@article{5559c68a13644b6fb76814079beba9e3,
title = "Genomics and response to long-term oxygen therapy in chronic obstructive pulmonary disease",
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 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.",
keywords = "Arylsulfatase B, Expression quantitative trait loci, Genome-wide association study, Microarray, Oxygen, Pharmacogenomics",
author = "Minseok Seo and Weiliang Qiu and William Bailey and Criner, {Gerard J.} and Dransfield, {Mark T.} and Fuhlbrigge, {Anne L.} and Reilly, {John J.} and Scholand, {Mary Beth} and Peter Castaldi and Robert Chase and Margaret Parker and Aabida Saferali and Yun, {Jeong H.} and Crapo, {James D.} and Cho, {Michael H.} and Beaty, {Terri H.} and Silverman, {Edwin K.} and Hersh, {Craig P.}",
note = "Funding Information: Members of the LOTT Research Group and the COPDGene Study investigators are listed in the online supplement. Dr. Criner reports grants from Boehringer-Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl, grants from Ikaria, grants from Aeris, grants from PneumRx, grants from Pulmonx, other from HGE Health Care Solutions, Inc., other from Amirall, other from Boehringer-Ingelheim, other from Holaira, outside the submitted work. Dr. Dransfield reports grants from NHLBI, during the conduct of the study; grants from Department of Defense, personal fees and other from Boehringer Ingeheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, personal fees and other from Boston Scientific, outside the submitted work. Dr. Fuhlbrigge has received grant support from the NHBLI, AHRQ, and PCORI related to asthma and COPD studies. She also has received personal fees from GSK, AstraZeneca, and Icon Medical Imaging for consulting on investigations in asthma, and COPD. Dr. Scholand reports other from Boehringer Ingelheim, other from Genentech, other from Fibrogen, other from Global Blood Therapeutics, outside the submitted work. In addition, Dr. Scholand has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued. Dr. Castaldi reports grants from GSK, personal fees from GSK, outside the submitted work. Dr. Cho reports grants from NHLBI, grants from GSK, during the conduct of the study; grants from Alpha-1 Foundation, outside the submitted work. Dr. Silverman reports grants from NIH, during the conduct of the study; personal fees from Novartis; and grant and travel support from GlaxoSmithKline, outside the submitted work. Dr. Hersh reports grants from National Institutes of Health, during the conduct of the study; personal fees from Mylan, personal fees from AstraZeneca, personal fees from Concert Pharmaceuticals, personal fees from 23andMe, grants from Novartis, grants from Boehringer-Ingelheim, outside the submitted work. Drs. Seo, Qiu, Bailey, Reilly, Parker, Saferali, Yun, Crapo, Beaty, and Mr. Chase report no competing interests. Funding Information: Conflict of interest Dr. Criner reports grants from Boehringer-Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl, grants from Ikaria, grants from Aeris, grants from PneumRx, grants from Pulmonx, other from HGE Health Care Solutions, Inc., other from Amirall, other from Boehringer-Ingelheim, other from Holaira, outside the submitted work. Dr. Dransfield reports grants from NHLBI, during the conduct of the study; grants from Department of Defense, personal fees and other from Boehringer Ingeheim, personal fees and other from GlaxoSmithKline, other from Novartis, personal fees and other from AstraZeneca, other from Yungjin, other from PneumRx/BTG, other from Pulmonx, personal fees from Genentech, personal fees and other from Boston Scientific, outside the submitted work. Dr. Fuhlbrigge has received grant support from the NHBLI, AHRQ, and PCORI related to asthma and COPD studies. She also has received personal fees from GSK, AstraZeneca, and Icon Medical Imaging for consulting on investigations in asthma, and COPD. Dr. Scholand reports other from Boehringer Ingelheim, other from Genentech, other from Fibrogen, other from Global Blood Therapeutics, outside the submitted work. In addition, Dr. Scholand has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued. Dr. Castaldi reports grants from GSK, personal fees from GSK, outside the submitted work. Dr. Cho reports grants from NHLBI, grants from GSK, during the conduct of the study; grants from Alpha-1 Foundation, outside the submitted work. Dr. Silverman reports grants from NIH, during the conduct of the study; personal fees from Novartis; and grant and travel support from GlaxoSmithKline, outside the submitted work. Dr. Hersh reports grants from National Institutes of Health, during the conduct of the study; personal fees from Mylan, personal fees from AstraZeneca, personal fees from Concert Pharmaceuticals, personal fees from 23andMe, grants from Novartis, grants from Boehringer-Ingelheim, outside the submitted work. Funding Information: The COPDGene{\textregistered} project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. Funding Information: Funding Funded by NIH grants R01HL094635, R01HL125583, R01HL130512, U01HL089897, U01HL089856, R01HL124233. Publisher Copyright: {\textcopyright} 2018, Springer-Verlag GmbH Germany, part of Springer Nature.",
year = "2018",
month = dec,
day = "1",
doi = "10.1007/s00109-018-1708-8",
language = "English (US)",
volume = "96",
pages = "1375--1385",
journal = "Clinical Investigator",
issn = "0946-2716",
publisher = "Springer Verlag",
number = "12",
}