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, el...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-05-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4006731?pdf=render |
| _version_ | 1818019027387154432 |
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| author | Louise V Wain Ian Sayers María Soler Artigas Michael A Portelli Eleftheria Zeggini Ma'en Obeidat Don D Sin Yohan Bossé David Nickle Corry-Anke Brandsma Anders Malarstig Ciara Vangjeli Scott A Jelinsky Sally John Iain Kilty Tricia McKeever Nick R G Shrine James P Cook Shrina Patel Tim D Spector Edward J Hollox Ian P Hall Martin D Tobin |
| author_facet | Louise V Wain Ian Sayers María Soler Artigas Michael A Portelli Eleftheria Zeggini Ma'en Obeidat Don D Sin Yohan Bossé David Nickle Corry-Anke Brandsma Anders Malarstig Ciara Vangjeli Scott A Jelinsky Sally John Iain Kilty Tricia McKeever Nick R G Shrine James P Cook Shrina Patel Tim D Spector Edward J Hollox Ian P Hall Martin D Tobin |
| author_sort | Louise V Wain |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:47:14Z |
| format | Article |
| id | doaj.art-80130c5b7ffc455eaf146a6e0dad6b17 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-14T07:47:14Z |
| publishDate | 2014-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-80130c5b7ffc455eaf146a6e0dad6b172022-12-22T02:05:18ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-05-01105e100431410.1371/journal.pgen.1004314Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.Louise V WainIan SayersMaría Soler ArtigasMichael A PortelliEleftheria ZegginiMa'en ObeidatDon D SinYohan BosséDavid NickleCorry-Anke BrandsmaAnders MalarstigCiara VangjeliScott A JelinskySally JohnIain KiltyTricia McKeeverNick R G ShrineJames P CookShrina PatelTim D SpectorEdward J HolloxIan P HallMartin D TobinChronic 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.http://europepmc.org/articles/PMC4006731?pdf=render |
| spellingShingle | Louise V Wain Ian Sayers María Soler Artigas Michael A Portelli Eleftheria Zeggini Ma'en Obeidat Don D Sin Yohan Bossé David Nickle Corry-Anke Brandsma Anders Malarstig Ciara Vangjeli Scott A Jelinsky Sally John Iain Kilty Tricia McKeever Nick R G Shrine James P Cook Shrina Patel Tim D Spector Edward J Hollox Ian P Hall Martin D Tobin Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. PLoS Genetics |
| title | Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. |
| title_full | Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. |
| title_fullStr | Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. |
| title_full_unstemmed | Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. |
| title_short | Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. |
| title_sort | whole exome re sequencing implicates ccdc38 and cilia structure and function in resistance to smoking related airflow obstruction |
| url | http://europepmc.org/articles/PMC4006731?pdf=render |
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