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Title: Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction.
Authors: Wilk, JB
Shrine, NR
Loehr, LR
Zhao, JH
Manichaikul, A
Lopez, LM
Smith, AV
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, TH
Couper, D
Crapo, JD
Davies, G
Dupuis, J
Franceschini, N
Gulsvik, A
Hancock, DB
Harris, TB
Hofman, A
Imboden, M
James, AL
Khaw, KT
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, MS
Starr, JM
Uitterlinden, AG
Wareham, NJ
Wijmenga, C
Zanen, P
Province, MA
Silverman, EK
Deary, IJ
Palmer, LJ
Cassano, PA
Gudnason, V
Barr, RG
Loos, RJ
Strachan, DP
London, SJ
Boezen, HM
Probst-Hensch, N
Gharib, SA
Hall, IP
O'Connor, GT
Tobin, MD
Stricker, BH
First Published: 1-Oct-2012
Citation: AM J RESPIR CRIT CARE MED, 2012, 186 (7), pp. 622-632
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 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. 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 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. 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.
DOI Link: 10.1164/rccm.201202-0366OC
eISSN: 1535-4970
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Health Sciences

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