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.
Abstract
The first GWAS of pulmonary MAC disease in Japanese, Korean and European patients. SNPs in the CHP2 region were associated with the disease risk. CHP2 may play an important role in host susceptibility to pulmonary MAC disease. https://bit.ly/39iCIio
Footnotes
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Availability of data and materials: All raw data are available by request to the corresponding author.
Author contributions: H. Namkoong, Y. Omae, K. Tokunaga and N. Hasegawa designed the study. H. Namkoong, Y. Omae, T. Asakura, Y. Kawai, K. Emoto, A.J. Oler, M. Yoshida, E.P. Szymanski, J. Hamamoto, H.J. Huh, H-H. Won, K. Kosaki, H. Tettelin, H. Matsubara, K. Tokunaga and N. Hasegawa analysed the data. H. Namkoong, T. Asakura, M. Ishii, S. Suzuki, K. Morimoto, S. Matsuda, K. Yagi, I. Hase, T. Nishimura, Y. Sasaki, T. Asami, T. Shiomi, H. Matsubara, H. Shimada, B.W. Jhun, S-Y. Kim, M. Ato, T. Betsuyaku, K. Fukunaga, A. Kurashima, H. Yanai, S. Mahasirimongkol, K.N. Olivier, Y. Hoshino, W-J. Koh, S.M. Holland and N. Hasegawa recruited participants and collected clinical data. All authors contributed to study conduct and approved the final manuscript.
Conflict of interest: H. Namkoong reports grants from JSPS (JSPS KAKENHI grant number 15H06590), AMED (2019 US-Japan Collaborative Proposal 28863) and NIAID/CBER Intramural Tuberculosis Research Initiative (FY19 Start-up support from CAN 8020315), during the conduct of the study.
Conflict of interest: Y. Omae reports grants from JSPS KAKENHI (18K15041), during the conduct of the study.
Conflict of interest: T. Asakura reports grants from JSPS, outside the submitted work.
Conflict of interest: M. Ishii reports grants from JSPS KAKENHI (18H02821, 18K19566), outside the submitted work.
Conflict of interest: S. Suzuki reports grants from JSPS, outside the submitted work.
Conflict of interest: K. Morimoto reports grants from AMED (2019 US-Japan Collaborative Proposal 28863), during the conduct of the study; personal fees for consultancy from INSMED, outside the submitted work.
Conflict of interest: Y. Kawai has nothing to disclose.
Conflict of interest: K. Emoto has nothing to disclose.
Conflict of interest: A.J. Oler has nothing to disclose.
Conflict of interest: E.P. Szymanski has nothing to disclose.
Conflict of interest: M. Yoshida reports grants from JSPS (grant-in-aid for young scientists (B), JSPS KAKENHI grant number 17K16066), during the conduct of the study.
Conflict of interest: S. Matsuda has nothing to disclose.
Conflict of interest: K. Yagi has nothing to disclose.
Conflict of interest: I. Hase has nothing to disclose.
Conflict of interest: T. Nishimura reports grants from JSPS KAKENHI (16K09942), outside the submitted work.
Conflict of interest: Y. Sasaki reports grants from JSPS (JSPS KAKENHI grant number 15H06590), during the conduct of the study.
Conflict of interest: T. Asami has nothing to disclose.
Conflict of interest: T. Shiomi has nothing to disclose.
Conflict of interest: H. Matsubara has nothing to disclose.
Conflict of interest: H. Shimada has nothing to disclose.
Conflict of interest: J. Hamamoto reports grants from JSPS KAKENHI (19K08610), outside the submitted work.
Conflict of interest: B.W. Jhun reports grants from AMED (2019 US-Japan Collaborative Proposal 28863), during the conduct of the study.
Conflict of interest: S-Y. Kim has nothing to disclose.
Conflict of interest: H.J. Huh has nothing to disclose.
Conflict of interest: H-H. Won has nothing to disclose.
Conflict of interest: M. Ato reports grants from Japan Agency for Medical Research and Development, during the conduct of the study.
Conflict of interest: K. Kosaki reports grants from Japan Agency for Medical Research and Development (AMED), outside the submitted work.
Conflict of interest: T. Betsuyaku reports grants from JSPS KAKENHI and Japan Agency for Medical Research and Development (AMED), outside the submitted work.
Conflict of interest: K. Fukunaga reports grants from JSPS KAKENHI and Japan Agency for Medical Research and Development (AMED), outside the submitted work.
Conflict of interest: A. Kurashima reports personal fees for consultancy from Insmed, during the conduct of the study.
Conflict of interest: H. Tettelin reports grants from NIAID (contract number HHSN272200900009CJSPS), during the conduct of the study.
Conflict of interest: H. Yanai has nothing to disclose.
Conflict of interest: S. Mahasirimongkol has nothing to disclose.
Conflict of interest: K.N. Olivier reports non-financial support from AIT Therapeutics, non-financial support from Insmed, outside the submitted work.
Conflict of interest: Y. Hoshino reports grants from The Japan Agency for Medical Research and Development/Japan International Cooperation Agency (AMED), during the conduct of the study (JP18fk0108043 and JP18fk0108075).
Conflict of interest: W-J. Koh reports grants from National Research Foundation of Korea (grant number NRF-2018R1A2A1A05018309), during the conduct of the study.
Conflict of interest: S.M. Holland has nothing to disclose.
Conflict of interest: K. Tokunaga reports grants from Japan Agency for Medical Research and Development (grant-in-aid for research JP17km0405205h0002), during the conduct of the study.
Conflict of interest: N. Hasegawa reports grants from Japan Agency for Medical Research and Development(AMED), during the conduct of the study; grants from JSPS KAKENHI, personal fees for consultancy from INSMED, outside the submitted work.
Support statement: This work was supported by Japan Agency for Medical Research and Development (AMED) (project numbers JP17FK0108116H0401, JP17KM0405205H0002, JP18FK0108043, JP18FK0108075, 18km0405205h0003, 19km0405205h9904, 19kk0205012h0004, US–Japan Cooperative Medical Sciences Program Collaborative Awards 2019), Keio Gijuku Academic Development Funds, grant-in-aid for research activity start-up (JSPS KAKENHI) (grant number 15H06590), grant-in-aid for young scientists (B) (JSPS KAKENHI) (grant numbers 15K19039, 17K16066), grant-in-aid for scientific research (B) (grant numbers 19H03704, 15H05271, 24406010), and National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (grant number NRF-2018R1A2A1A05018309). This work was supported in part by federal funds to the Institute for Genome Sciences from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272200900009CJSPS. This work was supported by NIAID/CBER Intramural Tuberculosis Research Initiative and by the intramural programs of the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, National Institutes of Health. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 25, 2019.
- Accepted December 30, 2020.
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