The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

Obeidat, M; Faiz, A; Li, X; van den Berge, M; Hansel, NN; Joubert, P; Hao, K; Brandsma, C-A; Rafaels, N; Mathias, R; Ruczinski, I; Beaty, TH; Barnes, KC; Man, SFP; Paré, PD; Sin, DD

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.

Obeidat, M Faiz, A

Li, X van den Berge, M Hansel, NN Joubert, P Hao, K Brandsma, C-A Rafaels, N Mathias, R Ruczinski, I Beaty, TH Barnes, KC Man, SFP Paré, PD Sin, DD

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Publisher:: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Publication Type:: Conference Proceeding
Citation:: The European respiratory journal, 2019, 54, (6)
Issue Date:: 2019-12-04

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Field	Value	Language
dc.contributor.author	Obeidat, M
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Li, X
dc.contributor.author	van den Berge, M
dc.contributor.author	Hansel, NN
dc.contributor.author	Joubert, P
dc.contributor.author	Hao, K
dc.contributor.author	Brandsma, C-A
dc.contributor.author	Rafaels, N
dc.contributor.author	Mathias, R
dc.contributor.author	Ruczinski, I
dc.contributor.author	Beaty, TH
dc.contributor.author	Barnes, KC
dc.contributor.author	Man, SFP
dc.contributor.author	Paré, PD
dc.contributor.author	Sin, DD
dc.date	2019-05-17
dc.date.accessioned	2020-05-01T21:50:31Z
dc.date.available	2019-08-22
dc.date.available	2020-05-01T21:50:31Z
dc.date.issued	2019-12-04
dc.identifier.citation	The European respiratory journal, 2019, 54, (6)
dc.identifier.issn	0903-1936
dc.identifier.issn	1399-3003
dc.identifier.uri	http://hdl.handle.net/10453/140392
dc.description.abstract	Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year-1, 95% CI 29.96-82.76 mL·year-1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β -27.57 mL·year-1, 95% CI -53.27- -1.87 mL·year-1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.
dc.format	Electronic-Print
dc.language	en
dc.publisher	EUROPEAN RESPIRATORY SOC JOURNALS LTD
dc.relation.ispartof	The European respiratory journal
dc.relation.ispartof	International Conference of the American-Thoracic-Society
dc.relation.isbasedon	10.1183/13993003.00521-2019
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1116 Medical Physiology, 11 Medical and Health Sciences
dc.subject.classification	Respiratory System
dc.title	The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.
dc.type	Conference Proceeding
utslib.citation.volume	54
utslib.location.activity	England
utslib.for	1116 Medical Physiology
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
dc.date.updated	2020-05-01T21:50:29Z
pubs.finish-date	2019-05-22
pubs.issue	6
pubs.publication-status	Published
pubs.start-date	2019-05-17
pubs.volume	54
utslib.citation.issue	6

Abstract:

Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10-6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10-6, replication p=5.9×10-5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year-1, 95% CI 29.96-82.76 mL·year-1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β -27.57 mL·year-1, 95% CI -53.27- -1.87 mL·year-1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.

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