Delgado-Vega Angélica M, Abelson Anna-Karin, Sánchez Elena, Witte Torsten, D'Alfonso Sandra, Galeazzi Mauro, Jiménez-Alonso Juan, Pons-Estel Bernardo A, Martin Javier, Alarcón-Riquelme Marta E
Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, Sweden.
Instituto de Biomedicina "López-Neyra", CSIC, Granada, Spain.
Genes Immun. 2009 Apr;10(3):248-53. doi: 10.1038/gene.2008.95. Epub 2008 Dec 18.
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.
肿瘤坏死因子配体超家族成员4基因（TNFSF4）编码OX40配体（OX40L），这是一种参与T细胞活化的共刺激分子。最近一项研究表明，位于上游区域的TNFSF4单倍型与系统性红斑狼疮（SLE）的患病风险或保护作用相关。为了重复这一关联研究，我们在来自德国、意大利、西班牙和阿根廷的1312例患者和1801例对照中，对标记先前相关单倍型并通过适当质量控制筛选的5个单核苷酸多态性（SNP）进行了检测。除西班牙外，在所有研究组中均重复了TNFSF4与SLE的关联。存在一种独特的风险单倍型，由SNP rs1234317（合并比值比（OR）=1.39，P=0.0009）和rs12039904（合并OR=1.38，P=0.0012）的次要等位基因标记。我们并未观察到如第一项研究所报道的与单一保护性标记（rs844644）或单倍型的关联；相反，我们观察到了不同的保护性单倍型，所有这些单倍型都携带SNP rs1234317和rs12039904的主要等位基因。基于单倍型背景的关联分析证实，这两个SNP解释了整个单倍型效应。这项首次重复研究证实了TNFSF4上游区域的基因变异与SLE易感性之间的关联。
