*2.3.3 Deficiency Glucose-6-phosphate dehydrogenase (G6PD) and* P. falciparum *malaria*

G6PD deficiency is a common X-linked recessive genetic disorder inherited from parents. Although, in most cases, G6PD-deficient individuals appear normal, it can lead to life-threatening anemia in severely G6PD-deficient individuals during oxidative stress-induced by the consumption of certain foodstuff (fava beans), legumes, and taking such as particular antimalarial (primaquine and pamaquine), sulfonamide, sulfamethoxazole, and other drugs and chemicals [123] and also probably infection with microorganisms [124]. Additionally, some authors show that G6PD deficiency increases the risk of severe neonatal hyperbilirubinemia, which can lead to lifetime disability with kernicterus if inadequately treated [115, 125].

However, there is a big beneficial effect of G6PD deficiency. Some studies have reported that G6PD deficiency provides resistance against malaria as the malaria parasite cannot complete its life cycle in compromised G6PD deficient RBC which have a decrease in life span or because of early phagocytosis of deficient RBC [126, 127]. Deficient G6PD enzyme activity has been shown to correlate with protection against severe malaria [43, 89]. Reduced parasite replication in G6PDdeficient erythrocytes is thought to be the mechanism of protection [128], but the parasite appears to counter this by manufacturing G6PD itself [129].

The geographical distribution of G6PD deficiency is consistent with evolutionary selection by malaria [130], and a hypothesis of positive selection [131–133]. The results of studies examining the risk of malaria for various G6PD-deficient genotypes are not consistent. Some authors [43, 134] found in Gambia and Kenya that the reduction in risk of severe malaria in male hemizygotes was 58% and that the reduction in risk for heterozygous females was 46%. Other hand, other authors found that in two populations in Mali, the reduction in risk of severe malaria in male hemizygotes was also 58%, but no reduction in risk in the female heterozygotes [93]. Some authors [27, 133] found no protective effect for either male hemizygotes or female heterozygotes. However, a protective effect has been reported on for females that were found to be G6PD deficient. This finding appears to be based on the incomplete correlation of genotype and phenotype for G6PD deficiency in female heterozygotes due to variable inactivation of the two X chromosomes [127].

Several mechanisms have been proposed to explain the malaria protection offered by G6PD deficiency [45, 127].

• Increased phagocytosis of ring-parasitized variant RBCs due to enhanced oxidative

