Journal
GENES AND IMMUNITY
Volume 10, Issue 3, Pages 248-253Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2008.95
Keywords
systemic lupus erythematosus; TNFSF4; OX40L; genetic association study
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Funding
- Swedish Research Council
- Gustav-Ve-80-year Jubilee Foundation
- Torsten and Ragnar Soderbegs Foundation
- Marcus Borgstroms Foundation
- Swedish Association Against Rheumatism
- Knut and Alice Wallenberg Foundation through the Royal Swedish Academy of Sciences
- MIUR, Rome
- Compagnia di San Paolo (Turin)
- Regione Piemonte
- Fondazione Monte dei Paschi di Siena
- BMBF Kompetenznetz Rheuma [C2.12]
- Plan Nacional de I+D (Spain) [SAF06-00398]
- Junta de Andalucia, Spain [CTS1880]
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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. Genes and Immunity (2009) 10, 248-253; doi:10.1038/gene.2008.95; published online 18 December 2008
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