Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection
Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection
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DOI：
10.1093/infdis/jiw347
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发表时间：
2016-10-15
影响因子：
6.4
通讯作者：
Hawn, Thomas R.
中科院分区：
文献类型：
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作者：
Horne, David J.;Graustein, Andrew D.;Hawn, Thomas R.
背景资料。与结核病不同的是，很少有研究评估潜在结核分枝杆菌感染(LTBI)易感性变异的宿主遗传基础。我们进行了自噬相关基因与LTB的候选基因关联研究。我们招募了肺结核患者的密切接触者，评估了LTBI的状况，并确定了LTBI的临床和社会人口学危险因素。在自认为是亚洲人或黑人的参与者中，我们比较了病例(n=143)和对照组(n=106)ULK1和GABARAP的单倍型标记单核苷酸多态(SNPs)。使用CRISPR/Cas9在U937单核细胞中，我们研究了ULK1缺乏对细胞因子表达、自噬和结核分枝杆菌复制的影响。在亚洲参与者中，我们发现了2个与LTBI相关的ULK1 SNP(rs12297124和rs7300908)。在调整了人群混合和LTBI的临床风险后，每个rs12297124微小等位基因可使LTBI风险降低80%(优势比为0.18；95%可信区间为0.07-0.46)。与对照组相比，经Toll样受体配体和结核分枝杆菌全细胞裂解物刺激后，ULK1缺陷细胞的肿瘤坏死因子分泌减少，结核分枝杆菌复制增加，选择性自噬减少。这些结果表明，非编码ULK1 SNP rs12297124与LTBI有很强的相关性，并在ULK1调节肿瘤坏死因子分泌、非特异性和结核分枝杆菌诱导的自噬以及单核细胞中结核分枝杆菌复制方面发挥作用。
Background. Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI.Methods. We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication.Results. In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy.Conclusions. These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.