title: Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease.
abstract: BACKGROUND
  The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Eva P
authors.initials: EP
authors.lastname: Szymanski
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Leung
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Cedar J
authors.initials: CJ
authors.lastname: Fowler
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Carissa
authors.initials: C
authors.lastname: Haney
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: 2 Department of Epidemiology, Bloomberg School of Public Health, and.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: 2 Department of Epidemiology, Bloomberg School of Public Health, and.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: 3 Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Oler
authors.affiliation: 4 Department of Microbiology and Immunology, School of Medicine, University of Miami, Miami, Florida.
authors.forename: Ryan
authors.initials: R
authors.lastname: McCormack
authors.affiliation: 4 Department of Microbiology and Immunology, School of Medicine, University of Miami, Miami, Florida.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Podack
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Drummond
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Browne
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: D Rebecca
authors.initials: DR
authors.lastname: Prevots
authors.affiliation: 5 Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Knowles
authors.affiliation: 6 McKusick-Nathans Institute of Genetic Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gary
authors.initials: G
authors.lastname: Cutting
authors.affiliation: 7 Institute for Genome Sciences.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Liu
authors.affiliation: 7 Institute for Genome Sciences.|8 Department of Medicine, and.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Devine
authors.affiliation: 7 Institute for Genome Sciences.|8 Department of Medicine, and.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Fraser
authors.affiliation: 7 Institute for Genome Sciences.|9 Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tettelin
authors.affiliation: 10 Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Olivier
authors.affiliation: 1 Laboratory of Clinical Infectious Diseases.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015984:Causality; D002923:Cilia / Q000235:genetics*; D015331:Cohort Studies; D003238:Connective Tissue; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D059472:Exome; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007109:Immunity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics*; D025341:Principal Component Analysis; D017422:Sequence Analysis, DNA; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: bronchiectasis; cilia; genetics; immune system diseases; nontuberculous mycobacteria