Chen Fei, Szymanski Eva P, Olivier Kenneth N, Liu Xinyue, Tettelin Hervé, Holland Steven M, Duggal Priya
1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
2 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland.
Am J Respir Crit Care Med. 2017 Dec 15;196(12):1599-1604. doi: 10.1164/rccm.201612-2479OC.
Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism.
To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013.
We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases.
The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis.
The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.
肺非结核分枝杆菌病（PNTM）常影响绝经后白人女性，她们体型瘦高，脊柱侧弯、漏斗胸、二尖瓣脱垂和囊性纤维化跨膜传导调节因子（CFTR）基因突变的发生率较高。这些临床特征以及该疾病的家族聚集性提示存在潜在的遗传机制。
为了定位与PNTM相关的基因，于2001年至2013年在美国国立卫生研究院临床中心招募了12个PNTM家族和57例散发病例进行全外显子组测序。
我们对9个PNTM家族（16例患者和20例未患病者）进行了变异水平和基因水平的参数连锁分析，并对9个PNTM家族和55例散发病例进行了基因水平的关联分析。
使用4328个独立的常见变异进行全基因组变异水平连锁分析，在隐性疾病模型（外显率100%，风险等位基因频率5%）下，在6号染色体6q12 - 6q16区域确定了一个20厘摩的区域（异质性对数优势分数 = 3.9）。然后，使用压缩单倍型模式方法在基因水平连锁分析中对6号染色体上的所有基因进行了检测。位于6号染色体6q14.1的TTK蛋白激酶基因（TTK）最为显著（异质性对数优势分数 = 3.38）。此外，在我们的基因水平关联分析中，MAP2K4、RCOR3、KRT83、IFNLR1和SLC29A1基因与PNTM相关。
TTK基因编码一种对有丝分裂检查点和DNA损伤反应至关重要的蛋白激酶。我们研究中确定的TTK和其他基因位点可能导致对非结核分枝杆菌感染的易感性增加及其向肺部疾病的进展。
