*2.3.1.4 HbE and* P. falciparum *malaria*

intra-erythrocytic development of the parasite leading to lower *P. falciparum* replication rates in subsets of CC erythrocytes [65]; *abnormal P. falciparum* erythrocyte membrane protein 1 (PfEMP-1) display, leading to reduced cytoadherence and possibly reduced parasite sequestration [85], and accelerated acquisition of immunity against malaria [63]. In addition, the protective effect of HbC may result from:

• Impairment of *P. falciparum* red cell invasion and growth under conditions of

• Reduced pathogenicity of *P. falciparum* infected red blood cells because of reduced expression of PfEMP1 [60, 85, 86] and Reduced cyto-adherence of

• Besides, on observations of reduced parasite cytoadherence abnormal PfEMP1 expression, clustering of erythrocyte band3 protein, and altered surface topography of the erythrocyte membrane in the presence of HbC, it would appear that the protective effect of HbC works by increasing the immune

Compared to healthy children, HbC appears to protect against severe malaria to a lesser degree than HbS and in proportion to allele frequency [31, 33, 44, 73, 89]. Protection from specific severe malaria syndromes has not been fully investigated in HbCC; in one study [90] HbAC showed mild protection from cerebral malaria (CM) and severe malarial anemia (SMA). When compared to children with uncomplicated malaria, protection from severe malaria is inconsistent: non-significant protection is reported from severe malaria in some studies [30, 33, 44, 69] of HbCC and HbAC, and from SMA in other studies [30, 33, 69] that combined homozygotes and heterozygotes. Significant protection from CM was reported in one study of Malian children that combined homo- and heterozygotes [30, 33] Prospective studies have not reported the incidence of severe syndromes in HbC children. Thus, convincing evidence for protection from severe malaria owing to HbC derives largely from few case–control studies. Also, a further strong evidence for overall protection comes from a recent GWAS, which concluded that for each copy of the HbC allele, the risk for severe *P. falciparum* malaria was reduced by 29% [56, 70].

Few studies have reported the risk of uncomplicated malaria associated with HbC. However some comparative studies [44, 72] and prospective studies have yielded conflicting results [26, 33, 74, 91]. Further studies are still needed to show the evidence of protection from uncomplicated malaria afforded by HbCC and HbAC.

In most studies cross-sectional surveys with adults and children, HbC has not been associated with a reduced prevalence of *P. falciparum* parasitaemia

• Increased immune clearance of infected erythrocytes [36, 46].

• Improved acquisition of malaria-specific immunity [60, 63, 78]

• increased immune clearance of infected erythrocytes [28, 36]

clearance of infected erythrocytes [85, 87, 88].

low oxygen tension [39, 55, 63]

*Human Blood Group Systems and Haemoglobinopathies*

infected erythrocyte [30]

*2.3.1.3 Severe* P. falciparum *malaria*

• Uncomplicated *P. falciparum* malaria

• *P. falciparum* parasitaemia

**16**

HbE is an extremely most common structural hemoglobin variant that occurs at high frequencies throughout Southeast Asia and has reached an allele frequency of up to 70% in some areas of northern Thailand and Cambodia [52]. It is a β-hemoglobin variant, which is produced at a slightly reduced rate and hence has the phenotype of a mild form of β thalassemia [95].

Generally, none of HbS or C variants are present in Southeast Asia and HbE is in general also absent from populations in which HbS and HbC are present [52].

HbE is an extremely most common structural hemoglobin variant that occurs at high frequencies throughout Southeast Asia and has reached an allele frequency of up to 70% in some areas of northern Thailand and Cambodia [34].

AE heterozygotes appear to have protection from invasion into erythrocytes by *P. falciparum* malaria [4, 65, 72, 96]. Moreover, the protective effect of HbE may result from impairment of *P. falciparum* red cell invasion and growth [96], lower intra-erythrocytic parasite growth, and enhanced phagocytosis of infected erythrocytes [28, 96].

When the frequency of HbE is high, some other red cell disorders, such as athalassemia, can be also in high frequency. Although extensive sequence analysis has not been carried out. [97]. However, the E allele found in China is on the same haplotype as that found in Thailand [98], suggesting that it does not have a different origin.

Few studies have been done to characterize the mechanisms of malaria protection. Three categories of effects are relevant: reduced parasite growth and development, altered adhesion of parasitized RBCs to endothelium, and impact on the immune system. In vitro studies of HbEE and HbAE RBCs have found reduced invasion and growth of HbE [96, 99]. Clearly, more work needs to be done to answer further questions about the protective impact of HbE.

• Severe *P. falciparum* malaria

Meta-analysis of few studies [21, 33, 100] that compared the prevalence of HbE in severe and uncomplicated malaria cases demonstrated no evidence of protection, though this should be interpreted cautiously given the significant.

Considering heterogeneity of the findings and the highly selected settings of the studies, more investigations are necessary to conclude on possible protection of HbE.

• Uncomplicated *P. falciparum* malaria

We have not identified studies that have quantified clearly susceptibility to malaria by HbE.

• *P. falciparum* parasitaemia

A cross-sectional study conducted in India reported a significantly lower prevalence of *P. falciparum* parasitaemia in patients with HbE (AE or EE) compared with patients with HbAA [101].

#### *2.3.1.5 Hemoglobins S/C and malaria transmission*

Some studies suggest that human genetic variation at the β-globin locus can influence the transmission of malaria. Indeed the same genetic variants that are protective against infection also showed an association with the intensity of malaria transmission. Hemoglobin variants C and S protect against severe malaria but their influence probably on parameters not directly linked to disease severity such as gametocyte carriage and infection chronicity. Moreover, some studies provided evidence that hemoglobin variants selected for the protection against malaria might also have a broader impact on local epidemiology by influencing the frequency of parasite, including the carriage of gametocytes [3, 32].

• Increased micro-erythrocyte count in homozygotes reduces the amount of Hb lost for given parasite density, thus protecting against SMA [55, 104, 110, 112]

*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria*

Some studies [90, 102–104] investigated α-thalassaemia showed protection against severe malaria, malarial anemia and additionally, protection from cerebral

Several prospective studies have assessed the incidence of uncomplicated malaria in α-thalassaemic children, with conflicting results. Indeed some studies showed the incidence of falciparum malaria was higher in α-thalassemia homozygotes and heterozygotes [94]; in contrast, other studies, found a lower incidence [37, 113]. However, other studies have found no protection for both homozygotes and heterozygotes

In cross-sectional studies, α-thalassaemia was not associated with the prevalence of parasitaemia [79, 103, 112, 114, 115]. In prospective study of children conducted in Papua New Guinea, both α- thalassaemia homozygotes and heterozygotes had fewer episodes of PCR-detectable parasitaemia than those without α thalassaemia,

Finally, there is no evident data to confirm a protective effect of α-thalassaemia

Haldane has explain the very high level of β-thalassemia in some Mediterranean

There is ordinarily only one copy of the HBB gene and βþ and β0 thalassemia showing the reduction and loss, respectively, of the production of functional protein. Individuals with α-thalassemia major, have profound anemia while Heterozygotes typically have mild anemia, however, symptoms can vary greatly in severity

Generally, β-thalassemia is more of a public health problem because of this

Several mechanisms have been also proposed to explain specific protection

• Reduced pathogenicity through reduced cytoadherence or resetting [121]

• Enhanced antibody binding and subsequent clearance of infected variant

• Increased phagocytosis of ring-parasitised variant RBCs [45, 102, 122]

• Reduced invasion and growth of *P. falciparum* parasites [119, 120]

[115, 116] though this outcome has not been investigated in other studies.

• Severe *P. falciparum* malaria

*DOI: http://dx.doi.org/10.5772/intechopen.93807*

• *P. falciparum* parasitaemia

*2.3.2.2 β–thalassemia*

• Uncomplicated *P. falciparum* malaria

against asymptomatic parasitaemia [112, 114].

higher morbidity than α-thalassemia.

• Severe *P. falciparum* malaria

against malaria-induced

RBCs [110]

**19**

populations by the 'malaria hypothesis' of Haldane [117].

• Enhanced removal of parasite-infected RBC [45]

from having severe anemia to being a symptomless carrier. [118]

malaria [94].

#### *2.3.2 Thalassemia (α and β) and P. falciparum malaria*

The thalassemias are the most common Mendelian diseases of humans and constitute a major global health problem [39]. This is a group of clinical disorders that result from defective production of α- or β-globin chains, which arise from deletions or other disruptions of the globin gene clusters on chromosomes 11 and 16 [9].

A study in Kenyan children found that both heterozygous and homozygous a1 thalassemia was protective against severe malaria [102], whereas a study in Ghanaian children found that heterozygotes were protected [103]. However, a study conducted in Papua New Guinea, founded the risk of severe malaria (other childhood infections) was reduced by 60% in children who were homozygous for α1 thalassemia and to a lesser degree in heterozygotes [104]. The protective mechanism of thalassemia is not well known. Flow-cytometry studies in vitro have shown that erythrocytes with the thalassemia phenotype show reduced parasite growth [105] and increased binding of antibodies from malaria-immune [106].

#### *2.3.2.1 α - thalassemia*

The distribution of both a and b thalassemia variants seems to correspond closely to the regions that have historically had high rates of malaria [23] and the local distribution of these variants also corresponds to endemic malaria [36, 107]. Several studies have shown protection from severe malaria for individuals with a α-thalassemia, compared with individuals without thalassemia [37, 103, 104]. In addition, some authors. In a case–control study have shown protection from severe malaria for a α heterozygotes and homozygotes compared to normal aa/aa genotype [7, 37]. Overall, it appears that.

many haplotypes that reduce the expression of α-globin provide a selective advantage in resistance to severe malaria. Indeed some mechanisms have been proposed to explain the malaria protection offered by α thalassemia:


*2.3.1.5 Hemoglobins S/C and malaria transmission*

*Human Blood Group Systems and Haemoglobinopathies*

parasite, including the carriage of gametocytes [3, 32].

*2.3.2 Thalassemia (α and β) and P. falciparum malaria*

11 and 16 [9].

*2.3.2.1 α - thalassemia*

[7, 37]. Overall, it appears that.

*P. falciparum* [94]

**18**

Some studies suggest that human genetic variation at the β-globin locus can influence the transmission of malaria. Indeed the same genetic variants that are protective against infection also showed an association with the intensity of malaria transmission. Hemoglobin variants C and S protect against severe malaria but their influence probably on parameters not directly linked to disease severity such as gametocyte carriage and infection chronicity. Moreover, some studies provided evidence that hemoglobin variants selected for the protection against malaria might also have a broader impact on local epidemiology by influencing the frequency of

The thalassemias are the most common Mendelian diseases of humans and

disorders that result from defective production of α- or β-globin chains, which arise from deletions or other disruptions of the globin gene clusters on chromosomes

A study in Kenyan children found that both heterozygous and homozygous a1 thalassemia was protective against severe malaria [102], whereas a study in Ghanaian children found that heterozygotes were protected [103]. However, a study conducted in Papua New Guinea, founded the risk of severe malaria (other childhood infections) was reduced by 60% in children who were homozygous for α1 thalassemia and to a lesser degree in heterozygotes [104]. The protective mechanism of thalassemia is not well known. Flow-cytometry studies in vitro have shown that erythrocytes with the thalassemia phenotype show reduced parasite growth

constitute a major global health problem [39]. This is a group of clinical

[105] and increased binding of antibodies from malaria-immune [106].

The distribution of both a and b thalassemia variants seems to correspond closely to the regions that have historically had high rates of malaria [23] and the local distribution of these variants also corresponds to endemic malaria [36, 107]. Several studies have shown protection from severe malaria for individuals with a α-thalassemia, compared with individuals without thalassemia [37, 103, 104]. In addition, some authors. In a case–control study have shown protection from severe malaria for a α heterozygotes and homozygotes compared to normal aa/aa genotype

many haplotypes that reduce the expression of α-globin provide a selective advantage in resistance to severe malaria. Indeed some mechanisms have been

• Reduced pathogenicity through reduced cytoadherence or resetting [108, 109]

• Immunological priming through cross-species immunity between *P. vivax and*

• increased phagocytosis of infected variant RBCs by monocytes and Enhanced antibody binding and subsequent clearance of infected variant RBCs [110, 111]

proposed to explain the malaria protection offered by α thalassemia:

• Specific protection against malaria-induced anemia [90, 104]

Some studies [90, 102–104] investigated α-thalassaemia showed protection against severe malaria, malarial anemia and additionally, protection from cerebral malaria [94].

• Uncomplicated *P. falciparum* malaria

Several prospective studies have assessed the incidence of uncomplicated malaria in α-thalassaemic children, with conflicting results. Indeed some studies showed the incidence of falciparum malaria was higher in α-thalassemia homozygotes and heterozygotes [94]; in contrast, other studies, found a lower incidence [37, 113]. However, other studies have found no protection for both homozygotes and heterozygotes
