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.

G6PD A- Deficiency and Severe Malaria in The Gambia: Heterozygote Advantage and Possible Homozygote Disadvantage

“…15 Subjects for our study were enrolled into a health center-based case-control study that has been described elsewhere. 15 Subjects were clinically assessed by a research physician and stringently classified as children with uncomplicated (mild) malaria (N = 146; 63 females and 83 males) and severe malaria (N = 135; 60 females and 75 males) resident in a restricted periurban area. Mild malaria was defined as an episode of fever (temperature 37.5 C) within the last 48 hours and more than 5,000 parasites/μL detected by slide microscopy.…”

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

“…While in the former study COHb might have been generally overestimated, there was a significant increase in COHb levels from healthy controls with moderately severe and severe malaria. While the smaller but significant increase in COHb in patients with moderately severe malaria might indeed reflect a protective effect from an adequate increase in HO-1 activity, further increases in COHb seem insufficient or harmful (46,53). Besides a possible harmful effect of HO-1 superactivation, induction of COHb leads to a decrease in blood oxygen-carrying capacity.…”

“…Studies from Myanmar, Angola, and Gambia have found an association between shorter (GT) n dinucleotide repeat polymorphisms in the Hmox-1 promoter region-correlated with higher expression of the gene and higher levels of HO-1 in peripheral blood-and the incidence of severe malaria (45)(46)(47). The authors of the Gambian study argued that while this observation may simply reflect an adequate but insufficient response, the higher induction of HO-1 in patients with shorter (GT) n repeat alleles indicates that levels of HO-1 above a certain threshold might directly participate in the disease pathogenesis (48).…”

“…The authors of the Gambian study argued that while this observation may simply reflect an adequate but insufficient response, the higher induction of HO-1 in patients with shorter (GT) n repeat alleles indicates that levels of HO-1 above a certain threshold might directly participate in the disease pathogenesis (48). Such deleterious effects might involve oxidative pathways via activation of the neutrophil oxidative burst (46) and release of iron (48).…”

The role of Vitamin D in malaria

“…HO-1 polymorphism is associated with susceptibility to malaria [51][52][53]. A genetic predisposition to higher levels of HO-1 is associated with severe malaria in Gambian children [54]. Moreover, vitamin D deficiency increases the expression of the hepatic mRNA levels of HO-1 in obese rats [41].…”