Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.
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 = 2.34 × 10(-4)) 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.
University of Leicester, Department of Health Sciences, Leicester, United Kingdom.
Louise V
LV
Wain
Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Ian
I
Sayers
University of Leicester, Department of Health Sciences, Leicester, United Kingdom.
María
M
Soler Artigas
Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Michael A
MA
Portelli
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Eleftheria
E
Zeggini
University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
Ma'en
M
Obeidat
University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
Don D
DD
Sin
Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada.
Yohan
Y
Bossé
Merck Research Laboratories, Boston, Massachusetts, United States of America; Merck, Rahway, New Jersey, United States of America.
David
D
Nickle
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, The Netherlands.
Corry-Anke
CA
Brandsma
Pfizer Worldwide R&D, Cambridge, United Kingdom.
Anders
A
Malarstig
Pfizer Worldwide R&D, Cambridge, United Kingdom.
Ciara
C
Vangjeli
Pfizer Worldwide R&D, Cambridge, Massachusetts, United States of America.
Scott A
SA
Jelinsky
Pfizer Worldwide R&D, Cambridge, Massachusetts, United States of America.
Sally
S
John
Pfizer Worldwide R&D, Cambridge, Massachusetts, United States of America.
Iain
I
Kilty
School of Community Health Sciences, University of Nottingham, Nottingham, United Kingdom.
Tricia
T
McKeever
University of Leicester, Department of Health Sciences, Leicester, United Kingdom.
Nick R G
NR
Shrine
University of Leicester, Department of Health Sciences, Leicester, United Kingdom.
James P
JP
Cook
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Shrina
S
Patel
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Tim D
TD
Spector
University of Leicester, Department of Genetics, Leicester, United Kingdom.
Edward J
EJ
Hollox
Division of Respiratory Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Ian P
IP
Hall
University of Leicester, Department of Health Sciences, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
Martin D
MD
Tobin
D000293:Adolescent; D000328:Adult; D000368:Aged; D002923:Cilia / Q000502:physiology*; D015331:Cohort Studies; D059472:Exome; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000503:physiopathology*; D040641:Quantitative Trait Loci; D012907:Smoking / Q000503:physiopathology*; D055815:Young Adult
C000593044:CCDC38 protein, human; D011506:Proteins