Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease

The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. Whole-exome sequen...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2015-09, Vol.192 (5), p.618-628
Main Authors: 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
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Case-Control Studies
Causality
Cilia - genetics
Cohort Studies
Connective Tissue
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Exome
Family
Female
Genetic Predisposition to Disease
Genetic Variation
Humans
Immunity - genetics
Male
Middle Aged
Mycobacterium Infections, Nontuberculous - genetics
Original
Principal Component Analysis
Sequence Analysis, DNA
Tuberculosis, Pulmonary - genetics
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Summary:The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. 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. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201502-0387OC