Association of TNFSF8 Regulatory Variants With Excessive Inflammatory Responses but not Leprosy Per Se
Association of TNFSF8 Regulatory Variants With Excessive Inflammatory Responses but not Leprosy Per Se
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DOI：
10.1093/infdis/jiu566
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发表时间：
2015-03-15
影响因子：
6.4
通讯作者：
Schurr, Erwin
中科院分区：
文献类型：
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作者：
Fava, Vinicius M.;Cobat, Aurelie;Schurr, Erwin
背景资料。1型反应(T1R)影响相当大比例的麻风患者。在患有T1R的患者中，宿主免疫反应在病理上对实际的感染威胁进行了过度补偿，导致神经损伤和永久性残疾。根据麻风本身全基因组关联研究的结果，我们调查了TNFSF15染色体区域对T1R易感性的可能贡献。我们对TNFSF15基因座进行了高分辨率的关联扫描，以评估在两个不同地理和种族人群中与T1R的关联：来自越南的一个基于家庭的样本和来自巴西的病例对照样本，总共包括1768个受试者。在越南样本中，47个单核苷酸多态(SNPs)重叠的TNFSF15和邻近的TNFSF8基因与T1R相关，但与麻风无关。在47个SNP中，39个是TNFSF8的顺式表达数量性状基因座(cis-eQTL)，包括位于TNFSF15基因内的SNPs。在巴西样本中，有18个与TNFSF8基因重叠的cis-eQTL SNPs被证实与T1R相关。综上所述，这些结果表明TNFSF8而不是TNFSF15是一个重要的T1R易感基因。我们的数据支持感染遗传学需要超越病原体控制的基因，探索与宿主反应相适应的基因。
Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R.Methods. We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects.Results. In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R.Conclusions. Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response.