Skip to main content

Research Repository

Advanced Search

Whole Exome Re-Sequencing Implicates CCDC38 and Cilia Structure and Function in Resistance to Smoking Related Airflow Obstruction

Wain, Louise V.; Sayers, Ian; Soler Artigas, María; Portelli, Michael A.; Zeggini, Eleftheria; Obeidat, Ma’en; Sin, Don D.; Bossé, Yohan; Nickle, David C.; Brandsma, Corry-Anke; Malarstig, Anders; Vangjeli, Ciara; Jelingsky, Scott A.; John, Sally; Kilty, Iain; McKeever, Tricia M.; Shrine, Nick; Cook, James P.; Patel, Shrina; Spector, Tim D.; Hollox, Edward J.; Hall, Ian P.; Tobin, Martin D.

Authors

Louise V. Wain

María Soler Artigas

Eleftheria Zeggini

Ma’en Obeidat

Don D. Sin

Yohan Bossé

David C. Nickle

Corry-Anke Brandsma

Anders Malarstig

Ciara Vangjeli

Scott A. Jelingsky

Sally John

Iain Kilty

TRICIA MCKEEVER tricia.mckeever@nottingham.ac.uk
Professor of Epidemiology and Medical Statistics

Nick Shrine

James P. Cook

Shrina Patel

Tim D. Spector

Edward J. Hollox

IAN HALL ian.hall@nottingham.ac.uk
Professor of Molecular Medicine

Martin D. Tobin



Contributors

Greg Gibson
Editor

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 (FEV1) 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 = 2.3461024) in CCDC38, a gene which has previously been reported to show association with FEV1/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.

Citation

Wain, L. V., Sayers, I., Soler Artigas, M., Portelli, M. A., Zeggini, E., Obeidat, M., …Tobin, M. D. (2014). Whole Exome Re-Sequencing Implicates CCDC38 and Cilia Structure and Function in Resistance to Smoking Related Airflow Obstruction. PLoS Genetics, 10(5), https://doi.org/10.1371/journal.pgen.1004314

Journal Article Type Article
Acceptance Date Mar 6, 2014
Online Publication Date May 1, 2014
Publication Date May 1, 2014
Deposit Date Apr 6, 2016
Publicly Available Date Apr 6, 2016
Journal PLoS Genetics
Print ISSN 1553-7390
Electronic ISSN 1553-7404
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 10
Issue 5
Article Number e1004314
DOI https://doi.org/10.1371/journal.pgen.1004314
Public URL http://eprints.nottingham.ac.uk/id/eprint/32645
Publisher URL http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004314
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

Wain PLoS Genet 2014.pdf (521 Kb)
PDF

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





You might also like



Downloadable Citations