Article Text

Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations
  1. Meghan A Coghlan1,
  2. Adrian Shifren2,
  3. Howard J Huang2,
  4. Tonya D Russell2,
  5. Robi D Mitra3,
  6. Qunyuan Zhang4,
  7. Daniel J Wegner1,
  8. F Sessions Cole1 and
  9. Aaron Hamvas1,5
  1. 1Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
  2. 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
  3. 3Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA
  4. 4Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
  5. 5Division of Neonatology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr Aaron Hamvas; ahamvas{at}


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.

  • Interstitial Fibrosis
  • Paediatric Lung Disaese
  • Rare lung diseases
  • COPD epidemiology

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