RT Journal Article
SR Electronic
T1 The Pharmacogenomics of Inhaled Corticosteroids and Lung Function Decline in COPD
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1900521
DO 10.1183/13993003.00521-2019
A1 Ma'en Obeidat
A1 Alen Faiz
A1 Xuan Li
A1 Maarten van den Berge
A1 Nadia N. Hansel
A1 Philippe Joubert
A1 Ke Hao
A1 Corry-Anke Brandsma
A1 Nicholas Rafaels
A1 Rasika Mathias
A1 Ingo Ruczinski
A1 Terri H. Beaty
A1 Kathleen C. Barnes
A1 S. F. Paul Man
A1 Peter D. Paré
A1 Don D. Sin
YR 2019
UL http://erj.ersjournals.com/content/early/2019/08/21/13993003.00521-2019.abstract
AB Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet with variable outcomes and adverse reactions which may be genetically determined. The primary aim of the study was to identify the genetic determinants for FEV1 changes related to ICS therapy. In the Lung Health Study 2 (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 (GWAS) for the genotype-by-ICS treatment effect on 3 years of forced expiratory volume in 1 s (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, 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 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 beta=56.35 mL·year−1, 95% confidence interval (CI)=29.96, 82.76 mL·yr−1) and also in patients who were assigned to placebo, though the relationship was weaker and in the opposite direction than that in the ICS group (C allele beta=−27.57 mL·year−1, 95% CI=−53.27, −1.87 mL·yr−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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Obeidat has nothing to disclose.Conflict of interest: Dr. Faiz has nothing to disclose.Conflict of interest: Ms. Li has nothing to disclose.Conflict of interest: Dr. van den Berge reports grants paid to University from GlaxoSmithKline, Chiesi, Teva, Astra Zeneca, outside the submitted work.Conflict of interest: Dr. Hansel reports grants and personal fees from AstraZeneca, grants and personal fees from GSK, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work.Conflict of interest: Dr. Joubert has nothing to disclose.Conflict of interest: Dr. Hao has nothing to disclose.Conflict of interest: Dr. Brandsma has nothing to disclose.Conflict of interest: Dr. Rafaels has nothing to disclose.Conflict of interest: Dr. Mathias has nothing to disclose.Conflict of interest: Dr. Ruczinski has nothing to disclose.Conflict of interest: Dr. Beaty reports grants from National Heart Lung & Blood Institute, during the conduct of the study.Conflict of interest: Dr. Barnes has nothing to disclose.Conflict of interest: Dr. Pare has nothing to disclose.Conflict of interest: Dr. Sin reports grants from AstraZeneca, during the conduct of the study; grants from Merck, personal fees from Sanofi-Aventis, personal fees from Regeneron, grants and personal fees from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Novartis, outside the submitted work.Conflict of interest: Dr. Man has nothing to disclose.