Genome-Wide Association Study in Patients with Pulmonary Mycobacterium Avium Complex Disease

Abstract

Background Pulmonary nontuberculous mycobacteria (NTM) disease is a chronic progressive lung disease caused by environmental mycobacteria. Although epidemiological data indicate a potential genetic predisposition to NTM disease, the nature of this remains unclear. The present study aimed to identify host genes associated with susceptibility to Mycobacterium avium complex (MAC), the most common NTM pathogen. Methods We conducted a genome-wide association study (GWAS) in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate SNPs in another group of patients and controls. For verification in European populations, we performed imputation to estimate genotypes of a candidate SNP from exome sequencing data. Findings The GWAS discovery set included 475 pulmonary MAC patients and 417 healthy subjects. After quality control filtering of genotyped variants, 622,723 autosomal variants were analysed. Both GWAS and replication analysis of 591 pulmonary MAC patients and 718 controls identified strongest association with chromosome 16p21, and particularly with rs109592 (p = 1.60E-13, odds ratio = 0.54). This SNP is located in an intronic region of the calcineurin like EF-hand protein 2 (CHP2) gene, and expression quantitative trait locus analysis showed association with lung CHP2 expression. Further, patient radiological findings showed that this SNP was associated with the nodular bronchiectasis disease subtype. This SNP is also significantly associated in European populations (p = 5.08E-06, odds ratio = 0.23). Interpretation These findings identify CHP2 as a candidate gene for further investigation of the pathogenesis of pulmonary MAC disease. Funding: JSPS KAKENHI, AMED, Keio Gijuku Academic Development Funds, NIH. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: This study was reviewed and approved by the research ethics committees of the Keio University School of Medicine (2012-0336), the Graduate School of Medicine, the University of Tokyo (G3579), and other collaborating institutions (UMI21692). Regarding European cohort, the subjects were enrolled in studies under National Institute of Allergy and Infectious Diseases Institutional Review Board-approved protocol (93-I-0119). All adult subjects provided written informed consent and all the experiments were performed in accordance with the relevant guidelines and regulations.