Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 696, Issue 1-3, Pages 136-142Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2012.08.015
Keywords
Chronic Obstructive Pulmonary Disease (COPD); Lung function decline; Multidrug resistance-associated protein-1; Protein expression; Single nucleotide polymorphisms (SNPs); Treatment
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Funding
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Asthma Foundation (NAF)
- GlaxoSmithKline
- Leiden University Medical Center (LUMC)
- University of Groningen (RUG)
- AstraZeneca
- GSK
- Nycomed
- Chiesi
- Amgen
- Boehringer Ingelheim
- Centocor
- Galapagos
- Netherlands Asthma Funds
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Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV1) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV1 level and inflammatory markers in COPD patients. We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV1 decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting beta 2-agonists. Additionally we investigate the association of MRP1 variants with FEV1 decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV1 decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV1 decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV1 decline than in those with a weak staining. None of the variants was associated with FEV1 decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV1 decline occurring selectively in COPD patients with long-term (30-month) ICS therapy. (C) 2012 Elsevier B.V. All rights reserved.
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