2. Academic Validation
  3. A genome-wide association study identified PRKCB as a causal gene and therapeutic target for Mycobacterium avium complex disease

A genome-wide association study identified PRKCB as a causal gene and therapeutic target for Mycobacterium avium complex disease

  • Cell Rep Med. 2025 Jan 15:101923. doi: 10.1016/j.xcrm.2024.101923.
Ruijuan Zheng 1,  Zhiqiang Li 2,  Weijun Fang 3,  Hai Lou 4,  Feng Liu 5,  Qin Sun 4,  Xiang Shi 4,  Hua Liu 6,  Qing Chen 6,  Xiaona Shen 4,  Lan Yao 4,  Liru Guan 3,  Jianxia Chen 7,  Yingzhou Xie 8,  Yifan Yang 3,  Hua Yang 9,  Ling Wang 9,  Lianhua Qin 10,  Xiaochen Huang 10,  Jie Wang 10,  Zhonghua Liu 10,  Haipeng Liu 11,  Baoxue Ge 12,  Jinfu Xu 13,  Wei Sha 14
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200049, China. Electronic address: zhruijuan923@163.com.
  • 2 The Affiliated Hospital of Qingdao University &The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266003, P.R. China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
  • 3 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China.
  • 4 Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
  • 5 Department of Otolaryngology Head and Neck Surgery and Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Road 600, Shanghai 200233, P.R. China.
  • 6 School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, P.R. China.
  • 7 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
  • 8 Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai, China.
  • 9 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200049, China.
  • 10 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
  • 11 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: haipengliu@tongji.edu.cn.
  • 12 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200049, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China. Electronic address: gebaoxue@sibs.ac.cn.
  • 13 Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai, China; Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, China. Electronic address: jfxu@tongji.edu.cn.
  • 14 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: shfksw@tongji.edu.cn.
PMID: 39848245 DOI: 10.1016/j.xcrm.2024.101923
Abstract

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic progressive lung disease that is increasing in incidence. Host genetic factors are associated with NTM-PD susceptibility. However, the heritability of NTM-PD is not well understood. Here, we perform a two-stage genome-wide association study (GWAS) and discover a susceptibility locus at 16p21 associated with NTM-PD, especially with pulmonary Mycobacterium avium complex (MAC) disease. As the lead variant, rs194800 C allele augments protein kinase C beta (PRKCB) gene expression and associates with severer NTM-PD. The functional studies show that PRKCB exacerbates M. avium Infection and promotes intracellular survival of M. avium in macrophages by inhibiting phagosomal acidification. Mechanistically, PRKCB interacts with subunit G of the vacuolar-H+-ATPase (V-ATPase) and vacuolar protein sorting-associated protein 16 homolog (VPS16), blocking the fusion between lysosomes and mycobacterial phagosomes. PRKCB inhibitor has therapeutic potential against M. avium Infection. These findings provide insights into the genetic etiology of NTM-PD and highlight PRKCB as an attractive target for host-directed therapy of MAC disease.

Keywords

GWAS; intracellular survival; mycobacterium avium complex disease; polymorphism; susceptibility.

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