Genome-wide association study in patients with pulmonary <i>Mycobacterium avium</i> complex disease

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

doi:10.1183/13993003.02269-2019

Cited by 20 publications

(9 citation statements)

References 32 publications

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“…Human genetic backgrounds influence susceptibility to and/or severity of infectious diseases. Genome-wide association studies (GWAS) have identified a number of genetic loci associated with infectious diseases, including class I human leukocyte antigen (HLA) and CCR5 implicated in HIV infection, 18q11 in tuberculosis, HBB in malaria infection, and 16p21 in Mycobacterium avium complex (MAC) [8][9][10][11] . Thus, human host genetics is expected to define the susceptibility to COVID-19 and explain the populational differences in disease mortality and morbidity.…”

Section: Introductionmentioning

confidence: 99%

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Namkoong

Edahiro

Fukunaga

et al. 2021

Preprint

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To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

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Section: Introductionmentioning

confidence: 99%

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Namkoong

Edahiro

Fukunaga

et al. 2021

Preprint

Self Cite

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“…Recently, a clinical study revealed a decrease in the estrogen level 21 and a genome-wide association study revealed a single nucleotide polymorphism pattern in the chromosomal region encoding the calcineurin-like DF-hand protein 2 (CHP2) 22 . These ndings may provide insight into the mechanism of persistent infection.…”

Section: Discussionmentioning

confidence: 99%

Virulence of Mycobacterium intracellulare clinical strains in a mouse model of lung infection – Role of neutrophilic inflammation in disease severity

Tateishi

Ozeki

Nishiyama

et al. 2022

Preprint

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Mycobacterium intracellulare is a major etiological agent of Mycobacterium avium-intracellulare pulmonary disease (MAC-PD). However, the characteristics of the virulence of M. intracellulare and the in vivo chemotherapeutic efficacy remain unclear. In this study, we examined the virulence of nine M. intracellulare strains with different clinical phenotypes and genotypes in C57BL/6 mice. We classified three types of virulence phenotypes (high, intermediate, and low) based on the kinetics of the bacterial load, histological lung inflammation, and neutrophilic infiltration. High virulence strains showed more severe neutrophilic infiltration in the lungs than intermediate and low virulence strains. In particular, the high virulence strain M.i.198 showed the highest mortality in mice, which corresponded to the rapid progression of clinical disease. In mice infected with the drug-sensitive high virulence strain M019, clarithromycin-containing chemotherapy showed the highest efficacy. While monotherapy with rifampicin rather exacerbated lung inflammation with increased lymphocytic and neutrophilic infiltration into the lungs. In conclusion, the virulence phenotypes of clinical strains of M. intracellulare were diverse, with high virulence strains being associated with neutrophilic infiltration and disease progression in infected mice. These high virulence strains were proposed as a useful subject for in vivo chemotherapeutic experiments.

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“…Second, we were unable to detect T-cell responses against MAC-specific peptides or increased reactivity compared to IGRA+HC against Mav lysate in multiple antigen-specific assays. (45)(46)(47). Further studies will be needed to assess the impact of both macrophage hyperreactivity and relative T-cell deficiency in Mav pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood T-cell deficiency and hyperinflammatory monocyte responses associate with MAC lung disease

Arlehamn

Benson

Kuan

et al. 2022

Preprint

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Rationale: Although nontuberculous mycobacterial (NTM) disease is a growing problem, available treatments are suboptimal and diagnostic tools are inadequate. Immunological mechanisms of susceptibility to NTM disease are poorly understood. Objective: To understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in individuals with MAC lung disease (MACDZ). Methods: We synthesized 15mer MAC-, NTM-, or MAC/Mtb-specific peptides and stimulated peripheral blood mononuclear cells (PBMC) with pools of these peptides. We measured T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mav-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. Measurements and Main Results: We were unable to detect T-cell responses against the peptide libraries or Mav lysate that has increased reactivity in MACDZ subjects compared to controls. T-cell responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and Mav-infected monocytes derived from MACDZ subjects compared to controls. Conclusions: Peripheral blood T-cell responses to Mycobacterial antigens and the frequency of Th1 and Th1* cell populations are diminished in individuals with MAC disease. In contrast, MACDZ subjects had hyperinflammatory monocyte responses. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation.

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

Cited by 20 publications

References 32 publications

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan

Virulence of Mycobacterium intracellulare clinical strains in a mouse model of lung infection – Role of neutrophilic inflammation in disease severity

Peripheral blood T-cell deficiency and hyperinflammatory monocyte responses associate with MAC lung disease

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