title: HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children.
abstract: 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.
authors.affiliation: Medical Research Council Laboratories, Fajara, Banjul, Gambia. Michael.Walther@nih.gov
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.forename: Adam
authors.initials: A
authors.lastname: De Caul
authors.forename: Peter
authors.initials: P
authors.lastname: Aka
authors.forename: Madi
authors.initials: M
authors.lastname: Njie
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.forename: Brigitte
authors.initials: B
authors.lastname: Walther
authors.forename: Irene M
authors.initials: IM
authors.lastname: Predazzi
authors.forename: Aubrey
authors.initials: A
authors.lastname: Cunnington
authors.forename: Susanne
authors.initials: S
authors.lastname: Deininger
authors.forename: Ebako N
authors.initials: EN
authors.lastname: Takem
authors.forename: Augustine
authors.initials: A
authors.lastname: Ebonyi
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weis
authors.forename: Robert
authors.initials: R
authors.lastname: Walton
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland-Jones
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005714:Gambia / Q000453:epidemiology; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000097:blood / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D016778:Malaria, Falciparum / Q000097:blood* / Q000175:diagnosis / Q000401:mortality; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016897:Respiratory Burst; D015996:Survival Rate
chemical_list: D012333:RNA, Messenger; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1