Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Intravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of the<jats:italic>HMOX1</jats:italic>and<jats:italic>Hp</jats:italic>genes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)<jats:italic>n</jats:italic>repeats in the microsatellite polymorphism region of the<jats:italic>HMOX1</jats:italic>gene, the<jats:italic>Hp2</jats:italic>allele, and the<jats:italic>Hp2.2</jats:italic>genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria.</jats:p>

Circulating Biomarkers of Pulmonary and Extrapulmonary Tuberculosis in Children

“…HO-1 has also been shown to be a useful biomarker in other infections (18,19). Interestingly, our data also suggest that HO-1 is probably a useful marker to distinguish individuals with active infection from healthy controls and could potentially serve as an important surrogate marker of disease.…”

“…Also, the levels of acute-phase proteins in PTB and ETB children did not differ significantly. Since HO-1 is an important marker of oxidative stress in a variety of diseases (18,19), we also examined the plasma levels of HO-1 in TB-infected and HC children. As shown in Fig.…”

Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children

“…15 More recent studies, conducted in The Gambia and Northern Ghana using polymerase chain reaction (PCR)-based genotyping methods, found no association between Hp genotype and severe malaria and an increased risk of severe malaria in children with the Hp2-2 genotype, respectively. 17,18 Recent studies investigating the relationship between Hp genotype and the risk of uncomplicated malaria are similarly inconclusive, finding variously an increased risk of symptomatic malaria in Hp2-2 individuals, 19 a reduced incidence among older children with the Hp2-2 genotype, 20,21 and an increased placental parasite density among pregnant mothers with the Hp1-1 genotype. 22 The effect of Hp concentration on the risk of severe malaria is also not known.…”

Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations

“…Apart from factors such as parasite virulence, drug resistance, transmission intensity, and environmental conditions, genetic factors of the human host also contribute to susceptibility/ resistance to disease. Several reports suggest evidence of ethnic differences in susceptibility to malaria (Mendonca et al, 2012) and polymorphisms in more than 30 genes have been associated with disease in different world populations (Kwiatkowski, 2005). One aspect of severe malaria pathogenesis is an excessive or dysregulated inflammatory response to infection (Clark et al, 1987;Day et al, 1999;Lyke et al, 2004;Sinha et al, 2008a).…”