Sobota Rafal S, Stein Catherine M, Kodaman Nuri, Maro Isaac, Wieland-Alter Wendy, Igo Robert P, Magohe Albert, Malone LaShaunda L, Chervenak Keith, Hall Noemi B, Matee Mecky, Mayanja-Kizza Harriet, Joloba Moses, Moore Jason H, Scott William K, Lahey Timothy, Boom W Henry, von Reyn C Fordham, Williams Scott M, Sirugo Giorgio
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, United States of America.
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
PLoS Genet. 2017 Jun 19;13(6):e1006710. doi: 10.1371/journal.pgen.1006710. eCollection 2017 Jun.
One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an "experiment of nature" design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.
三分之一的人曾感染过结核分枝杆菌（MTB），而HIV感染者感染MTB的风险更高。我们推测，生活在结核病流行地区的未感染结核分枝杆菌的HIV阳性个体具有遗传抗性。利用在我们之前的研究中被证明成功的“自然实验”设计，我们对来自坦桑尼亚和乌干达结核病前瞻性研究队列的469名HIV阳性患者进行了结核菌素皮肤试验阳性的全基因组关联研究，以确定在HIV感染背景下与MTB感染相关的基因位点。在这些个体中，244人在入组时或超过8年的随访期间结核菌素皮肤试验（TST）呈阳性，而225人则为阴性。我们在合并队列中发现rs877356的显性模型与二元TST状态之间存在全基因组显著关联（优势比 = 0.2671，p = 1.22×10 - 8）。将TST硬结作为连续性状进行检查时，关联以相似的显著性得到重复。该变异位于5q31.1区域，距离IL9下游57kb。对rs877356附近变异的两位点关联分析表明，由rs877356和IL9错义变异rs2069885组成的单倍型具有最显著的关联（p = 1.59×10 - 12）。我们还重复了先前在2号、5号和11号染色体上发现的相关位点。IL9是肥大细胞和TH2细胞在炎症反应过程中产生的一种细胞因子，这可能为气道炎症与预防MTB感染之间提供了联系。我们的结果表明，研究未感染但有广泛暴露的HIV阳性参与者可提高在复杂传染病中检测关联的能力。
