Epiregulin (EREG) variation is associated with susceptibility to tuberculosis.
Epiregulin (EREG) variation is associated with susceptibility to tuberculosis.
复制标题
上皮调节蛋白（EREG）变异与结核病易感性相关。
DOI：
10.1038/gene.2011.83
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发表时间：
2012
影响因子：
5
通讯作者：
Dunstan,SJ
中科院分区：
文献类型：
--
作者：
Thuong,NTT;Hawn,TR;Chau,TTH;Bang,ND;Yen,NTB;Thwaites,GE;Teo,YY;Seielstad,M;Hibberd,M;Lan,NTN;Caws,M;Farrar,JJ;Dunstan,SJ
尽管宿主遗传学影响对结核分枝杆菌的易感性，但调节发病机制的人类基因仍然很大程度上未知。我们使用结核分枝杆菌刺激的巨噬细胞基因表达谱与病例对照遗传关联研究相结合，发现上皮调节蛋白（EREG）作为一种新的候选结核病（TB）易感基因。使用全基因组关联研究数据集，我们发现在诱导超过 50 倍的 21 个基因中，EREG 具有与结核病相关的最多多态性。我们对发现数据集（N = 337例，N = 380例对照）和验证数据集（N = 332例）中的单倍型标记多态性进行了基因分型，并且EREG多态性（rs7675690）与结核病易感性相关（基因型比较；校正P = 0.00007）。与非北京菌株相比，rs7675690 与北京谱系结核分枝杆菌引起的感染的相关性更强（对照 vs 北京菌株，OR 7.81，P= 8.7× 10−5；非北京菌株，OR 3.13，P= 0.074）。此外，用结核分枝杆菌以及TLR4和TLR2/1/6配体刺激的单核细胞和外周血单核细胞中诱导EREG表达。在小鼠巨噬细胞中，结核分枝杆菌诱导的 EREG 表达是 MYD88 和 TLR2 依赖性的。总之，这些数据为 EREG 作为人类结核病易感基因的重要作用提供了第一个证据。
Although host genetics influences susceptibility to Mycobacterium tuberculosis, the human genes regulating pathogenesis remain largely unknown. We used M. tuberculosis-stimulated macrophage gene expression profiling in conjunction with a case–control genetic association study to discover epiregulin (EREG), as a novel candidate tuberculosis (TB) susceptibility gene. Using a genome-wide association study dataset, we found that among the 21 genes with greater than 50-fold induction, EREG had the most polymorphisms associated with TB. We genotyped haplotype-tagging polymorphisms in discovery (N= 337 cases, N= 380 controls) and validation (N= 332 cases) datasets and an EREG polymorphism (rs7675690) was associated with susceptibility to TB (genotypic comparison; corrected P= 0.00007). rs7675690 was also associated more strongly with infections caused by the Beijing lineage of M. tuberculosis when compared with non-Beijing strains (controls vs Beijing, OR 7.81, P= 8.7× 10− 5; non-Beijing, OR 3.13, P= 0.074). Furthermore, EREG expression was induced in monocytes and peripheral blood mononuclear cells stimulated with M. tuberculosis as well as TLR4 and TLR2/1/6 ligands. In murine macrophages, EREG expression induced by M. tuberculosis was MYD88-and TLR2-dependent. Together, these data provide the first evidence for an important role for EREG as a susceptibility gene for human TB.