Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus

• Published in: Genes and immunity Vol. 10; no. 3; pp. 248 - 253
• Main Authors: Delgado-Vega, A M, Abelson, A-K, Sánchez, E, Witte, T, D'Alfonso, S, Galeazzi, M, Jiménez-Alonso, J, Pons-Estel, B A, Martin, J, Alarcón-Riquelme, M E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2009; Nature Publishing Group
• Subjects: Alleles; Association analysis; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Cell activation; Cytokines; Gene Expression; Gene Frequency - genetics; Genes; Genetic aspects; genetic association study; Genetic diversity; Genetic Predisposition to Disease; Genetics; Haplotypes; Human Genetics; Humans; Immunology; Ligands; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocytes; Lymphocytes T; MEDICIN; MEDICINE; original-article; OX40 Ligand - genetics; OX40L; Ox40L protein; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic; Replication; Risk factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Systemic lupus erythematosus; TNFSF4; Tumor necrosis factor; Tumor necrosis factor-TNF; Sweden; Argentina; United States > US; Oklahoma; Italy; Germany; Spain; OX40L; systemic lupus erythematosus; genetic association study
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2008.95

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.