Data from: A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa

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 the dominant model of rs877356 and binary TST status in the combined cohort (OR=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 T¬H2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected participants with extensive exposure increases the power to detect associations in complex infectious disease.

每三人中就有一人曾感染结核分枝杆菌（Mycobacterium tuberculosis, MTB），而人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）感染者的MTB感染风险甚至更高。我们提出假说：居住在结核病流行地区、却未感染结核分枝杆菌的HIV阳性个体，存在遗传抗性。借助我们前期工作中验证有效的「自然实验」设计，我们利用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，开展了针对结核菌素皮肤试验阳性的全基因组关联研究，以鉴定HIV感染背景下与MTB感染相关的遗传位点。在本研究的受试者中，244人在入组阶段或为期8年以上的随访期间结核菌素皮肤试验（Tuberculin Skin Test, TST）结果为阳性，另有225人结果呈阴性。在合并队列中，我们发现rs877356的显性遗传模型与二分类TST结果之间存在全基因组显著关联（比值比OR=0.2671，P=1.22×10^-8）。当将TST硬结作为连续性状进行分析时，该关联也得到了验证，且显著性水平相近。该变异位点位于5q31.1区域，距离白细胞介素9（Interleukin 9, IL9）基因下游57kb处。针对rs877356附近变异的双位点关联分析显示，由rs877356与IL9错义变异（missense variant）rs2069885组成的单倍型（haplotype）具有最显著的关联信号（P=1.59×10^-12）。我们还验证了此前已被关联的2号、5号及11号染色体上的遗传位点。IL9是一种由肥大细胞（mast cells）和辅助性T细胞2（T helper 2, Th2）在炎症应答过程中产生的细胞因子（cytokine），这为气道炎症与抗MTB感染之间的潜在关联提供了机制依据。本研究结果表明，针对具有广泛暴露风险的未感染受试者开展研究，可提升复杂传染病关联分析的统计效力。