title: Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors: Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Boston, MA 02120, USA. jwilk@rics.bwh.harvard.edu
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mesh_terms: D000368:Aged; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics*; D012907:Smoking / Q000235:genetics; D014797:Vital Capacity / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D044422:Receptors, Serotonin, 5-HT4; C447158:CHRNA5 protein, human