肺复合型疾病患者的全基因组关联研究。

Genome-wide association study in patients with pulmonary complex disease.

机构信息

Division of Pulmonary Medicine, Dept of Medicine, Keio University School of Medicine, Tokyo, Japan.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.

出版信息

Eur Respir J. 2021 Aug 12;58(2). doi: 10.1183/13993003.02269-2019. Print 2021 Aug.

DOI:10.1183/13993003.02269-2019

PMID:33542050

Abstract

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 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=1.64×10, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (). 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=2.18×10, OR 0.54) and European (p=5.12×10, OR 0.63) ancestry.

CONCLUSIONS

We identified rs109592 in the locus as a susceptibility marker for pulmonary MAC disease.

摘要

背景

非结核分枝杆菌（NTM）是环境分枝杆菌，可导致慢性进行性肺部疾病。尽管流行病学数据表明存在潜在的遗传易感性，但具体性质仍不清楚。

目的

我们旨在鉴定复杂型（MAC）分枝杆菌的宿主易感性基因座，MAC 是最常见的 NTM 病原体。

方法

本项全基因组关联研究（GWAS）纳入了日本肺部 MAC 患者和健康对照者，随后在另一日本队列中对候选单核苷酸多态性（SNP）进行基因分型。为了通过韩国和欧洲血统进行验证，我们进行了 SNP 基因分型。

结果

GWAS 发现组纳入了 475 例肺部 MAC 病例和 417 例对照者。GWAS 以及对 591 例肺部 MAC 病例和 718 例对照者的复制分析均显示与 16p21 最强相关，特别是与 rs109592（p=1.64×10，OR 0.54），该 SNP 位于钙调磷酸酶样 EF 手蛋白 2 （）的内含子区域。表达数量性状基因座分析表明与肺部 CHP2 表达相关。CHP2 在肺部 MAC 疾病的肺组织中表达。该 SNP 与结节性支气管扩张亚型相关。此外，该 SNP 与韩国（p=2.18×10，OR 0.54）和欧洲（p=5.12×10，OR 0.63）患者的疾病显著相关。