Fava Vinicius M, Cobat Aurélie, Van Thuc Nguyen, Latini Ana Carla P, Stefani Mariane M A, Belone Andrea F, Ba Nguyen Ngoc, Orlova Marianna, Manry Jérémy, Mira Marcelo T, Thai Vu Hong, Abel Laurent, Alcaïs Alexandre, Schurr Erwin
Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada.
Hospital for Dermato-Venerology, Ho Chi Minh City, District 3, Vietnam.
J Infect Dis. 2015 Mar 15;211(6):968-77. doi: 10.1093/infdis/jiu566. Epub 2014 Oct 15.
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.
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.
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.
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.
1型反应（T1R）影响着相当一部分麻风病患者。在患有T1R的患者中，宿主免疫反应在病理上对实际感染威胁反应过度，导致神经损伤和永久性残疾。基于麻风病本身的全基因组关联研究结果，我们研究了TNFSF15染色体区域对T1R易感性的可能影响。
我们对TNFSF15基因座进行了高分辨率关联扫描，以评估其与T1R在2个地理和种族不同的人群中的关联：一个来自越南的基于家庭的样本和一个来自巴西的病例对照样本，共1768名受试者。
在越南样本中，47个与TNFSF15和相邻的TNFSF8基因重叠的单核苷酸多态性（SNP）与T1R相关，但与麻风病无关。在这47个SNP中，39个是TNFSF8的顺式表达数量性状位点（cis-eQTL），包括位于TNFSF15基因内的SNP。在巴西样本中，这些与TNFSF8基因重叠的顺式eQTL SNP中有18个被验证与T1R相关。
综上所述，这些结果表明TNFSF8而非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基因，去探索参与相应宿主反应的基因。
