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

Tuesday,2013-10-01 10:34 America/Los_Angeles — poolea2
TitleGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.
Publication TypeJournal Article
Year of Publication2012
AuthorsWilk, JB, Shrine, NRG, Loehr, LR, Zhao, JH, Manichaikul, A, Lopez, LM, Smith, AVernon, Heckbert, SR, Smolonska, J, Tang, W, Loth, DW, Curjuric, I, Hui, J, Cho, MH, Latourelle, JC, Henry, AP, Aldrich, M, Bakke, P, Beaty, TH, Bentley, AR, Borecki, IB, Brusselle, GG, Burkart, KM, Chen, T-H, Couper, D, Crapo, JD, Davies, G, Dupuis, J, Franceschini, N, Gulsvik, A, Hancock, DB, Harris, TB, Hofman, A, Imboden, M, James, AL, Khaw, K-T, Lahousse, L, Launer, LJ, Litonjua, A, Liu, Y, Lohman, KK, Lomas, DA, Lumley, T, Marciante, KD, McArdle, WL, Meibohm, B, Morrison, AC, Musk, AW, Myers, RH, North, KE, Postma, DS, Psaty, BM, Rich, SS, Rivadeneira, F, Rochat, T, Rotter, JI, Artigas, MSoler, Starr, JM, Uitterlinden, AG, Wareham, NJ, Wijmenga, C, Zanen, P, Province, MA, Silverman, EK, Deary, IJ, Palmer, LJ, Cassano, PA, Gudnason, V, R Barr, G, Loos, RJF, Strachan, DP, London, SJ, H Boezen, M, Probst-Hensch, N, Gharib, SA, Hall, IP, O'Connor, GT, Tobin, MD, Stricker, BH
JournalAm J Respir Crit Care Med
Volume186
Issue7
Pagination622-32
Date Published2012 Oct 01
ISSN1535-4970
KeywordsAged, Female, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Receptors, Nicotinic, Receptors, Serotonin, 5-HT4, Smoking, Vital Capacity
Abstract<p><b>RATIONALE: </b>Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.</p><p><b>OBJECTIVES: </b>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.</p><p><b>METHODS: </b>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 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.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>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 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.</p><p><b>CONCLUSIONS: </b>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.</p>
DOI10.1164/rccm.201202-0366OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID22837378
PubMed Central IDPMC3480517
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
N01HR76113 / HR / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
018996 / / Wellcome Trust / United Kingdom
R01-HL-088215 / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
N01HR76107 / HR / NHLBI NIH HHS / United States
R01 HL089897 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
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N01-HC-95162 / HC / NHLBI NIH HHS / United States
P01 HL083069 / HL / NHLBI NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
N01HR76104 / HR / NHLBI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
N01HR76118 / HR / NHLBI NIH HHS / United States
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HHSN268201100010C / HL / NHLBI NIH HHS / United States
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R01-DK-8925601 / DK / NIDDK NIH HHS / United States
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HHSN268201100005G / HL / NHLBI NIH HHS / United States
RC1AG035835 / AG / NIA NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
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HL105756 / HL / NHLBI NIH HHS / United States
RR-024156 / RR / NCRR NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
G1000861 / / Medical Research Council / United Kingdom
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WT 084703MA / / Wellcome Trust / United Kingdom
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