Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration
Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration
复制标题
DOI：
10.1038/ng.3248
复制
发表时间：
2015-05-01
期刊：
影响因子：
30.8
通讯作者：
Nejentsev, Sergey
中科院分区：
文献类型：
--
作者：
Curtis, James;Luo, Yang;Nejentsev, Sergey
人类遗传因素易患结核病 (TB)。我们研究了 5,530 名肺结核患者和 5,607 名健康对照者的 760 万个基因变异。在对这些受试者和随访队列（总共 15,087 名结核病患者和对照）的综合分析中，我们发现结核病与位于染色体 8q24 上 ASAP1 基因内含子的变异之间存在关联（rs4733781 的 P = 2.6 x 10(-11)；rs10956514 的 P = 1.0 x 10(-10)）。树突状细胞（DC）表现出高ASAP1表达，但在结核分枝杆菌感染后降低，rs10956514与ASAP1表达水平降低相关。 ASAP1 蛋白参与肌动蛋白和膜重塑，并与足体相关。 ASAP1 耗尽的 DC 表现出基质降解和迁移受损。因此，在结核分枝杆菌感染的 DC 中，基因决定的 ASAP1 表达过度减少可能会导致其迁移受损，这表明了结核病易感性的潜在机制。
Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 x 10(-11) for rs4733781; P = 1.0 x 10(-10) for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in Mycobacterium tuberculosis-infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.