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Meta-Analysis
. 2012 Oct 1;186(7):622-32.
doi: 10.1164/rccm.201202-0366OC. Epub 2012 Jul 26.

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

Jemma B Wilk  1 , Nick R G Shrine, Laura R Loehr, Jing Hua Zhao, Ani Manichaikul, Lorna M Lopez, Albert Vernon Smith, Susan R Heckbert, Joanna Smolonska, Wenbo Tang, Daan W Loth, Ivan Curjuric, Jennie Hui, Michael H Cho, Jeanne C Latourelle, Amanda P Henry, Melinda Aldrich, Per Bakke, Terri H Beaty, Amy R Bentley, Ingrid B Borecki, Guy G Brusselle, Kristin M Burkart, Ting-hsu Chen, David Couper, James D Crapo, Gail Davies, Josée Dupuis, Nora Franceschini, Amund Gulsvik, Dana B Hancock, Tamara B Harris, Albert Hofman, Medea Imboden, Alan L James, Kay-Tee Khaw, Lies Lahousse, Lenore J Launer, Augusto Litonjua, Yongmei Liu, Kurt K Lohman, David A Lomas, Thomas Lumley, Kristin D Marciante, Wendy L McArdle, Bernd Meibohm, Alanna C Morrison, Arthur W Musk, Richard H Myers, Kari E North, Dirkje S Postma, Bruce M Psaty, Stephen S Rich, Fernando Rivadeneira, Thierry Rochat, Jerome I Rotter, María Soler Artigas, John M Starr, André G Uitterlinden, Nicholas J Wareham, Cisca Wijmenga, Pieter Zanen, Michael A Province, Edwin K Silverman, Ian J Deary, Lyle J Palmer, Patricia A Cassano, Vilmundur Gudnason, R Graham Barr, Ruth J F Loos, David P Strachan, Stephanie J London, H Marike Boezen, Nicole Probst-Hensch, Sina A Gharib, Ian P Hall, George T O'Connor, Martin D Tobin, Bruno H Stricker
Affiliations
Meta-Analysis

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

Jemma B Wilk et al. Am J Respir Crit Care Med. .

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.

Trial registration: ClinicalTrials.gov NCT00292552.

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Figures

Figure 1.
Figure 1.
Regional association plot for chromosome 15 presenting results from combined meta-analysis of discovery and replication studies. X-axis is megabase (Mb) position. Y-axis is negative log of the P values. Linkage disequilibrium to the named single-nucleotide polymorphism (SNP) (purple) is depicted by degree of color according to the legend. Nonsynonymous SNPs are depicted by an inverted triangle and other coding SNPs by a square. (A) Ever smokers. (B) Never smokers.
Figure 2.
Figure 2.
Forest plot depicting the association results for rs1051730 (CHRNA3) and airflow obstruction among never smokers in each cohort and the meta-analysis. AGES = Age, Gene, Environment Susceptibility; ARIC = Atherosclerosis Risk in Communities; B58C = British 1958 Birth Cohort; BHS = Bussleton Health Study; CHS = Cardiovascular Health Study; EPIC = European Prospective Investigation into Cancer and Nutrition; FamHS = Family Heart Study; FHS = Framingham Heart Study; SAPALDIA = Swiss Study on Air Pollution and Lung and Heart Disease in Adults.
See this image and copyright information in PMC

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