2012-10-01
Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction
Publication
Publication
American Journal of Respiratory and Critical Care Medicine , Volume 186 - Issue 7 p. 622- 632
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 ofCOPD assessedby 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 metaanalysis 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 theHTR4 gene in the etiology of airflow obstruction.
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| doi.org/10.1164/rccm.201202-0366OC, hdl.handle.net/1765/74960 | |
| American Journal of Respiratory and Critical Care Medicine | |
| Organisation | Erasmus MC: University Medical Center Rotterdam |
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Wilk, J., Shrine, N., Loehr, L., Zhao, J. H., Manichaikul, A., Lopez, L., … Stricker, B. (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. doi:10.1164/rccm.201202-0366OC |
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