title: Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations.
abstract: BACKGROUND
  Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes.
  
  
  OBJECTIVE
  To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server.
  
  
  METHODS
  We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF.
  
  
  RESULTS
  We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant.
  
  
  CONCLUSIONS
  Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation.
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Meghan A
authors.initials: MA
authors.lastname: Coghlan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Shifren
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Tonya D
authors.initials: TD
authors.lastname: Russell
authors.affiliation: Department of Genetics , Center for Genome Sciences and Systems Biology, Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Robi D
authors.initials: RD
authors.lastname: Mitra
authors.affiliation: Division of Statistical Genomics, Department of Genetics , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wegner
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics , Washington University School of Medicine , St. Louis, Missouri , USA.
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
authors.affiliation: Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics , Washington University School of Medicine , St. Louis, Missouri , USA ; Division of Neonatology, Department of Pediatrics , Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, Illinois , USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
keywords: COPD epidemiology; Interstitial Fibrosis; Paediatric Lung Disaese; Rare lung diseases