Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction

Wain, Louise V. and Sayers, Ian and Artigas, María Soler and Portelli, Michael A. and Zeggini, Eleftheria and Obeidat, Ma’en and Sin, Don D. and Bossé, Yohan and Nickle, David C. and Brandsma, Corry-Anke and Malarstig, Anders and Vangjeli, Ciara and Jelingsky, Scott A. and John, Sally and Kilty, Iain and McKeever, Tricia M. and Shrine, Nick and Cook, James P. and Patel, Shrina and Spector, Tim D. and Hollox, Edward J. and Hall, Ian P. and Tobin, Martin D. (2014) Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. PLoS Genetics, 10 (5). e1004314/1-e1004314/14. ISSN 1553-7404

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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.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Medicine > Division of Epidemiology and Public Health
University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Health Sciences
University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
Identification Number: https://doi.org/10.1371/journal.pgen.1004314
Depositing User: Eprints, Support
Date Deposited: 06 Apr 2016 09:44
Last Modified: 15 Oct 2016 12:07
URI: http://eprints.nottingham.ac.uk/id/eprint/32645

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