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Title: Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction
Authors: Wain, Louise V.
Sayers, Ian
Soler Artigas, Marıa
Portelli, Michael A.
Zeggini, Eleftheria
Obeidat, Ma’en
Sin, Don D.
Bossé, Yohan
Nickle, David
Brandsma, Corry-Anke
Malarstig, Anders
Vangjeli, Ciara
Jelinsky, Scott A.
John, Sally
Kilty, Iain
McKeever, Tricia
Shrine, Nick R. G.
Cook, James P.
Patel, Shrina
Spector, Tim D.
Hollox, Edward J.
Hall, Ian P.
Tobin, Martin D.
First Published: 1-May-2014
Publisher: Public Library of Science
Citation: PLoS Genetics, 2014, 10 (5), e1004314
Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV[subscript 1]) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10[superscript -4]) in CCDC38, a gene which has previously been reported to show association with FEV[subscript 1]/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.
DOI Link: 10.1371/journal.pgen.1004314
ISSN: 1553-7390
eISSN: 1553-7404
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: PMCID: PMC4006731
Appears in Collections:Published Articles, Dept. of Genetics

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