Novel Genetic Loci for Nontuberculous Mycobacterial Pulmonary Disease and Potential Protective Effect of Body Mass Index
<b>Rationale:</b> Although nontuberculous mycobacteria (NTM) are widespread, only some individuals develop NTM pulmonary disease (NTM-PD), suggesting the involvement of host factors. <b>Objectives:</b> To identify the genomic structure of NTM-PD and determine whether a definitive association exists between NTM-PD and nine risk factors. <b>Methods:</b> We performed genome-wide association studies in two independent Korean cohorts involving 1,949 patients with NTM-PD and 2,955 healthy participants. Significantly associated genetic variants were validated in Japanese (1,137 cases, 1,546 controls) and European (243 cases, 570 controls) cohorts, respectively. Genes associated with lead variants were identified and their roles in NTM-PD were supported by single-cell transcriptome datasets. Genetic correlations and Mendelian randomization between NTM-PD and nine risk factors were examined. <b>Measurements and Main Results:</b> We identified two novel loci and replicated a locus associated with NTM-PD: rs60084385 (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.21-1.48; <i>P</i> = 6.97 × 10<sup>-9</sup>), rs1479595 (OR, 1.40; 95% CI, 1.27-1.55; <i>P</i> = 7.08 × 10<sup>-11</sup>), and rs194792 (OR, 1.70; 95% CI, 1.50-1.93; <i>P</i> = 1.39 × 10<sup>-16</sup>). These associations were replicated in the independent cohorts. The three loci were significantly associated with expression of <i>IL1Rs</i>, <i>PDE8B</i> (phosphodiesterase 8B), and <i>PRKCB</i> (protein kinase C β), respectively, whose involvement in the pathogenesis of NTM-PD was further validated. Among the risk factors, only body mass index demonstrated both a significant genetic correlation with NTM-PD (<i>r<sub>g</sub></i>, -0.57; false discovery rate, 1.33 × 10<sup>-5</sup>) and a potential causal relationship (OR, 0.38; 95% CI, 0.24-0.59; false discovery rate, 8.55 × 10<sup>-5</sup>). <b>Conclusions:</b> Our study identified three genetic loci associated with NTM-PD and a negative association of body mass index with NTM-PD.
Authors
- Kozo Morimoto (ORCID: https://orcid.org/0000-0002-8239-9275)
- Atsuyuki Kurashima (ORCID: https://orcid.org/0000-0002-4170-6195)
- Yosuke Kawai (ORCID: https://orcid.org/0000-0003-0666-1224)
- Kyungtaek Park (ORCID: https://orcid.org/0000-0003-0786-6969)
- Joanne Berghout (ORCID: https://orcid.org/0000-0002-9250-9159)
- Byung Woo Jhun (ORCID: https://orcid.org/0000-0002-6348-8731)
- Hee Jae Huh (ORCID: https://orcid.org/0000-0001-8999-7561)
- Hong‐Hee Won (ORCID: https://orcid.org/0000-0001-5719-0552)
- Katsushi Tokunaga (ORCID: https://orcid.org/0000-0001-5501-0503)
- Steven M. Holland (ORCID: https://orcid.org/0000-0003-3207-5464)
- Takanori Asakura (ORCID: https://orcid.org/0000-0003-3122-6937)
- Ho Namkoong (ORCID: https://orcid.org/0000-0001-6181-4284)
- Jae‐Joon Yim (ORCID: https://orcid.org/0000-0002-9605-0074)
- Yosuke Omae (ORCID: https://orcid.org/0000-0001-9978-4869)
- Tomoyasu Nishimura (ORCID: https://orcid.org/0000-0001-9662-5694)
- Sungho Won (ORCID: https://orcid.org/0000-0001-5751-5089)
- Kevin P. Fennelly (ORCID: https://orcid.org/0000-0001-9416-0686)
- Hyejin Kim (ORCID: https://orcid.org/0000-0002-7937-2733)
- Jaeyoung Cho (ORCID: https://orcid.org/0000-0002-6537-8843)
- Naoki Hasegawa
Institutions
- National Institutes of Health (US)
- Colorado Department of Public Health and Environment (US)
- Seoul National University (KR)
- Keio University (JP)
- Samsung Medical Center (KR)
- Seoul National University Hospital (KR)
- Jeonbuk State Institute (KR)
- National Center for Global Health and Medicine (JP)
- Japan Anti Tuberculosis Association (JP)
- National Heart, Lung, and Blood Institute (US)
- National Institute of Allergy and Infectious Diseases (US)
- Institute of Bioinformatics (IN)
- Fukujuji Hospital (JP)
- Unidad de Investigación en Salud Digital (ES)
- Pulmonary and Critical Care Associates (US)
- The University of Tokyo (JP)
- Jeonbuk National University (KR)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- American Journal of Respiratory and Critical Care Medicine
- Published
- 2025-09-12
- DOI
- https://doi.org/10.1164/rccm.202406-1253oc
- Citations
- 1
- Primary Topic
- Mycobacterium research and diagnosis
- Type
- article
- Field-Weighted Citation Impact
- 1.35