The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD.
Eur Respir J
; 54(6)2019 12.
Article
em En
| MEDLINE
| ID: mdl-31537701
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 1â
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 6â
months for 3â
years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3â
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 ß 56.36â
mL·year-1, 95% CI 29.96-82.76â
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 ß -27.57â
mL·year-1, 95% CI -53.27- -1.87â
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Farmacogenética
/
Volume Expiratório Forçado
/
Corticosteroides
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Doença Pulmonar Obstrutiva Crônica
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Aged
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article