*2.3.1.1 HbS and* P. falciparum *malaria*

Heterozygosity for the sickle mutation (genotype AS) offers considerable protection against all forms of severe malaria, as well as protection against uncomplicated malaria [26, 32, 33] and parasitaemia [26, 32, 50, 51]. The different potential protective mechanisms that have been proposed and supported for sickle cell include, the growth of malarial parasites is suppressed in sickle cells [52], the abnormal display of PfEMP-1 [53], and the acceleration of acquired immunity [54]. It has also been shown that the growth rate of *P. falciparum* is retarded in HbS containing erythrocytes under conditions of low oxygen tension in vitro [55]; inhibition parasite growth by [44], miRNAs found more commonly in sickle cell trait cells than in normal cells inhibit parasite growth [56, 57].

The mechanism of the most strongly protective variant (HbS) against *P. falciparum* [1], is very complex. However studies have been shown here are two plausible mechanisms, which are not mutually exclusive, in suppression of parasite growing in red cells [55] and enhanced splenic clearance of parasitized erythrocytes [58]. Furthermore, a study summarized other possible protective effects of HbC. Indeed effects may result from [59]:


*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria DOI: http://dx.doi.org/10.5772/intechopen.93807*


A study with children (between the ages of 2 and 10 years) found that the protective effect of HbAS against malaria increased from 20% to 56%, which implies that it enhances or acts in synergy with the acquired immune response [54, 67].

The compromise between risks and benefits allows us to maintain the HbS polymorphism at allele frequencies of environ 10% in many parts of Africa, despite the lethal consequences for homozygotes, which provides the most striking known example of heterozygote advantage in human genetics [9].

• Severe *P. falciparum* malaria

the malaria parasite and a wide range of genetic polymorphisms has been developed to modify the individual response to this disease. Gene mutations involved in susceptibility and resistance to *P. falciparum* malaria. It has been shown that the severity of several malaria infections (such as asymptomatic, CM and SMA) varies significantly between individuals and between populations [5]. Many of the protective variants identified thus far affect erythrocytes, where the malaria parasite spends a crucial stage of its life cycle. Several of the best studied mutations affect the globin genes encoding hemoglobin [46]. Haemoglobinopathies and G6PD deficiency are among the most common single-gene disorders, which affect RBC stability and integrity [47]. More than 700 abnormal hemoglobin have been described worldwide and more

than 200 million people worldwide have RBC enzyme abnormality [48].

deficiency genes.

infection particularly *P. falciparum* malaria.

*Human Blood Group Systems and Haemoglobinopathies*

*2.3.1.1 HbS and* P. falciparum *malaria*

Indeed effects may result from [59]:

low oxygen tension [39, 55, 59]

expression of PfEMP1 [53, 60, 61]

**14**

cells than in normal cells inhibit parasite growth [56, 57].

These genetic mutations are major causes of morbidity and mortality around the world [49]. Sickle hemoglobin and G6PD deficiency are genetically independent, their loci is located on chromosome 11 for sickle and chromosome X for G6PD

**Table 1** summarizes the Common Erythrocyte variant that affects malaria

Sickle hemoglobin (HbS) and hemoglobin C (HbC) are both caused by point mutations in the beta globin gene, and both offer substantial malaria protection.

Heterozygosity for the sickle mutation (genotype AS) offers considerable protection against all forms of severe malaria, as well as protection against uncomplicated malaria [26, 32, 33] and parasitaemia [26, 32, 50, 51]. The different potential protective mechanisms that have been proposed and supported for sickle cell include, the growth of malarial parasites is suppressed in sickle cells [52], the abnormal display of PfEMP-1 [53], and the acceleration of acquired immunity [54]. It has also been shown that the growth rate of *P. falciparum* is retarded in HbS containing erythrocytes under conditions of low oxygen tension in vitro [55]; inhibition parasite growth by [44], miRNAs found more commonly in sickle cell trait

The mechanism of the most strongly protective variant (HbS) against *P. falciparum* [1], is very complex. However studies have been shown here are two plausible mechanisms, which are not mutually exclusive, in suppression of parasite growing in red cells [55] and enhanced splenic clearance of parasitized erythrocytes [58]. Furthermore, a study summarized other possible protective effects of HbC.

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

• Reduced pathogenicity of *P. falciparum* infected RBC because of reduced

• Inhibition of parasite growth due to oxygen-dependent polymerization [37]

• Enhanced removal of parasite-infected red blood cell [39, 58, 59]

• Improved acquisition of malaria-specific immunity [60, 62–64]

*2.3.1 Sickle hemoglobin (HbS), hemoglobin C (HbC) and* P. falciparum *malaria*

Some case–control and prospective cohort studies [10, 33, 54, 68–71] indicate that HbAS is consistently associated with large reductions in the risk of severe malaria.

• Uncomplicated *P. falciparum* malaria

A comparative studies [33, 44, 71–73] and several prospective studies [5, 26, 37, 74] have shown the reduction of risk in malaria attributable to HbS. In fact, the HbAS genotype protects against uncomplicated *P. falciparum* malaria by about 30% [33, 71]. In addition, this has been further confirmed by some genome-wide association studies [70, 71].

#### • *P. falciparum* parasitaemia

Cross-sectional studies have reported conflicting data on the prevalence of *P. falciparum* parasitemia in asymptomatic HbAS children compared with HbAA children.

A lower prevalence of parasitaemia in HbAS children was reported in some studies, [6, 26, 75], when others studies found contrary results of similar prevalence [72, 76, 77] or of higher prevalence [78, 79].

In these surveys, parasite densities were reported in HbAS children as lower [6, 62, 76, 79, 80] or similar [27, 78, 81, 82] to those in HbAA children. We can conclude that HbAS does not consistently protect from *P. falciparum* parasitaemia.

#### *2.3.1.2 HbC and* P. falciparum *malaria*

A recent meta-analysis concluded that homozygotes for βC (Hb CC) were strongly protected against severe malaria, and heterozygotes (HbAC) were mildly protected [10, 33]. It has also been found that both both heterozygotes and homozygotes of HbC are protected against severe malaria [26, 30, 31, 44, 83] but the protective effect appears to be substantially greater in homozygotes [44].

Although a cohort study in Mali reports an increase in the incidence of clinical malaria in AC individuals relative to AA [84].

HbC genotypes are not fully elucidated [56], but several mechanisms have been proposed to explain the malaria protection offered by HbC [32], including abnormal 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:

[76, 78, 80, 92, 93] or *P. falciparum* density [76, 78, 80, 94]. The incidence of asymptomatic parasitaemia did not differ between HbAC and HbAA children in Mali study [26, 74]. However, in Burkina Study HbAC genotype was associated with a lower incidence of clinical malaria relative to AA among children. Thus, HbC

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

Generally, none of HbS or C variants are present in Southeast Asia and HbE is in

HbE is an extremely most common structural hemoglobin variant that occurs at high frequencies throughout Southeast Asia and has reached an allele frequency of

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

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

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,

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

We have not identified studies that have quantified clearly susceptibility to

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

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.

though this should be interpreted cautiously given the significant.

• Severe *P. falciparum* malaria

• Uncomplicated *P. falciparum* malaria

• *P. falciparum* parasitaemia

patients with HbAA [101].

general also absent from populations in which HbS and HbC are present [52].

up to 70% in some areas of northern Thailand and Cambodia [34].

does not appear to modify the risk of *P. falciparum* parasitaemia.

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

*2.3.1.4 HbE and* P. falciparum *malaria*

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

erythrocytes [28, 96].

origin.

malaria by HbE.

**17**

phenotype of a mild form of β thalassemia [95].

