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

Publication ,  Journal Article
Wilk, JB; Shrine, NRG; Loehr, LR; Zhao, JH; Manichaikul, A; Lopez, LM; Smith, AV; Heckbert, SR; Smolonska, J; Tang, W; Loth, DW; Curjuric, I ...
Published in: Am J Respir Crit Care Med
October 1, 2012

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.

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Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

October 1, 2012

Volume

186

Issue

7

Start / End Page

622 / 632

Location

United States

Related Subject Headings

  • Vital Capacity
  • Smoking
  • Respiratory System
  • Receptors, Serotonin, 5-HT4
  • Receptors, Nicotinic
  • Pulmonary Disease, Chronic Obstructive
  • Polymorphism, Single Nucleotide
  • Nerve Tissue Proteins
  • Middle Aged
  • Male
 

Citation

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Wilk, J. B., Shrine, N. R. G., Loehr, L. R., Zhao, J. H., Manichaikul, A., Lopez, L. M., … Stricker, B. H. (2012). Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am J Respir Crit Care Med, 186(7), 622–632. https://doi.org/10.1164/rccm.201202-0366OC
Wilk, Jemma B., Nick R. G. Shrine, Laura R. Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M. Lopez, Albert Vernon Smith, et al. “Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.Am J Respir Crit Care Med 186, no. 7 (October 1, 2012): 622–32. https://doi.org/10.1164/rccm.201202-0366OC.
Wilk JB, Shrine NRG, 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. Am J Respir Crit Care Med. 2012 Oct 1;186(7):622–32.
Wilk, Jemma B., et al. “Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.Am J Respir Crit Care Med, vol. 186, no. 7, Oct. 2012, pp. 622–32. Pubmed, doi:10.1164/rccm.201202-0366OC.
Wilk JB, Shrine NRG, 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 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, Soler Artigas M, 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 RJF, Strachan DP, London SJ, Boezen HM, Probst-Hensch N, Gharib SA, Hall IP, O’Connor GT, Tobin MD, Stricker BH. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am J Respir Crit Care Med. 2012 Oct 1;186(7):622–632.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

October 1, 2012

Volume

186

Issue

7

Start / End Page

622 / 632

Location

United States

Related Subject Headings

  • Vital Capacity
  • Smoking
  • Respiratory System
  • Receptors, Serotonin, 5-HT4
  • Receptors, Nicotinic
  • Pulmonary Disease, Chronic Obstructive
  • Polymorphism, Single Nucleotide
  • Nerve Tissue Proteins
  • Middle Aged
  • Male