A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.
A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.
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人类 MR1 的多态性与 mRNA 表达和结核病易感性相关。
DOI：
10.1038/gene.2016.41
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发表时间：
2017
影响因子：
5
通讯作者：
Hawn,TR
中科院分区：
文献类型：
--
作者：
Seshadri,C;Thuong,NTT;Mai,NTH;Bang,ND;Chau,TTH;Lewinsohn,DM;Thwaites,GE;Dunstan,SJ;Hawn,TR
MR1抗原呈递系统在哺乳动物中是保守的，并使T细胞能够识别由细菌病原体产生的小分子，包括结核分枝杆菌（M. tb）。然而，尚不清楚mr1介导的抗原呈递对预防分枝杆菌疾病的保护性免疫是否重要。我们假设MR1表达的遗传控制与结核感染的临床结果相关。我们进行了一项MR1候选基因关联研究，并在越南成年结核病患者的发现和验证队列中发现了一个内含子单核苷酸多态性（rs1052632），该多态性与结核病易感性显著相关。疾病部位分层显示rs1052632基因型GG与脑膜结核的发生密切相关(优势比= 2.99,95%可信区间（CI） 1.64-5.43；P = 0.00006)。在脑膜疾病患者中，缺少G等位基因与死亡风险增加相关（风险比= 3.86;95% CI 1.49-9.98； P= 0.005）。使用公共数据库的变体注释工具表明，rs1052632与淋巴母细胞样细胞中的MR1基因表达密切相关（P= 0.004），并且位于上皮角质形成细胞的转录增强子内。这些数据通过揭示rs1052632与MR1基因表达和越南结核病易感性相关，支持MR1在人类结核病发病机制中的作用。
The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M. tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio= 2.99; 95% confidence interval (CI) 1.64–5.43; P= 0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio= 3.86; 95% CI 1.49–9.98; P= 0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P= 0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.