Cobat Aurelie, Gallant Caroline J, Simkin Leah, Black Gillian F, Stanley Kim, Hughes Jane, Doherty T Mark, Hanekom Willem A, Eley Brian, Jaïs Jean-Philippe, Boland-Auge Anne, van Helden Paul, Casanova Jean-Laurent, Abel Laurent, Hoal Eileen G, Schurr Erwin, Alcaïs Alexandre
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de Santé et de Recherche Médicale, Paris 75015, France.
J Exp Med. 2009 Nov 23;206(12):2583-91. doi: 10.1084/jem.20090892. Epub 2009 Nov 9.
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).
生活在结核病高度流行地区的人群中，约20%的人结核菌素皮肤试验（TST）持续无反应，似乎对结核分枝杆菌感染具有天然抵抗力。在那些反应呈阳性的人中，TST反应强度差异很大。TST反应的遗传基础尚不清楚。我们报告了一项全基因组连锁搜索，以寻找影响TST反应的基因座，TST反应在一组来自南非结核病高度流行地区的128个家庭（包括350名兄弟姐妹）中，定义为零反应与非零反应（TST-BINa）或TST以毫米为单位的范围（TST-数量性状基因座[QTL]）。我们在染色体区域11p14上检测到一个主要基因座（TST1）（P = 1.4×10⁻⁵），它控制TST-BINa，无反应表明对结核分枝杆菌具有不依赖T细胞的抵抗力。我们还在染色体区域5p15上检测到第二个主要基因座（TST2）（P < 10⁻⁵），它控制TST-QTL或对结核菌素的T细胞介导的迟发型超敏反应（DTH）强度。对该区域的精细定位确定了编码多巴胺转运体DAT1的SLC6A3作为进一步研究的一个有前景的基因。我们的结果为理解流行地区对结核分枝杆菌感染的抵抗力所涉及的分子机制（TST1）以及鉴定对结核菌素的T细胞依赖性DTH的关键调节因子（TST2）铺平了道路。
