Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Am J Respir Crit Care Med. 2012 Oct 1;186(7):622-32. doi: 10.1164/rccm.201202-0366OC. Epub 2012 Jul 26.

Abstract

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

Measurements and main results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Trial registration: ClinicalTrials.gov NCT00292552.

Publication types

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

MeSH terms

  • Aged
  • Female
  • Forced Expiratory Volume / genetics
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Receptors, Nicotinic / genetics*
  • Receptors, Serotonin, 5-HT4 / genetics*
  • Smoking / genetics
  • Vital Capacity / genetics

Substances

  • CHRNA5 protein, human
  • Nerve Tissue Proteins
  • Receptors, Nicotinic
  • nicotinic receptor subunit alpha3
  • Receptors, Serotonin, 5-HT4

Associated data

  • ClinicalTrials.gov/NCT00292552

Grants and funding