Genome-wide association study reveals putative bacterial risk factors for cavitary Mycobacterium avium complex lung disease

Mycobacterium avium complex (MAC) lung disease is a slowly progressive disease, and its increasing incidence has garnered increased research interests. Cavitary MAC lung disease is associated with a higher mortality rate. Though genetic studies have unraveled the human risk factors, the role of microbial factors on pathogenesis behind the disease remains elusive. In this study, M. avium isolates were collected from sputum specimens of 109 distinct Japanese patients with or without a cavity (60 with a cavity and 49 without cavity) in a hospital located in Osaka prefecture. M. avium genomes were sequenced and searched for DNA motifs associated with cavity formation using a bacterial GWAS. Excluding known macrolide resistance mutations; cavity formation was found to be primarily associated with variants of cytochrome P450 of the CYP139 family, type I polyketide synthase Pks13, and the promoter region of an operon encoding membrane-anchored protease FtsH and folate synthesis pathway enzymes. Cavity risk variants at these three loci were frequent in the MahEastAsia2 lineage among the six lineages detected in M. avium global populations. Furthermore, the study demonstrated a correlation between the cavity risk promoter variant and increased sulfamethoxazole/trimethoprim resistance. Together, these findings suggest that natural variation in the biosynthesis and maintenance processes of M. avium membrane components influences the disease type of MAC lung disease. Although further validation is needed, the bacterial genetic markers listed in the present study could contribute to prognosis prediction based on bacterial genotyping and help develop treatment strategies in the future. IMPORTANCENontuberculous mycobacterial lung disease is of great concern in countries with an increasingly aging population. The disease types can largely be classified into non-cavitary nodular bronchiectasis and cavitary diseases (fibrocavitary, nodular bronchiectasis with cavity) that require different treatment strategies depending on the causal agents. Several studies have reported human risk factors for the disease; however, little efforts were made to investigate the risk factors in nontuberculous mycobacteria. Moreover, molecular genetics experiments have been difficult to search for virulence factors in M. avium, which the population genomics approaches could overcome. Here, the GWAS results suggested variants in three chromosomal loci associated with mycobacterial membrane components as risk factors for cavitary MAC lung disease. These findings could help develop treatment strategies for MAC lung disease in the future.