HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti...

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Main Authors:	Walther, Michael, De Caul, Adam, Aka, Peter, Njie, Madi, Amambua-Ngwa, Alfred, Walther, Brigitte, Predazzi, Irene M., Cunnington, Aubrey, Deininger, Susanne, Takem, Ebako N., Ebonyi, Augustine, Weis, Sebastian, Walton, Robert, Rowland-Jones, Sarah, Sirugo, Giorgio, Williams, Scott M., Conway, David J.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305414/

id	pubmed-3305414
recordtype	oai_dc
spelling	pubmed-33054142012-03-21 HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children Walther, Michael De Caul, Adam Aka, Peter Njie, Madi Amambua-Ngwa, Alfred Walther, Brigitte Predazzi, Irene M. Cunnington, Aubrey Deininger, Susanne Takem, Ebako N. Ebonyi, Augustine Weis, Sebastian Walton, Robert Rowland-Jones, Sarah Sirugo, Giorgio Williams, Scott M. Conway, David J. Research Article Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients. Public Library of Science 2012-03-15 /pmc/articles/PMC3305414/ /pubmed/22438807 http://dx.doi.org/10.1371/journal.ppat.1002579 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Walther, Michael De Caul, Adam Aka, Peter Njie, Madi Amambua-Ngwa, Alfred Walther, Brigitte Predazzi, Irene M. Cunnington, Aubrey Deininger, Susanne Takem, Ebako N. Ebonyi, Augustine Weis, Sebastian Walton, Robert Rowland-Jones, Sarah Sirugo, Giorgio Williams, Scott M. Conway, David J.
spellingShingle	Walther, Michael De Caul, Adam Aka, Peter Njie, Madi Amambua-Ngwa, Alfred Walther, Brigitte Predazzi, Irene M. Cunnington, Aubrey Deininger, Susanne Takem, Ebako N. Ebonyi, Augustine Weis, Sebastian Walton, Robert Rowland-Jones, Sarah Sirugo, Giorgio Williams, Scott M. Conway, David J. HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
author_facet	Walther, Michael De Caul, Adam Aka, Peter Njie, Madi Amambua-Ngwa, Alfred Walther, Brigitte Predazzi, Irene M. Cunnington, Aubrey Deininger, Susanne Takem, Ebako N. Ebonyi, Augustine Weis, Sebastian Walton, Robert Rowland-Jones, Sarah Sirugo, Giorgio Williams, Scott M. Conway, David J.
author_sort	Walther, Michael
title	HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
title_short	HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
title_full	HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
title_fullStr	HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
title_full_unstemmed	HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children
title_sort	hmox1 gene promoter alleles and high ho-1 levels are associated with severe malaria in gambian children
description	Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305414/
_version_	1611514681165348864

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

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