Human Molecular Genetics Advance Access published online on March 11, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp111
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Association of TRPV4 Gene Polymorphisms with Chronic Obstructive Pulmonary Disease
1 GlaxoSmithKline, RTP, NC, United States 2 International COPD Genetics Network, Alvar Agusti, Son Dureta Hospital, Fundación Caubet-Cimera and CIBER Enfermedades Respiratorias (CIBERES), Palma de Mallorca, Spain; Peter M.A. Calverley, University of Liverpool, U.K; Claudio F. Donner, Division of Pulmonary Disease, S. Maugeri Foundation, Veruno (NO), Italy; Robert D. Levy, University of British Columbia, Vancouver, Canada; Barry J. Make, National Jewish Medical and Research Centre, Denver, Colorado, USA; Peter D. Paré, University of British Columbia, Vancouver, Canada; Stephen I. Rennard, University of Nebraska, Omaha, USA; Jørgen Vestbo, Department of Cardiology and Respiratory Medicine, Hvidovre Hospital, Copenhagen, Denmark; Emiel F.M. Wouters, University Hospital Maastricht, Netherlands 3 University of Bergen, Bergen, Norway 4 Center for Excellence in Drug Discovery (Respiratory), GlaxoSmithKline, Upper Merion, PA 5 Cambridge Institute for Medical Research, Cambridge, UK 6 Brigham and Women's Hospital, Boston, MA
* Correspondence and requests for reprints: Sreekumar G. Pillai Genetics, GlaxoSmithKline R&D, 5 Moore Drive, Research Triangle Park, NC 27709 USA, Phone: (919) 483-1815, FAX: (919) 315-0311, E-mail: sreekumar.g.pillai{at}gsk.com
Received October 16, 2008; Revised February 27, 2009; Accepted March 9, 2009
Chronic obstructive pulmonary disease (COPD) is characterized by airway epithelial damage, bronchoconstriction, parenchymal destruction, and mucus hypersecretion. Upon activation by a broad range of stimuli, transient receptor potential vanilloid 4 (TRPV4) functions to control airway epithelial cell volume, and epithelial and endothelial permeability; it also triggers bronchial smooth muscle contraction and participates in autoregulation of mucociliary transport. These functions of TRPV4 may be important for regulation of COPD pathogenesis, so TRPV4 is a candidate gene for COPD.
We genotyped 20 single nucleotide polymorphisms (SNPs) in TRPV4, and tested qualitative COPD and quantitative FEV1 and FEV1/(F)VC phenotypes in two independent large populations. The family population had 606 pedigrees including 1,891 individuals, and the case-control sample included 953 COPD cases and 956 controls. Family-based association tests were performed in the family data. Logistic regression and linear models were used in the case-control data to replicate the association results. In the family data, seven out of 20 SNPs tested were associated with COPD (2.5 x 10–4 
P 0.04) and six SNPs were associated with FEV1/VC (0.02 P 0.03) from FBAT (PBAT) analysis. Four out of the seven SNPs associated with COPD demonstrated replicated associations with the same effect directions in the case-control population (0.02 P 0.03). Significant haplotype associations supported the results of single SNP analyses. Thus, polymorphisms in the TRPV4 gene are associated with COPD.