The Pharmacogenomics of Inhaled Corticosteroids and Lung Function Decline in COPD

Obeidat, M., Faiz, A., Li, X., van den Berge, M., Hansel, N. N., Joubert, P., Hao, K., Brandsma, C-A., Rafaels, N., Mathias, R., Ruczinski, I., Beaty, T. H., Barnes, K. C., Paul Man, S. F., Paré, P. D. & Sin, D. D., 1-Dec-2019, In : European Respiratory Journal. 54, 6, 12 p., 1900521.

Research output: Contribution to journalArticleAcademicpeer-review

  • Ma'en Obeidat
  • Alen Faiz
  • Xuan Li
  • Maarten van den Berge
  • Nadia N Hansel
  • Philippe Joubert
  • Ke Hao
  • Corry-Anke Brandsma
  • Nicholas Rafaels
  • Rasika Mathias
  • Ingo Ruczinski
  • Terri H Beaty
  • Kathleen C Barnes
  • S F Paul Man
  • Peter D Paré
  • Don D Sin

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.

Original languageEnglish
Article number1900521
Number of pages12
JournalEuropean Respiratory Journal
Issue number6
Early online date19-Sep-2019
Publication statusPublished - 1-Dec-2019

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