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J Mol Med (Berl). 2018 Dec;96(12):1375-1385. doi: 10.1007/s00109-018-1708-8. Epub 2018 Oct 23.

Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease.

Author information

1
Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, 02115, USA.
2
Harvard Medical School, Boston, MA, USA.
3
Lung Health Center, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
4
Department of Thoracic Medicine and Surgery, Temple University, Philadelphia, PA, USA.
5
University of Colorado School of Medicine, Denver, CO, USA.
6
Division of Pulmonary Medicine, University of Utah, Salt Lake City, UT, USA.
7
Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO, USA.
8
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
9
Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, 02115, USA. craig.hersh@channing.harvard.edu.
10
Harvard Medical School, Boston, MA, USA. craig.hersh@channing.harvard.edu.

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia. However, the Long-term Oxygen Treatment Trial (LOTT), a large randomized trial, found no benefit of oxygen therapy in COPD patients with moderate hypoxemia. We hypothesized that there may be differences in response to oxygen which depend on genotype or gene expression. In a genome-wide time-to-event analysis of the primary outcome of death or hospitalization in 331 subjects, 97 single nucleotide polymorphisms (SNPs) showed evidence of interaction with oxygen therapy at Pā€‰<ā€‰1e-5, including 7 SNPs near arylsulfatase B (ARSB; Pā€‰=ā€‰6e-6). In microarray expression profiling on 51 whole blood samples from 37 individuals, at screening and/or at 12-month follow-up, ARSB expression was associated with the primary outcome depending on oxygen treatment. The significant SNPs were conditional expression quantitative trait loci for ARSB expression. In a network analysis of genes affected by long-term oxygen, two observed clusters including 26 co-expressed genes were enriched in mitochondrial function. Using data from the observational COPDGene Study, we validated the expression of 25 of these 26 genes, plus ARSB. The effect of long-term oxygen therapy in COPD varied based on ARSB expression and genotype. ARSB has previously been shown to be associated with hypoxemia in human bronchial and colonic epithelial cells and in a mouse model. In peripheral blood, long-term oxygen treatment affected expression of mitochondrial-related genes, a biologically relevant pathway in COPD. SNPs and expression of ARSB are associated with response to long-term oxygen in COPD. The ARSB SNPs were expression quantitative trait loci depending on oxygen therapy. Genes differentially expressed by long-term oxygen were enriched in mitochondrial functions. This suggests a potential biomarker to personalize use of long-term oxygen in COPD.

KEYWORDS:

Arylsulfatase B; Expression quantitative trait loci; Genome-wide association study; Microarray; Oxygen; Pharmacogenomics

PMID:
30353303
PMCID:
PMC6240374
[Available on 2019-12-01]
DOI:
10.1007/s00109-018-1708-8

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