Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis
Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis
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DOI：
10.1084/jem.20090892
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发表时间：
2009-11-23
影响因子：
15.3
通讯作者：
Alcais, Alexandre
中科院分区：
文献类型：
--
作者：
Cobat, Aurelie;Gallant, Caroline J.;Alcais, Alexandre
生活在结核病高流行地区的大约20%的人表现出持续缺乏结核菌素皮肤试验（TST）反应性，似乎对结核分枝杆菌感染具有天然抗性。在阳性反应组中，TST反应性强度差异较大。TST反应性的遗传基础尚不清楚。我们报告了对TST反应性有影响的基因座的全基因组连锁搜索，其定义为零与非零（TST- bina）或以毫米为单位的TST范围（TST数量性状位点[QTL]），来自南非结核病高流行地区的128个家庭，包括350个兄弟姐妹。我们在染色体11p14区检测到一个主要位点（TST1） （P = 1.4 x 10(-5)），该位点控制着TST-BINa，缺乏反应性，表明T细胞对结核分枝杆菌具有不依赖的耐药性。我们还在5p15染色体区域检测到第二个主要位点（TST2） （P < 10(-5)），它控制着TST-QTL或T细胞介导的延迟型超敏反应（DTH）对结核菌素的强度。该区域的精细定位鉴定出编码多巴胺转运体DAT1的SLC6A3基因是一个有希望进一步研究的基因。我们的研究结果为了解结核分枝杆菌在流行地区（TST1）感染耐药性的分子机制以及鉴定T细胞依赖性DTH对结核菌素（TST2）的关键调节因子铺平了道路。
Approximately 20% of persons living in areas hyperendemic for tuberculosis (TB) display persistent lack of tuberculin skin test (TST) reactivity and appear to be naturally resistant to infection by Mycobacterium tuberculosis. Among those with a positive response, the intensity of TST reactivity varies greatly. The genetic basis of TST reactivity is not known. We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as zero versus nonzero (TST-BINa) or as extent of TST in millimeters (TST-quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST1) on chromosomal region 11p14 (P = 1.4 x 10(-5)), which controls TST-BINa, with a lack of responsiveness indicating T cell-independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10(-5)), which controls TST-QTL or the intensity of T cell-mediated delayed type hypersensitivity (DTH) to tuberculin. Fine mapping of this region identified SLC6A3, encoding the dopamine transporter DAT1, as a promising gene for further studies. Our results pave the way for the understanding of the molecular mechanisms involved in resistance to M. tuberculosis infection in endemic areas (TST1) and for the identification of critical regulators of T cell-dependent DTH to tuberculin (TST2).