Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis

Abstract

SUMMARY Background Haemoglobinopathies variously reduce the risk of developing malaria syndromes. Quantifying these relationships may strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods The databases of MEDLINE and Embase (1950 – September 9, 2011) were searched to identify studies that estimated the risk of malaria in patients with and without haemoglobinopathies. Additional studies were identified from reference lists. Included outcomes were Plasmodium falciparum-related outcomes of severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and P. vivax malaria. Two independent reviewers identified studies, assessed their quality, and extracted data; data were meta-analyzed when outcomes were reported in more than one study. Findings Of 62 identified studies, 44 reported on HbAS, 19 on HbAC and HbCC, and 18 on α-thalassaemia. Case-control studies showed a decreased risk of severe malaria for HbAS (summary Odds Ratio [OR] 0.09; 95% confidence interval [CI] 0.06 – 0.12), HbCC (summary OR 0.27; 95% CI 0.11 – 0.63), homozygous α-thalassaemia (summary OR 0.63; 95% CI 0.48 – 0.83), HbAC (summary OR 0.83; 95% CI 0.74 – 0.92), and heterozygous α-thalassaemia (summary OR 0.83; 95% CI 0.74 – 0.92). Only HbAS was consistently associated with protection from uncomplicated malaria (summary Incidence Rate Ratio 0.69; 95% CI 0.61 – 0.79); none demonstrated protection from asymptomatic parasitaemia. There was a paucity of clinical studies investigating β-thalassaemia, HbE, P. vivax malaria, and pregnancy-associated malaria. Interpretation Protection from severe malaria syndromes is significant for HbAS, HbCC, HbAC, and homozygous and heterozygous α-thalassaemia, but these haemoglobinopathies differ substantially in the degrees of protection. Protection from uncomplicated malaria and asymptomatic parasitaemia is mild or absent. By attenuating the severity of malaria, haemoglobinopathies serve as a model for investigating the mechanisms of malaria pathogenesis and immunity.

The triumph of good over evil: protection by the sickle gene against malaria

“…8,13 A recent meta-analysis encompassing 62 studies confirmed the robust protection from AS hemoglobin from severe disease but found little or no protection against uncomplicated malaria or asymptomatic parasitemia. 12 This result is fully in keeping with a recent genome-wide association study involving 1325 cases of severe anemia or cerebral malaria in Ghana, compared with 828 unaffected controls, that revealed the highest protection scores with single nucleotide polymorphisms at the ␤-globin locus on chromosome 11. 14 This brief overview focuses on the mechanisms by which persons with sickle trait have enhanced resistance to falciparum malaria.…”

Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria

“…It is also clear that malaria has driven selection for some genetic traits, such as sickle cell anemia and other hemoglobinopathies, in human populations living in highly endemic areas (98), because these traits protect the host from severe malaria (12,72). However, until recently, there has been no clear evidence that the mosquito immune system exerts a selective force on Plasmodium parasite populations or that the parasite exerts a selective pressure on mosquito vectors.…”

Absence of Association Between Sickle Trait Hemoglobin and Placental Malaria Outcomes

“…[1][2][3][4] Across ethnic groups and transmission settings, HbAS reduces the risk of severe malaria by 91% and the risk of uncomplicated malaria by 31% but offers no protection against asymptomatic parasitemia.…”

“…Several hypotheses have been investigated in vitro, including 1) a restriction of parasite growth within HbAS red blood cells (RBCs) owing to increased oxidative damage stress to RBCs 5 ; 2) more rapid clearance and destruction of parasitized HbAS RBCs 6 ; and 3) abnormal or reduced display of the parasite's major cytoadherence ligand and virulence factor, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), resulting in attenuated binding of the infected RBCs (iRBCs) to extracellular ligands. 2,5,7 Although HbAS offers a model of malaria protection with which to identify mechanisms of parasite pathogenesis, there is a paucity of mechanistic investigations in vivo.…”