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

Jemma B Wilk, Nick RG Shrine, Laura R Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M Lopez, Albert Vernon Smith, Susan R Heckbert, Joanna Smolonska and Wenbo Tang, et al. (2012) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 186(7). p.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 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
single-nucleotide polymorphism, chronic obstructive pulmonary disease, genes, NICOTINIC ACETYLCHOLINE-RECEPTOR, PULMONARY-DISEASE, LUNG-CANCER, SUSCEPTIBILITY LOCUS, SMOKING-BEHAVIOR, 15Q25 LOCUS, RISK, EXPRESSION, VARIANTS, COPD
journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Am. J. Respir. Crit. Care Med.
volume
186
issue
7
pages
622 - 632
Web of Science type
Article
Web of Science id
000309383600013
JCR category
RESPIRATORY SYSTEM
JCR impact factor
11.041 (2012)
JCR rank
1/50 (2012)
JCR quartile
1 (2012)
ISSN
1073-449X
DOI
10.1164/rccm.201202-0366OC
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3052062
handle
http://hdl.handle.net/1854/LU-3052062
date created
2012-11-13 13:52:20
date last changed
2012-11-13 14:43:49
@article{3052062,
  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.},
  author       = {Wilk, Jemma B and Shrine, Nick RG and Loehr, Laura R and Zhao, Jing Hua and Manichaikul, Ani and Lopez, Lorna M and Smith, Albert Vernon and Heckbert, Susan R and Smolonska, Joanna and Tang, Wenbo and Loth, Daan W and Curjuric, Ivan and Hui, Jennie and Cho, Michael H and Latourelle, Jeanne C and Henry, Amanda P and Aldrich, Melinda and Bakke, Per and Beaty, Terri H and Bentley, Amy R and Borecki, Ingrid B and Brusselle, Guy and Burkart, Kristin M and Chen, Ting-hsu and Couper, David and Crapo, James D and Davies, Gail and Dupuis, Jos{\'e}e and Franceschini, Nora and Gulsvik, Amund and Hancock, Dana B and Harris, Tamara B and Hofman, Albert and Imboden, Medea and James, Alan L and Khaw, Kay-Tee and Lahousse, Lies and Launer, Lenore J and Litonjua, Augusto and Liu, Yongmei and Lohman, Kurt K and Lomas, David A and Lumley, Thomas and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and Musk, Arthur W and Myers, Richard H and North, Kari E and Postma, Dirkje S and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Rochat, Thierry and Rotter, Jerome I and Artigas, Maria Soler and Starr, John M and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Wijmenga, Cisca and Zanen, Pieter and Province, Michael A and Silverman, Edwin K and Deary, Ian J and Palmer, Lyle J and Cassano, Patricia A and Gudnason, Vilmundur and Barr, R Graham and Loos, Ruth JF and Strachan, David P and London, Stephanie J and Boezen, H Marike and Probst-Hensch, Nicole and Gharib, Sina A and Hall, Ian P and O'Connor, George T and Tobin, Martin D and Stricker, Bruno H},
  issn         = {1073-449X},
  journal      = {AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE},
  keyword      = {single-nucleotide polymorphism,chronic obstructive pulmonary disease,genes,NICOTINIC ACETYLCHOLINE-RECEPTOR,PULMONARY-DISEASE,LUNG-CANCER,SUSCEPTIBILITY LOCUS,SMOKING-BEHAVIOR,15Q25 LOCUS,RISK,EXPRESSION,VARIANTS,COPD},
  language     = {eng},
  number       = {7},
  pages        = {622--632},
  title        = {Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction},
  url          = {http://dx.doi.org/10.1164/rccm.201202-0366OC},
  volume       = {186},
  year         = {2012},
}

Chicago
Wilk, Jemma B, Nick RG Shrine, Laura R Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M Lopez, Albert Vernon Smith, et al. 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): 622–632.
APA
Wilk, J. B., Shrine, N. R., Loehr, L. R., Zhao, J. H., Manichaikul, A., Lopez, L. M., Smith, A. V., et al. (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), 622–632.
Vancouver
1.
Wilk JB, Shrine NR, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, et al. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 2012;186(7):622–32.
MLA
Wilk, Jemma B, Nick RG Shrine, Laura R Loehr, et al. “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 (2012): 622–632. Print.