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Variations within oxygen-regulated gene expression in humans

Brooks, JTS; Elvidge, GP; Glenny, L; Gleadle, JM; Liu, C; Ragoussis, J; ... Robbins, PA; + view all (2009) Variations within oxygen-regulated gene expression in humans. J APPL PHYSIOL , 106 (1) 212 - 220. 10.1152/japplphysiol.90578.2008.

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Abstract

Brooks JT, Elvidge GP, Glenny L, Gleadle JM, Liu C, Ragoussis J, Smith TG, Talbot NP, Winchester L, Maxwell PH, Robbins PA. Variations within oxygen-regulated gene expression in humans. J Appl Physiol 106: 212-220, 2009. First published November 13, 2008; doi:10.1152/japplphysiol.90578.2008.-The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant (P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

Type:Article
Title:Variations within oxygen-regulated gene expression in humans
DOI:10.1152/japplphysiol.90578.2008
Keywords:hypoxia-inducible factor, reverse transcription quantitative polymerase chain reaction, oxygen tension, peripheral blood lymphocytes, HYPOXIA-INDUCIBLE FACTOR, ENDOTHELIAL GROWTH-FACTOR, MICE PARTIALLY DEFICIENT, CHUVASH POLYCYTHEMIA, PULMONARY-HYPERTENSION, LYMPHOCYTE DEVELOPMENT, VENTILATORY RESPONSE, CELL-PROLIFERATION, TUMOR-SUPPRESSOR, T-LYMPHOCYTES
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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