Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease
Identifieur interne : 001A03 ( Ncbi/Checkpoint ); précédent : 001A02; suivant : 001A04Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease
Auteurs : Nadia N. Hansel ; Peter D. Paré ; Nicholas Rafaels ; Don D. Sin ; Andrew Sandford ; Denise Daley ; Candelaria Vergara ; Lili Huang ; W. Mark Elliott ; Chris D. Pascoe ; Bryna A. Arsenault ; Dirkje S. Postma ; H. Marike Boezen ; Yohan Bossé ; Maarten Van Den Berge ; Pieter S. Hiemstra ; Michael H. Cho ; Augusto A. Litonjua ; David Sparrow ; Carole Ober ; Robert A. Wise ; John Connett ; Enid R. Neptune ; Terri H. Beaty ; Ingo Ruczinski ; Rasika A. Mathias ; Kathleen C. BarnesSource :
- American Journal of Respiratory Cell and Molecular Biology [ 1044-1549 ] ; 2015.
Abstract
Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (
Url:
DOI: 10.1165/rcmb.2014-0198OC
PubMed: 25514360
PubMed Central: 4566043
Affiliations:
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<author><name sortKey="Hiemstra, Pieter S" sort="Hiemstra, Pieter S" uniqKey="Hiemstra P" first="Pieter S." last="Hiemstra">Pieter S. Hiemstra</name>
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<author><name sortKey="Sparrow, David" sort="Sparrow, David" uniqKey="Sparrow D" first="David" last="Sparrow">David Sparrow</name>
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<author><name sortKey="Ober, Carole" sort="Ober, Carole" uniqKey="Ober C" first="Carole" last="Ober">Carole Ober</name>
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<front><div type="abstract" xml:lang="en"><p>Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (<italic>n</italic>
= 2,814) and Year 5 (<italic>n</italic>
= 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by <italic>LINGO2</italic>
met a predetermined threshold of genome-wide significance (<italic>P</italic>
< 9.57 × 10<sup>−8</sup>
). Markers on chromosomes 3q13.1 (flanked by <italic>MYH15</italic>
), 5q33 (<italic>SGCD</italic>
), and 6q21 (<italic>PDSS2</italic>
) yielded suggestive evidence of association (9.57 × 10<sup>−8</sup>
< <italic>P</italic>
≤ 4.6 × 10<sup>−6</sup>
). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for <italic>SGCD</italic>
(<italic>P</italic>
= 2.57 × 10<sup>−9</sup>
) and <italic>MYH15</italic>
(<italic>P</italic>
= 1.62 × 10<sup>−6</sup>
), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.</p>
</div>
</front>
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<name sortKey="Beaty, Terri H" sort="Beaty, Terri H" uniqKey="Beaty T" first="Terri H." last="Beaty">Terri H. Beaty</name>
<name sortKey="Boezen, H Marike" sort="Boezen, H Marike" uniqKey="Boezen H" first="H. Marike" last="Boezen">H. Marike Boezen</name>
<name sortKey="Bosse, Yohan" sort="Bosse, Yohan" uniqKey="Bosse Y" first="Yohan" last="Bossé">Yohan Bossé</name>
<name sortKey="Cho, Michael H" sort="Cho, Michael H" uniqKey="Cho M" first="Michael H." last="Cho">Michael H. Cho</name>
<name sortKey="Connett, John" sort="Connett, John" uniqKey="Connett J" first="John" last="Connett">John Connett</name>
<name sortKey="Daley, Denise" sort="Daley, Denise" uniqKey="Daley D" first="Denise" last="Daley">Denise Daley</name>
<name sortKey="Elliott, W Mark" sort="Elliott, W Mark" uniqKey="Elliott W" first="W. Mark" last="Elliott">W. Mark Elliott</name>
<name sortKey="Hansel, Nadia N" sort="Hansel, Nadia N" uniqKey="Hansel N" first="Nadia N." last="Hansel">Nadia N. Hansel</name>
<name sortKey="Hiemstra, Pieter S" sort="Hiemstra, Pieter S" uniqKey="Hiemstra P" first="Pieter S." last="Hiemstra">Pieter S. Hiemstra</name>
<name sortKey="Huang, Lili" sort="Huang, Lili" uniqKey="Huang L" first="Lili" last="Huang">Lili Huang</name>
<name sortKey="Litonjua, Augusto A" sort="Litonjua, Augusto A" uniqKey="Litonjua A" first="Augusto A." last="Litonjua">Augusto A. Litonjua</name>
<name sortKey="Mathias, Rasika A" sort="Mathias, Rasika A" uniqKey="Mathias R" first="Rasika A." last="Mathias">Rasika A. Mathias</name>
<name sortKey="Neptune, Enid R" sort="Neptune, Enid R" uniqKey="Neptune E" first="Enid R." last="Neptune">Enid R. Neptune</name>
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<name sortKey="Pare, Peter D" sort="Pare, Peter D" uniqKey="Pare P" first="Peter D." last="Paré">Peter D. Paré</name>
<name sortKey="Pascoe, Chris D" sort="Pascoe, Chris D" uniqKey="Pascoe C" first="Chris D." last="Pascoe">Chris D. Pascoe</name>
<name sortKey="Postma, Dirkje S" sort="Postma, Dirkje S" uniqKey="Postma D" first="Dirkje S." last="Postma">Dirkje S. Postma</name>
<name sortKey="Rafaels, Nicholas" sort="Rafaels, Nicholas" uniqKey="Rafaels N" first="Nicholas" last="Rafaels">Nicholas Rafaels</name>
<name sortKey="Ruczinski, Ingo" sort="Ruczinski, Ingo" uniqKey="Ruczinski I" first="Ingo" last="Ruczinski">Ingo Ruczinski</name>
<name sortKey="Sandford, Andrew" sort="Sandford, Andrew" uniqKey="Sandford A" first="Andrew" last="Sandford">Andrew Sandford</name>
<name sortKey="Sin, Don D" sort="Sin, Don D" uniqKey="Sin D" first="Don D." last="Sin">Don D. Sin</name>
<name sortKey="Sparrow, David" sort="Sparrow, David" uniqKey="Sparrow D" first="David" last="Sparrow">David Sparrow</name>
<name sortKey="Van Den Berge, Maarten" sort="Van Den Berge, Maarten" uniqKey="Van Den Berge M" first="Maarten" last="Van Den Berge">Maarten Van Den Berge</name>
<name sortKey="Vergara, Candelaria" sort="Vergara, Candelaria" uniqKey="Vergara C" first="Candelaria" last="Vergara">Candelaria Vergara</name>
<name sortKey="Wise, Robert A" sort="Wise, Robert A" uniqKey="Wise R" first="Robert A." last="Wise">Robert A. Wise</name>
</noCountry>
</tree>
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