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

Wilk, J. B. and Shrine, N. R. and Loehr, L. R. and Zhao, J. H. and Manichaikul, A. and Lopez, L. M. and Smith, A. V. and Heckbert, S. R. and Smolonska, J. and Tang, W. and Loth, D. W. and Curjuric, I. and Hui, J. and Cho, M. H. and Latourelle, J. C. and Henry, A. P. and Aldrich, M. and Bakke, P. and Beaty, T. H. and Bentley, A. R. and Borecki, I. B. and Brusselle, G. G. and Burkart, K. M. and Chen, T. H. and Couper, D. and Crapo, J. D. and Davies, G. and Dupuis, J. and Franceschini, N. and Gulsvik, A. and Hancock, D. B. and Harris, T. B. and Hofman, A. and Imboden, M. and James, A. L. and Khaw, K. T. and Lahousse, L. and Launer, L. J. and Litonjua, A. and Liu, Y. and Lohman, K. K. and Lomas, D. A. and Lumley, T. and Marciante, K. D. and McArdle, W. L. and Meibohm, B. and Morrison, A. C. and Musk, A. W. and Myers, R. H. and North, K. E. and Postma, D. S. and Psaty, B. M. and Rich, S. S. and Rivadeneira, F. and Rochat, T. and Rotter, J. I. and Soler, A. M. and Starr, J. M. and Uitterlinden, A. G. and Wareham, N. J. and Wijmenga, C. and Zanen, P. and Province, M. A. and Silverman, E. K. and Deary, I. J. and Palmer, L. J. and Cassano, P. A. and Gudnason, V. and Barr, R. G. and Loos, R. J. and Strachan, D. P. and London, S. J. and Boezen, H. M. and Probst-Hensch, N. and Gharib, S. A. and Hall, I. P. and O'Connor, G. T. and Tobin, M. D. and Stricker, B. 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, Vol. 186, H. 7. pp. 622-632.

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Official URL: http://edoc.unibas.ch/dok/A6094192

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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 controls). Airflow obstruction was defined as forced expiratory volume in one second (FEV(1)) and its ratio to forced vital capacity (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 SNP in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top SNPs 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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology
UniBasel Contributors:Curjuric, Ivan and Imboden, Medea
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Thoracic Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Jul 2013 07:43
Deposited On:19 Jul 2013 07:39

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