• Jemma B Wilk, Nick R G Shrine, Laura R Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M Lopez, Albert Vernon Smith, Susan R Heckbert, Joanna Smolonska, Wenbo Tang, Daan W Loth, Ivan Curjuric, Jennie Hui, Michael H Cho, Jeanne C Latourelle, Amanda P Henry, Melinda Aldrich, Per Bakke, Terri H Beaty, Amy R Bentley, Ingrid B Borecki, Guy G Brusselle, Kristin M Burkart, Ting-hsu Chen, David Couper, James D Crapo, Gail Davies, Josée Dupuis, Nora Franceschini, Amund Gulsvik, Dana B Hancock, Tamara B Harris, Albert Hofman, Medea Imboden, Alan L James, Kay-Tee Khaw, Lies Lahousse, Lenore J Launer, Augusto Litonjua, Yongmei Liu, Kurt K Lohman, David A Lomas, Thomas Lumley, Kristin D Marciante, Wendy L McArdle, Bernd Meibohm, Alanna C Morrison, Arthur W Musk, Richard H Myers, Kari E North, Dirkje S Postma, Bruce M Psaty, Stephen S Rich, Fernando Rivadeneira, Thierry Rochat, Jerome I Rotter, Soler ArtigasMaríaM, John M Starr, André G Uitterlinden, Nicholas J Wareham, Cisca Wijmenga, Pieter Zanen, Michael A Province, Edwin K Silverman, Ian J Deary, Lyle J Palmer, Patricia A Cassano, Vilmundur Gudnason, R Graham Barr, Ruth J F Loos, David P Strachan, Stephanie J London, H Marike Boezen, Nicole Probst-Hensch, Sina A Gharib, Ian P Hall, George T O'Connor, Martin D Tobin, and Bruno H Stricker.
• Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Boston, MA 02120, USA. jwilk@rics.bwh.harvard.edu
• Am. J. Respir. Crit. Care Med. 2012 Oct 1; 186 (7): 622632622-32.

RationaleGenome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.ObjectivesPerform 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.MethodsFifteen 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 ResultsThe 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.ConclusionsThese 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.

24 keywords...

hide…