Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.
Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.
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结核分枝杆菌感染耐药性的全基因组关联研究在三个不同的人群中确定了10q26.2位点。
DOI：
10.1371/journal.pgen.1009392
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发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Cobat A
中科院分区：
文献类型：
--
作者：
Quistrebert J;Orlova M;Kerner G;Ton LT;Luong NT;Danh NT;Vincent QB;Jabot-Hanin F;Seeleuthner Y;Bustamante J;Boisson-Dupuis S;Huong NT;Ba NN;Casanova JL;Delacourt C;Hoal EG;Alcaïs A;Thai VH;Thành LT;Abel L;Schurr E;Cobat A
结核（TB）的自然史的特点是暴露于结核分枝杆菌后个体间的结果差异很大。具体来说，通过结核菌素皮肤试验（TST）或干扰素释放试验（IGRAs）推断，一些高度暴露的个体仍然对结核杆菌感染具有耐药性。我们在越南南部的一个流行地区进行了对结核分枝杆菌感染耐药性的全基因组关联研究。我们招募了肺结核病例的家庭接触者（HHC），并将TST和IGRA均阴性的受试者（n = 185）与TST和IGRA均阳性或诊断为结核病的感染者（n = 353）进行比较。我们在染色体10q26.2上发现了一个全基因组显著的位点，该位点上的一组变异与抗结核分枝杆菌感染的强保护相关（OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10−8，对于基因型变异rs17155120）。该位点在法国多民族HHC队列和来自南非高流行地区的家族混合队列中被复制，rs17155120的总体OR估计为0.50 （95%CI 0.45-0.55, P = 1.26×10−9）。这些变异位于内含子区和C10orf90上游，C10orf90是一种肿瘤抑制基因，编码一种激活转录因子p53的泛素连接酶。硅分析表明，保护性等位基因与附近基因ADAM12在单核细胞中的表达降低相关，这可能导致Th17淋巴细胞的反应增强。我们的研究结果揭示了在不同人群中控制结核分枝杆菌感染耐药性的一个新的位点。有强有力的流行病学证据表明，一部分高度暴露个体对结核分枝杆菌感染仍然具有耐药性，如结核菌素皮肤试验（TST）或IFN-γ释放试验（IGRAs）的阴性结果所示。我们在耐药个体和感染个体之间进行了全基因组关联研究，这些个体是通过家庭接触设计精心挑选的，以最大限度地增加感染指数患者的暴露。我们采用严格定义的TST和IGRA检测结果来避免错误分类。我们在越南发现队列中发现10q26.2位点与结核分枝杆菌感染耐药性相关。这一基因座可在来自不同流行病学背景和不同祖先的两个独立队列中复制，这些队列分别在法国和南非登记。
The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35–0.49, P = 3.71×10−8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45–0.55, P = 1.26×10−9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations. There is strong epidemiological evidence that a proportion of highly exposed individuals remain resistant to M. tuberculosis infection, as shown by a negative result for Tuberculin Skin Test (TST) or IFN-γ Release Assays (IGRAs). We performed a genome-wide association study between resistant and infected individuals, which were carefully selected employing a household contact design to maximize exposure by infectious index patients. We employed stringently defined concordant results for both TST and IGRA assays to avoid misclassifications. We discovered a locus at 10q26.2 associated with resistance to M. tuberculosis infection in a Vietnamese discovery cohort. This locus could be replicated in two independent cohorts from different epidemiological settings and of diverse ancestries enrolled in France and South Africa.
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影响因子：
7.3
作者：
Cruz A;Ludovico P;Torrado E;Gama JB;Sousa J;Gaifem J;Appelberg R;Rodrigues F;Cooper AM;Pedrosa J;Saraiva M;Castro AG
通讯作者：
Castro AG
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
30.8
作者：
Calderon, Diego;Nguyen, Michelle L. T.;Pritchard, Jonathan K.
通讯作者：
Pritchard, Jonathan K.
凋亡是巨噬细胞对结核分枝杆菌的先天防御功能。
影响因子：
8
作者：
通讯作者：
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影响因子：
14.9
作者：
Haeussler M;Zweig AS;Tyner C;Speir ML;Rosenbloom KR;Raney BJ;Lee CM;Lee BT;Hinrichs AS;Gonzalez JN;Gibson D;Diekhans M;Clawson H;Casper J;Barber GP;Haussler D;Kuhn RM;Kent WJ
通讯作者：
Kent WJ