Wilk, Jemma B. and Shrine, Nick R. G. and Loehr, Laura R. and Zhao, Jing Hua and Manichaikul, Ani and Lopez, Lorna M. and Smith, Albert Vernon and Heckbert, Susan R. and Smolonska, Joanna and Tang, Wenbo and Loth, Daan W. and Curjuric, Ivan and Hui, Jennie and Cho, Michael H. and Latourelle, Jeanne C. and Henry, Amanda P. and Aldrich, Melinda and Bakke, Per and Beaty, Terri H. and Bentley, Amy R. and Borecki, Ingrid B. and Brusselle, Guy G. and Burkart, Kristin M. and Chen, Ting-hsu and Couper, David and Crapo, James D. and Davies, Gail and Dupuis, Josée and Franceschini, Nora and Gulsvik, Amund and Hancock, Dana B. and Harris, Tamara B. and Hofman, Albert and Imboden, Medea and James, Alan L. and Khaw, Kay-Tee and Lahousse, Lies and Launer, Lenore J. and Litonjua, Augusto and Liu, Yongmei and Lohman, Kurt K. and Lomas, David A. and Lumley, Thomas and Marciante, Kristin D. and McArdle, Wendy L. and Meibohm, Bernd and Morrison, Alanna C. and Musk, Arthur W. and Myers, Richard H. and North, Kari E. and Postma, Dirkje S. and Psaty, Bruce M. and Rich, Stephen S. and Rivadeneira, Fernando and Rochat, Thierry and Rotter, Jerome I. and Artigas, María Soler and Starr, John M. and Uitterlinden, André G. and Wareham, Nicholas J. and Wijmenga, Cisca and Zanen, Pieter and Province, Michael A. and Silverman, Edwin K. and Deary, Ian J. and Palmer, Lyle J. and Cassano, Patricia A. and Gudnason, Vilmundur and Barr, R. Graham and Loos, Ruth J. F. and Strachan, David P. and London, Stephanie J. and Boezen, H. Marike and Probst-Hensch, Nicole and Gharib, Sina A. and Hall, Ian P. and O’Connor, George T. and Tobin, Martin D. and Stricker, Bruno H. (2012) Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction. American Journal of Respiratory and Critical Care Medicine, 186 (7). pp. 622-632. ISSN 1535-4970

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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 FEV1 and its ratio to FVC (FEV1/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 FEV1/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.

Item Type:	Article
Keywords:	chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17395
Identification Number:	https://doi.org/10.1164/rccm.201202-0366OC
Depositing User:	Lorna Lopez
Date Deposited:	10 Jul 2023 15:07
Journal or Publication Title:	American Journal of Respiratory and Critical Care Medicine
Publisher:	American Thoracic Society
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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