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Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease
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نویسنده
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Seo Minseok ,Qiu Weiliang ,Bailey William ,Criner Gerard J. ,Dransfield Mark T. ,Fuhlbrigge Anne L. ,Reilly John J. ,Scholand Mary Beth ,Castaldi Peter ,Chase Robert ,Parker Margaret ,Saferali Aabida ,Yun Jeong H. ,Crapo James D. ,Cho Michael H. ,Beaty Terri H. ,Silverman Edwin K. ,Hersh Craig P.
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منبع
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journal of molecular medicine - 2018 - دوره : 96 - شماره : 12 - صفحه:1375 -1385
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چکیده
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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 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 p < 1e−5, including 7 snps near arylsulfatase b (arsb; p = 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.
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کلیدواژه
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Arylsulfatase B ,Pharmacogenomics ,Expression quantitative trait loci ,Genome-wide association study ,Microarray ,Oxygen
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آدرس
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Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, University of Alabama at Birmingham, Division of Pulmonary, USA, Temple University, Department of Thoracic Medicine and Surgery, USA, University of Alabama at Birmingham, Division of Pulmonary, USA, University of Colorado School of Medicine, USA, University of Colorado School of Medicine, USA, University of Utah, Division of Pulmonary Medicine, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Harvard Medical School, USA. Brigham and Women’s Hospital, Channing Division of Network Medicine, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Division of Pulmonary, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA, Brigham and Women’s Hospital, Channing Division of Network Medicine, USA. Harvard Medical School, USA
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Authors
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