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


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    Wilk, Jemma B., Shrine, Nick R. G., Loehr, Laura R., Zhao, Jing Hua, Manichaikul, Ani, Lopez, Lorna M., Smith, Albert Vernon, Heckbert, Susan R., Smolonska, Joanna, Tang, Wenbo, Loth, Daan W., Curjuric, Ivan, Hui, Jennie, Cho, Michael H., Latourelle, Jeanne C., Henry, Amanda P., Aldrich, Melinda, Bakke, Per, Beaty, Terri H., Bentley, Amy R., Borecki, Ingrid B., Brusselle, Guy G., Burkart, Kristin M., Chen, Ting-hsu, Couper, David, Crapo, James D., Davies, Gail, Dupuis, Josée, Franceschini, Nora, Gulsvik, Amund, Hancock, Dana B., Harris, Tamara B., Hofman, Albert, Imboden, Medea, James, Alan L., Khaw, Kay-Tee, Lahousse, Lies, Launer, Lenore J., Litonjua, Augusto, Liu, Yongmei, Lohman, Kurt K., Lomas, David A., Lumley, Thomas, Marciante, Kristin D., McArdle, Wendy L., Meibohm, Bernd, Morrison, Alanna C., Musk, Arthur W., Myers, Richard H., North, Kari E., Postma, Dirkje S., Psaty, Bruce M., Rich, Stephen S., Rivadeneira, Fernando, Rochat, Thierry, Rotter, Jerome I., Artigas, María Soler, Starr, John M., Uitterlinden, André G., Wareham, Nicholas J., Wijmenga, Cisca, Zanen, Pieter, Province, Michael A., Silverman, Edwin K., Deary, Ian J., Palmer, Lyle J., Cassano, Patricia A., Gudnason, Vilmundur, Barr, R. Graham, Loos, Ruth J. F., Strachan, David P., London, Stephanie J., Boezen, H. Marike, Probst-Hensch, Nicole, Gharib, Sina A., Hall, Ian P., O’Connor, George T., 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: 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
    Related URLs:
    URI: https://mural.maynoothuniversity.ie/id/eprint/17395
    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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