Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

Ho Namkoong; Yosuke Omae; Takanori Asakura; Makoto Ishii; Shoji Suzuki; Kozo Morimoto; Yosuke Kawai; Katsura Emoto; Andrew J Oler; Eva P Szymanski; Mitsunori Yoshida; Shuichi Matsuda; Kazuma Yagi; Isano Hase; Tomoyasu Nishimura; Yuka Sasaki; Takahiro Asami; Tetsuya Shiomi; Hiroaki Matsubara; Hisato Shimada; Junko Hamamoto; Byung Woo Jhun; Su-Young Kim; Hee Jae Huh; Hong-Hee Won; Manabu Ato; Kenjiro Kosaki; Tomoko Betsuyaku; Koichi Fukunaga; Atsuyuki Kurashima; Hervé Tettelin; Hideki Yanai; Surakameth Mahasirimongkol; Kenneth N Olivier; Yoshihiko Hoshino; Won-Jung Koh; Steven M Holland; Katsushi Tokunaga; Naoki Hasegawa; Nontuberculous Mycobacteriosis and Bronchiectasis – Japan Research Consortium (NTM-JRC)

doi:10.1183/13993003.02269-2019

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease

Eur Respir J. 2021 Aug 12;58(2):1902269. doi: 10.1183/13993003.02269-2019. Print 2021 Aug.

Authors

Ho Namkoong^{1

2

3

4

5}, Yosuke Omae^{6

7

4}, Takanori Asakura^{1

8}, Makoto Ishii¹, Shoji Suzuki¹, Kozo Morimoto⁹, Yosuke Kawai^{6

7}, Katsura Emoto¹⁰, Andrew J Oler¹¹, Eva P Szymanski², Mitsunori Yoshida⁸, Shuichi Matsuda⁹, Kazuma Yagi¹, Isano Hase¹², Tomoyasu Nishimura¹³, Yuka Sasaki⁹, Takahiro Asami¹, Tetsuya Shiomi¹⁴, Hiroaki Matsubara¹⁵, Hisato Shimada¹⁶, Junko Hamamoto¹, Byung Woo Jhun¹⁷, Su-Young Kim¹⁷, Hee Jae Huh¹⁸, Hong-Hee Won¹⁹, Manabu Ato⁸, Kenjiro Kosaki²⁰, Tomoko Betsuyaku¹, Koichi Fukunaga¹, Atsuyuki Kurashima⁹, Hervé Tettelin^{21

22}, Hideki Yanai²³, Surakameth Mahasirimongkol²⁴, Kenneth N Olivier²⁵, Yoshihiko Hoshino⁸, Won-Jung Koh¹⁷, Steven M Holland², Katsushi Tokunaga^{6

7

5}, Naoki Hasegawa^{26

5}; Nontuberculous Mycobacteriosis and Bronchiectasis – Japan Research Consortium (NTM-JRC)

Affiliations

¹ Division of Pulmonary Medicine, Dept of Medicine, Keio University School of Medicine, Tokyo, Japan.
² Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
³ JSPS Overseas Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
⁴ H. Namkoong and Y. Omae are co-first authors.
⁵ H. Namkoong, N. Hasegawa and K. Tokunaga contributed equally to this article as lead authors and supervised the work.
⁶ Dept of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan.
⁸ Dept of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
⁹ Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.
¹⁰ Dept of Pathology, Keio University School of Medicine, Tokyo, Japan.
¹¹ Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
¹² Dept of Respiratory Medicine, National Hospital Organization Utsunomiya Hospital, Tochigi, Japan.
¹³ Keio University Health Center, Tokyo, Japan.
¹⁴ Dept of Pulmonary Medicine, Keiyu Hospital, Kanagawa, Japan.
¹⁵ Dept of Pulmonary Medicine, Fussa Hospital, Tokyo, Japan.
¹⁶ Dept of Pulmonary Medicine, Kawasaki Municipal Ida Hospital, Kanagawa, Japan.
¹⁷ Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
¹⁸ Dept of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
¹⁹ Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
²⁰ Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
²¹ Dept of Microbiology and Immunology, School of Medicine, University of Maryland, Bethesda, MD, USA.
²² Institute for Genome Sciences, School of Medicine, University of Maryland, Bethesda, MD, USA.
²³ Dept of Clinical Laboratory, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.
²⁴ Medical Genetics Center, Medical Life Sciences Institute, Dept of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
²⁵ Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
²⁶ Dept of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.

PMID: 33542050
DOI: 10.1183/13993003.02269-2019

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 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=1.64×10^-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=2.18×10^-12, OR 0.54) and European (p=5.12×10^-03, OR 0.63) ancestry.

Conclusions: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Genome-Wide Association Study
Humans
Lung Diseases*
Mycobacterium Infections, Nontuberculous* / genetics
Mycobacterium avium Complex
Mycobacterium avium-intracellulare Infection*
Nontuberculous Mycobacteria