HMOX1 genetic polymorphisms and outcomes in infectious disease: a systematic review

Introduction:
HMOX1, also known as heme oxygenase is a gene that encodes for the protein HMOX1. It has been established to have a critical role in cellular stress and is ubiquitous in living organisms.[1–3] HMOX1 catabolises free heme into equimolar amounts of Fe2+, carbon monoxide (CO), and bilverdin, which is subsequently modified into bilirubin. Multiple in-vitro and in-vivo studies have established the toxicity of free heme and its central iron, which can lead to free radical production via Fenton chemistry, provoke excessive inflammation, and induce programmed cell death. Equally well established is the ability of HMOX1 to protect against heme-induced toxicity.[1,4–6]
It is also clear that the role of iron, heme, and HMOX1 in human infection is complex. Iron is critical for all prokaryotic and eukaryotic life, with pathogens and hosts battling to control iron, while avoiding the ramifications of its toxicity.[7] Multiple studies based on model organisms have identified that the presence HMOX1 is critical to defend against certain infections, with some data supporting experimental upregulation of this enzyme being protective in animal sepsis and malaria models.[4,5,8–13]
In humans, the HMOX1 gene has a short tandem GT(n) repeat (STR) in its promoter region, which varies from around 20 to 40 repeats. In multiple in vitro and in-vivo studies, the length of this repeat has been shown to alter HMOX1 expression which typically occurs in response to cellular stresses.[14–21] Recent work has suggested that this promoter may, in fact, be intronic and has tried to elucidate the mechanism of increased transcription. Possible mechanisms include the formation of Z-DNA, or alteration of transcription factor binding.[22] In general with larger numbers of repeats there is reduced expression, although this analysis is complicated by experimental design and classification of repeat length.
Multiple studies (>200), have investigated the impact of this STR on clinical outcomes across a broad range of human diseases, last formally reviewed in 2004.[23] In that review, multiple signals of benefit were identified, suggesting carriage of a shorter allele might be beneficial across abroad range of conditions. Since then, meta-analyses have confirmed an association with incidence of neonatal hyperbilirubinaemia (increased with shorter length),[24] type II diabetes (increased with longer length)[25], chronic obstructive pulmonary disease (increased with longer length),[26] with an uncertain relationship with the incidence of cancer.[27]
Although data is limited on the background of this STR, where data is available, the length of the repeat appears to be dramatically different in African populations, who tend to have longer repeats than many other populations, often with a trimodal distribution, rather than bimodal.[19,28,29] Some authors have expressed the possibility this may be due to the selective pressure of malaria, although this remains unproven.[30] As much in-vitro and in-vivo work suggests there is a link between HMOX1 activity and outcomes in infection, we aimed to systematically review the literature on the HMOX1 GT(n) repeat polymorphism and outcomes in infection.