Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

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, akeypathophysiologiccharacteristicofCOPDassessedbyspirometry,inpopulation-basedcohortsexaminingallparticipants,eversmokers, 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 ofcase-controlstudieswere usedfor replicationandregional 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 identi-fiedoneregiononchromosome15q25.1meetinggenome-widesig-nificanceineversmokersthatincludes 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 incombinedmeta-analysis.Topsingle-nucleotidepolymorphismsin ADAM19 , RARB , PPAP2B ,and ADAMTS19 werenominallyreplicatedin the COPD meta-analysis. Conclusions :Theseresultssuggestanimportantroleforthe CHRNA5/ 3 region as a genetic risk factor for airflow obstruction that may be independentofsmokingandimplicatethe HTR4 geneintheetiology of airflow obstruction. obstruction. We also implicate the HTR4 gene in the pathogenesis of airflow obstruction. 60 SNPs with P values less than or equal to 1 3 10 2 5 in any of the five discovery meta-analyses were selected for replication. Combined meta-analysis was performed with the Family Heart Study (FamHS), which evaluated the same airflow obstruction phenotype as used in the discovery phase (331 affected and 2,550 un- affected). Replication was further evaluated in a meta-analysis of studies with clinically ascertained COPD (3,499 cases and 1,922 control subjects) (24). Gene expression in lung tissues was evaluated for two genes on chromosome 15.

[1]  Edwin K Silverman,et al.  Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. , 2012, Human molecular genetics.

[2]  L. Edwards,et al.  A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. , 2012, Human molecular genetics.

[3]  K. Shianna,et al.  Alpha‐nicotinic acetylcholine receptor and tobacco smoke exposure: Effects on bronchial hyperresponsiveness in children , 2012, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[4]  Christian Gieger,et al.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function , 2011, Nature Genetics.

[5]  T. Beaty,et al.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease , 2011, PloS one.

[6]  Z. Herceg,et al.  CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression. , 2011, Carcinogenesis.

[7]  N. Laird,et al.  The Association Of Genome-Wide Significant Spirometric Loci With COPD Susceptibility , 2011, ATS 2011.

[8]  P. Broderick,et al.  Chromosome 15q25 (CHRNA3-CHRNA5) Variation Impacts Indirectly on Lung Cancer Risk , 2011, PloS one.

[9]  Inês Barroso,et al.  Genome-wide association study identifies five loci associated with lung function , 2010, Nature Genetics.

[10]  G. Gamble,et al.  Chromosome 4q31 locus in COPD is also associated with lung cancer , 2010, European Respiratory Journal.

[11]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[12]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[13]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[14]  Ming D. Li,et al.  Genome-wide meta-analyses identify multiple loci associated with smoking behavior , 2010, Nature Genetics.

[15]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[16]  T. Dragani,et al.  Nicotine dependence may link the 15q25 locus to lung cancer risk. , 2010, Carcinogenesis.

[17]  Christoph Lange,et al.  Variants in FAM13A are associated with chronic obstructive pulmonary disease , 2010, Nature Genetics.

[18]  A. Hofman,et al.  Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function , 2010, Nature Genetics.

[19]  A. Hofman,et al.  Hedgehog-interacting protein is a COPD susceptibility gene: the Rotterdam Study , 2009, European Respiratory Journal.

[20]  W. Cardoso,et al.  Mechanisms of lung development: contribution to adult lung disease and relevance to chronic obstructive pulmonary disease. , 2009, Proceedings of the American Thoracic Society.

[21]  D. DeMeo,et al.  Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. , 2009, American journal of human genetics.

[22]  D. Postma,et al.  Expression of ADAMs (“a disintegrin and metalloprotease”) in the human lung , 2009, Virchows Archiv.

[23]  K. Shianna,et al.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci , 2009, PLoS genetics.

[24]  U. Pastorino,et al.  Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk , 2009, Clinical Cancer Research.

[25]  J Stocks,et al.  Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction , 2008, Thorax.

[26]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[27]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[28]  M. Idzko,et al.  Serotoninergic receptors on human airway epithelial cells. , 2007, American journal of respiratory cell and molecular biology.

[29]  T. Louis,et al.  Feasibility of retinoids for the treatment of emphysema study. , 2006, Chest.

[30]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[31]  M. Nanjundan,et al.  Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[32]  Víctor Quesada,et al.  Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. , 2002, Gene.

[33]  R. Pauwels,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. , 2001, Respiratory care.

[34]  M. Province,et al.  Evidence for major genes influencing pulmonary function in the NHLBI Family Heart Study , 2000, Genetic epidemiology.

[35]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[36]  J L Hankinson,et al.  Spirometric reference values from a sample of the general U.S. population. , 1999, American journal of respiratory and critical care medicine.

[37]  B Rosner,et al.  Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis. , 1998, American journal of respiratory and critical care medicine.

[38]  D. Massaro,et al.  Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats , 1997, Nature Medicine.