

Correspondence: Professor ME Alarcón-Riquelme, The Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, Uppsala SE-751 85, Sweden. E-mail: marta.alarcon@genpat.uu.se

⁹Other clinical collaborators who provided samples are listed in the acknowledgements.

¹⁰Bernardo Pons-Estel is the coordinator of the Argentine Collaborative Group

¹¹These authors contributed equally to this work.

Received 3 September 2008; Accepted 17 November 2008; Published online 18 December 2008.

Abstract

The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.