Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

Nat Commun. 2015 Sep 29:6:8382. doi: 10.1038/ncomms9382.


The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Transport Systems
  • Amino Acid Transport Systems, Neutral / genetics
  • Child
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / pathology
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Lung / metabolism
  • Lung / pathology*
  • Male
  • Middle Aged
  • Mucin-4 / genetics
  • Mucins / genetics
  • Severity of Illness Index
  • Transcription Factors / genetics
  • Young Adult


  • Amino Acid Transport Systems
  • Amino Acid Transport Systems, Neutral
  • EHF protein, human
  • MUC20 protein, human
  • MUC4 protein, human
  • Mucin-4
  • Mucins
  • SLC6A14 protein, human
  • Transcription Factors