Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

JB Wilk, NRG Shrine, LR Loehr, JH Zhao, A Manichaikul, LM Lopez, AV Smith, SR Heckbert, J Smolonska, WB Tang, Daan Loth, I Curjuric, J Hui, MH Cho, JC Latourelle, AP Henry, M Aldrich, P Bakke, TH Beaty, AR BentleyIB Borecki, Guy Brusselle, KM Burkart, TH Chen, D Couper, JD Crapo, G Davies, J Dupuis, N Franceschini, A Gulsvik, DB Hancock, TB Harris, Bert Hofman, M Imboden, AL James, KT Khaw, Lies Lahousse, LJ (Lenore) Launer, A Litonjua, YM Liu, KK Lohman, DA Lomas, T Lumley, KD Marciante, WL McArdle, B Meibohm, AC Morrison, AW Musk, RH Myers, KE North, DS Postma, BM Psaty, SS Rich, Fernando Rivadeneira, T Rochat, JI Rotter, MS Artigas, JM Starr, André Uitterlinden, NJ Wareham, C Wijmenga, P Zanen, MA Province, EK Silverman, IJ Deary, LJ Palmer, PA Cassano, V Gudnason, RG Barr, RJF Loos, DP Strachan, SJ London, HM Boezen, N Probst-Hensch, SA Gharib, IP Hall, GT O'Connor, MD Tobin, Bruno Stricker

Research output: Contribution to journalArticleAcademicpeer-review

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 statistic 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.
Original languageUndefined/Unknown
Pages (from-to)622-632
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number7
DOIs
Publication statusPublished - 2012

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