DSP variants may be associated with longitudinal change in quantitative emphysema.
COPD
Emphysema
Emphysema progression
GWAS
Genetics
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
19 Jul 2019
19 Jul 2019
Historique:
received:
22
03
2019
accepted:
12
06
2019
entrez:
21
7
2019
pubmed:
22
7
2019
medline:
17
1
2020
Statut:
epublish
Résumé
Emphysema, characterized by lung destruction, is a key component of Chronic Obstructive Pulmonary Disease (COPD) and is associated with increased morbidity and mortality. Genome-wide association studies (GWAS) have identified multiple genetic factors associated with cross-sectional measures of quantitative emphysema, but the genetic determinants of longitudinal change in quantitative measures of emphysema remain largely unknown. Our study aims to identify genetic variants associated with longitudinal change in quantitative emphysema measured by computed tomography (CT) imaging. We included current and ex-smokers from two longitudinal cohorts: COPDGene, a study of Non-Hispanic Whites (NHW) and African Americans (AA), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). We calculated annual change in two quantitative measures of emphysema based on chest CT imaging: percent low attenuation area (≤ - 950HU) (%LAA-950) and adjusted lung density (ALD). We conducted GWAS, separately in 3030 NHW and 1158 AA from COPDGene and 1397 Whites from ECLIPSE. We further explored effects of 360 previously reported variants and a lung function based polygenic risk score on annual change in quantitative emphysema. In the genome-wide association analysis, no variants achieved genome-wide significance (P < 5e-08). However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (β (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (β (SE) = - 0.06 (0.02), P = 2.88e-03). A lung function based polygenic risk score was associated with annual change in %LAA-950 (P = 4.03e-02) and with baseline measures of quantitative emphysema (P < 1e-03) and showed a trend toward association with annual change in ALD (P = 7.31e-02). DSP variants may be associated with longitudinal change in quantitative emphysema. Additional investigation of the DSP gene are likely to provide further insights into the disease progression in emphysema and COPD. Clinicaltrials.gov Identifier: NCT00608764 , NCT00292552 .
Sections du résumé
BACKGROUND
BACKGROUND
Emphysema, characterized by lung destruction, is a key component of Chronic Obstructive Pulmonary Disease (COPD) and is associated with increased morbidity and mortality. Genome-wide association studies (GWAS) have identified multiple genetic factors associated with cross-sectional measures of quantitative emphysema, but the genetic determinants of longitudinal change in quantitative measures of emphysema remain largely unknown. Our study aims to identify genetic variants associated with longitudinal change in quantitative emphysema measured by computed tomography (CT) imaging.
METHODS
METHODS
We included current and ex-smokers from two longitudinal cohorts: COPDGene, a study of Non-Hispanic Whites (NHW) and African Americans (AA), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). We calculated annual change in two quantitative measures of emphysema based on chest CT imaging: percent low attenuation area (≤ - 950HU) (%LAA-950) and adjusted lung density (ALD). We conducted GWAS, separately in 3030 NHW and 1158 AA from COPDGene and 1397 Whites from ECLIPSE. We further explored effects of 360 previously reported variants and a lung function based polygenic risk score on annual change in quantitative emphysema.
RESULTS
RESULTS
In the genome-wide association analysis, no variants achieved genome-wide significance (P < 5e-08). However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (β (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (β (SE) = - 0.06 (0.02), P = 2.88e-03). A lung function based polygenic risk score was associated with annual change in %LAA-950 (P = 4.03e-02) and with baseline measures of quantitative emphysema (P < 1e-03) and showed a trend toward association with annual change in ALD (P = 7.31e-02).
CONCLUSIONS
CONCLUSIONS
DSP variants may be associated with longitudinal change in quantitative emphysema. Additional investigation of the DSP gene are likely to provide further insights into the disease progression in emphysema and COPD.
TRIAL REGISTRATION
BACKGROUND
Clinicaltrials.gov Identifier: NCT00608764 , NCT00292552 .
Identifiants
pubmed: 31324189
doi: 10.1186/s12931-019-1097-8
pii: 10.1186/s12931-019-1097-8
pmc: PMC6642569
doi:
Substances chimiques
DSP protein, human
0
Desmoplakins
0
Banques de données
ClinicalTrials.gov
['NCT00608764', 'NCT00292552']
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
160Subventions
Organisme : NHLBI NIH HHS
ID : U01 HL089856
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL089897
Pays : United States
Organisme : GlaxoSmithKline
ID : NCT00292552
Références
Hum Mol Genet. 2000 Nov 1;9(18):2761-6
pubmed: 11063735
Am J Respir Crit Care Med. 2001 Nov 1;164(9):1655-9
pubmed: 11719305
Nat Cell Biol. 2001 Dec;3(12):1076-85
pubmed: 11781569
Am J Hum Genet. 2005 Oct;77(4):653-60
pubmed: 16175511
Eur Respir J. 2008 Apr;31(4):869-73
pubmed: 18216052
Proc Am Thorac Soc. 2008 Dec 15;5(9):919-24
pubmed: 19056717
Eur Respir J. 2009 Jun;33(6):1345-53
pubmed: 19196813
Circ Cardiovasc Genet. 2009 Oct;2(5):428-35
pubmed: 20031617
Nat Genet. 2010 Mar;42(3):200-2
pubmed: 20173748
COPD. 2010 Feb;7(1):32-43
pubmed: 20214461
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Am J Respir Crit Care Med. 2011 Jan 1;183(1):43-9
pubmed: 20709820
Hum Mol Genet. 2012 Feb 15;21(4):947-57
pubmed: 22080838
Nat Genet. 2013 Jun;45(6):613-20
pubmed: 23583980
J Thorac Imaging. 2013 Sep;28(5):284-90
pubmed: 23748651
Am J Respir Crit Care Med. 2013 Oct 15;188(8):941-7
pubmed: 23972146
Am J Respir Crit Care Med. 2014 Feb 15;189(4):408-18
pubmed: 24383474
Lancet Respir Med. 2013 Apr;1(2):129-36
pubmed: 24429093
Lancet Respir Med. 2014 Mar;2(3):214-25
pubmed: 24621683
Am J Respir Crit Care Med. 2014 Aug 15;190(4):399-409
pubmed: 25006744
Lancet. 2015 Jul 25;386(9991):360-8
pubmed: 26026936
Am J Respir Crit Care Med. 2015 Sep 1;192(5):559-69
pubmed: 26030696
Am J Respir Crit Care Med. 2015 Jul 1;192(1):114-6
pubmed: 26131993
Cell Commun Adhes. 2015;22(1):15-28
pubmed: 26133535
Am J Respir Crit Care Med. 2016 May 15;193(10):1151-60
pubmed: 26669357
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Nat Genet. 2017 Mar;49(3):426-432
pubmed: 28166215
Chest. 2018 Jan;153(1):65-76
pubmed: 28943279
Chest. 2018 Mar;153(3):638-645
pubmed: 29066389
Nat Genet. 2019 Mar;51(3):481-493
pubmed: 30804560
Nat Genet. 2019 Mar;51(3):494-505
pubmed: 30804561