Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease

Eva P. Szymanski, Janice M. Leung, Cedar J. Fowler, Carissa Haney, Amy P. Hsu, Fei Chen, Priya Duggal, Andrew J. Oler, Ryan McCormack, Eckhard Podack, Rebecca A. Drummond, Michail S. Lionakis, Sarah K. Browne, D. Rebecca Prevots, Michael Knowles, Gary Cutting, Xinyue Liu, Scott E. Devine, Claire M. Fraser, Hervé TettelinKenneth N. Olivier, Steven M. Holland

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Rationale: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. Objectives: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. Methods: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. Measurements and Main Results: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10<sup>-6</sup> and P = 2.7 × 10<sup>-8</sup>, respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10<sup>-17</sup>), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. Conclusions: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.

Original languageEnglish (US)
Pages (from-to)618-628
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume192
Issue number5
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint

Nontuberculous Mycobacteria
Lung
Cilia
Infection
Connective Tissue
Nontuberculous Mycobacterium Infections
Cystic Fibrosis
Genes
Exome
Environmental Exposure
Genetic Association Studies
Proteins
Control Groups

Keywords

  • Bronchiectasis
  • Cilia
  • Genetics
  • Immune system diseases
  • Nontuberculous mycobacteria

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Szymanski, E. P., Leung, J. M., Fowler, C. J., Haney, C., Hsu, A. P., Chen, F., ... Holland, S. M. (2015). Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease. American Journal of Respiratory and Critical Care Medicine, 192(5), 618-628. https://doi.org/10.1164/rccm.201502-0387OC

Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease. / Szymanski, Eva P.; Leung, Janice M.; Fowler, Cedar J.; Haney, Carissa; Hsu, Amy P.; Chen, Fei; Duggal, Priya; Oler, Andrew J.; McCormack, Ryan; Podack, Eckhard; Drummond, Rebecca A.; Lionakis, Michail S.; Browne, Sarah K.; Prevots, D. Rebecca; Knowles, Michael; Cutting, Gary; Liu, Xinyue; Devine, Scott E.; Fraser, Claire M.; Tettelin, Hervé; Olivier, Kenneth N.; Holland, Steven M.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 192, No. 5, 01.09.2015, p. 618-628.

Research output: Contribution to journalArticle

Szymanski, EP, Leung, JM, Fowler, CJ, Haney, C, Hsu, AP, Chen, F, Duggal, P, Oler, AJ, McCormack, R, Podack, E, Drummond, RA, Lionakis, MS, Browne, SK, Prevots, DR, Knowles, M, Cutting, G, Liu, X, Devine, SE, Fraser, CM, Tettelin, H, Olivier, KN & Holland, SM 2015, 'Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease', American Journal of Respiratory and Critical Care Medicine, vol. 192, no. 5, pp. 618-628. https://doi.org/10.1164/rccm.201502-0387OC
Szymanski, Eva P. ; Leung, Janice M. ; Fowler, Cedar J. ; Haney, Carissa ; Hsu, Amy P. ; Chen, Fei ; Duggal, Priya ; Oler, Andrew J. ; McCormack, Ryan ; Podack, Eckhard ; Drummond, Rebecca A. ; Lionakis, Michail S. ; Browne, Sarah K. ; Prevots, D. Rebecca ; Knowles, Michael ; Cutting, Gary ; Liu, Xinyue ; Devine, Scott E. ; Fraser, Claire M. ; Tettelin, Hervé ; Olivier, Kenneth N. ; Holland, Steven M. / Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease. In: American Journal of Respiratory and Critical Care Medicine. 2015 ; Vol. 192, No. 5. pp. 618-628.
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AU - Haney, Carissa

AU - Hsu, Amy P.

AU - Chen, Fei

AU - Duggal, Priya

AU - Oler, Andrew J.

AU - McCormack, Ryan

AU - Podack, Eckhard

AU - Drummond, Rebecca A.

AU - Lionakis, Michail S.

AU - Browne, Sarah K.

AU - Prevots, D. Rebecca

AU - Knowles, Michael

AU - Cutting, Gary

AU - Liu, Xinyue

AU - Devine, Scott E.

AU - Fraser, Claire M.

AU - Tettelin, Hervé

AU - Olivier, Kenneth N.

AU - Holland, Steven M.

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N2 - Rationale: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. Objectives: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. Methods: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. Measurements and Main Results: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 × 10-6 and P = 2.7 × 10-8, respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 × 10-17), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. Conclusions: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection.

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KW - Bronchiectasis

KW - Cilia

KW - Genetics

KW - Immune system diseases

KW - Nontuberculous mycobacteria

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