Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease
Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease
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DOI：
10.1183/13993003.02269-2019
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发表时间：
2021-08-01
影响因子：
24.3
通讯作者：
Hasegawa, Naoki
中科院分区：
文献类型：
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作者：
Namkoong, Ho;Omae, Yosuke;Hasegawa, Naoki
原理：非结核分枝杆菌（NTM）是一种可引起慢性进行性肺部疾病的环境分枝杆菌。尽管流行病学数据表明潜在的遗传易感性，但其性质仍不清楚。目的确定最常见的NTM病原体鸟分枝杆菌复合体（MAC）的宿主易感位点。方法在日本肺MAC患者和健康对照者中进行全基因组关联研究（GWAS），然后在另一个日本队列中对候选单核苷酸多态性（snp）进行基因分型。为了验证韩国和欧洲血统，我们进行了SNP基因分型。结果GWAS发现组包括475例肺MAC病例和417例对照组。591例肺MAC病例和718例对照的GWAS和复制分析显示，与染色体16p21的相关性最强，尤其是rs109592 (p=1.64 × 10(-13), OR 0.54)，它位于钙调神经磷酸酶样efhand蛋白2 （CHP2）的含子区。表达数量性状位点分析显示与肺CHP2表达相关。CHP2在肺MAC病肺组织中表达。该SNP与结节性支气管扩张亚型相关。此外，该SNP与韩国（p=2.18x10(-12), OR 0.54）和欧洲（p= 5.12 x10(-03), OR 0.63）血统患者的疾病显著相关。结论：我们发现CHP2位点的rs109592是肺部MAC疾病的易感标志物。
Rationale Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear.Objectives We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen.Methods This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping.Results The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64x10(-13), OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18x10(-12), OR 0.54) and European ( p=5.12 x10(-03), OR 0.63) ancestry.Conclusions We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.