**5. Association of HbS, G6PD and FY gene polymorphisms and malaria**

#### **5.1 Introduction**

Understanding the molecular mechanisms that underlies the adaptation is of crucial importance in evolutionary biology. Among the plethora of genes that causes adaptive variation in fitness-related features in natural populations, very few are identified [93, 94]. The hemoglobins, oxygen-carrying proteins, tightly connect cell metabolic activities with environmental conditions and thus represent convenient system for analyzing adaptive changes [93, 94]. Also, inherited disorders of hemoglobin are the most common human monogenic diseases [95]. Each year, there are between 300,000 and 400,000 newborns with some of the serious hemoglobin disorders and up to 90% of them are born in low- or middle-income countries [96].

Hemoglobin is the oxygen-carrying protein of red blood cells (RBCs), normally formed of two α-globins and two β-globins that constitute adult hemoglobin A (HbA). Without specific medical treatment, the most severe hemoglobinopathies — HbSS homozygosity (sickle-cell disease) and the thalassemias major are not compatible with life after early childhood. People with HbAS, HbAC, HbCC, HbAE, HbEE, and the thalassemias minor have usually normal life expectancy and are rarely directly associated with morbidity [97].

*Plasmodium spp.* parasites represent vector-borne pathogens which attack the red cells of reptiles, birds, and primates [98]. Out of five Plasmodium species that parasitize and cause malaria in humans, *P. falciparum* and *P. vivax* are the most common in human populations. *P. falciparum* is endemic in tropical areas worldwide, including Mediterranean [99]. Like the other four Plasmodium species, *P. falciparum* is injected into a human skin via female *Anopheles spp*. mosquitoes as a vector. Then, the sporozoites migrate to the liver where they attack hepatocytes and develop within them for 7–10 days. As a consequence, numerous merozoites are formed which, subsequently, enters erythrocytic stage of RBSs life cycle. In that time, typical features of malaria clinical picture develop [97, 98].

As a disease which is a main cause of morbidity and mortality, malaria caused by *P. falciparum* imposed remarkable evolutionary pressure on the human genome.. Also, malaria caused by *P. falciparum* is in relation with numerous genetic polymorphisms that are responsible for protection against this disease [97, 100]. Hemoglobin mutants S, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Dufy Antigen/Receptor for Chemokines (DARC) gene mutation are mostly distributed in the areas where *P. falciparum* malaria is endemic. These genes expression have high levels of prevalence in malaria endemic areas which is considered to be the consequence of their protective role against *P. falciparum* [101]. In this context, malaria can be defined as an infectious disease that has pronouncedely higher selective pressure on the human genome in comparison with all other infectious diseases [101]. Polymorphysms of the above-mentioned genes are typical examples

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*Adaptation to Mediterranea*

heterozygotes [102].

*DOI: http://dx.doi.org/10.5772/intechopen.94081*

**5.2 HbS gene polymorphisms and malaria**

acquired immunity to *P. falciparum* [109].

due to resistance to *P. falciparum* [111].

sickle cell disease which does not endanger their lives [106].

of Haldane's idea of balanced polymorphism. According to this author, balanced polymorphism exists when certain genes have fixed high frequency in susceptible populations since enhanced fitness encompanied with heterozygotes multiple times overweights morbidity and mortality associated with homozygotes and compound

Sickle hemoglobin (HbS) is best characterized genetic polymorphism tightly interconnected with malaria. HbS represents a structural variant of normal adult hemoglobin (HbAA) and results from a single point mutation (Glu → Val) on the sixth codon of the beta globin gene [103]. Homozygotes for hemoglobin S (HbSS) have sickle cell disease that further causes high morbidity and mortality. Also, heterozygous for HbS have 10-fold lower risk of dying from malaria compared to homozygous [97, 104, 105]. Heterozygotes (HbAS) have generally asymptomatic

It has been found that, in the conditions of selection for fitness against malaria,

Knowledge of the existing relationship between malaria infection and extension

and prevalence of hemoglobinopathies in Mediterranean region are not new [102, 110]. Sickle-cell homozygous persons have short life expectancy and commonly die before adulthood. However, the gene responsible for sickle cell disease "hidden" within the genotype of heterozygous carrier can achieve high frequency

There are lots of described biological mechanisms that are considered to be responsible for protection against malaria. First, there were only two mechanisms described regarding a manner in which the presence of HbS in heterozygotes protects against malaria: sickling of circulating infected RBCs and impaired parasite growth and oxidant damage [101]. It has been found that formation of sickle RBSc shapes under low oxygen presure occured more frequently in RBCs infected with *P. falciparum* compared to uninfected RBCs [112]. When parasite triggers sickling of erythrocytes once, sickled cells are removed by macrophages [113]. This action of may macrophages'possibly occurs due to their ability to produce and release numerous cytokines that further recruit more phagocytic cells [114]. In addition, it has been discovered that enchanced sickling was limited to RBCs infected with small Plasmodium forms [115]. On the other hand, impaired parasyte growth and oxygen damage was discovered thanks to *in vitro* studies [112]. In the conditions of normal oxygen pressure, there were no differences in the invasion, growth, and multiplication of *P. falciparum* in HbAS cells compared to HbAA RBCs. In the opposite, hypoxic consitions caused reduced fraction of *P. falciparum* in HbAS cells and a block in the maturation of ring forms to trophozoites and schizonts.

nearly 45 generations (or 1000 years) were necessary to pass until sickle gene frequency reached a stable equilibrium [107]. People with HbAS have 50–90% lower parasite density [105] in comparison with individuals with normal hemoglobin (HbAA). Sub-Saharan Africa is an area with closely 80% of people born with sickle cell anemia and where most *P. falciparum* malaria cases and deaths occur [108]. Besides sub-Saharan Africa, sickle cell anemia is present, although rarely with frequency higher than 20–25%, in the Mediterranean region, the Middle East, and the Indian subcontinent [95]. There is a strong connection between high HbS allele frequency and high malarial endemicity in the world although this finding is based on the observations made in Africa: HbS allele frequency gradually increases from epidemic areas to endemic areas in Africa which is in accordance with the hypothesis that malaria protection by HbS includes the enhancement of innate and

#### *Adaptation to Mediterranea DOI: http://dx.doi.org/10.5772/intechopen.94081*

*Genetic Variation*

**5.1 Introduction**

Considering the monogenic nature of the disease, the most challenging, yet possible therapy approach, may be an interference in the globin chains imbalance, achieved by gene therapy and genome editing [68]. Alternative pharmaceutical approaches would be use of agents acting as potent stimulators of late stage erythropoiesis and increased hepcidin expression, throughout its substitution or stimulation of its endogenous production. Even though there has been a substantial progress in the development of therapy options for individuals affected with thalassemia, the best approach to the disease management remains prevention of

**5. Association of HbS, G6PD and FY gene polymorphisms and malaria**

Understanding the molecular mechanisms that underlies the adaptation is of crucial importance in evolutionary biology. Among the plethora of genes that causes adaptive variation in fitness-related features in natural populations, very few are identified [93, 94]. The hemoglobins, oxygen-carrying proteins, tightly connect cell metabolic activities with environmental conditions and thus represent convenient system for analyzing adaptive changes [93, 94]. Also, inherited disorders of hemoglobin are the most common human monogenic diseases [95]. Each year, there are between 300,000 and 400,000 newborns with some of the serious hemoglobin disorders and up to 90% of them are born in low- or middle-income countries [96]. Hemoglobin is the oxygen-carrying protein of red blood cells (RBCs), normally

formed of two α-globins and two β-globins that constitute adult hemoglobin A (HbA). Without specific medical treatment, the most severe hemoglobinopathies — HbSS homozygosity (sickle-cell disease) and the thalassemias major are not

rarely directly associated with morbidity [97].

compatible with life after early childhood. People with HbAS, HbAC, HbCC, HbAE, HbEE, and the thalassemias minor have usually normal life expectancy and are

*Plasmodium spp.* parasites represent vector-borne pathogens which attack the red cells of reptiles, birds, and primates [98]. Out of five Plasmodium species that parasitize and cause malaria in humans, *P. falciparum* and *P. vivax* are the most common in human populations. *P. falciparum* is endemic in tropical areas worldwide, including Mediterranean [99]. Like the other four Plasmodium species, *P. falciparum* is injected into a human skin via female *Anopheles spp*. mosquitoes as a vector. Then, the sporozoites migrate to the liver where they attack hepatocytes and develop within them for 7–10 days. As a consequence, numerous merozoites are formed which, subsequently, enters erythrocytic stage of RBSs life cycle. In that

As a disease which is a main cause of morbidity and mortality, malaria caused by *P. falciparum* imposed remarkable evolutionary pressure on the human genome.. Also, malaria caused by *P. falciparum* is in relation with numerous genetic polymorphisms that are responsible for protection against this disease [97, 100]. Hemoglobin mutants S, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Dufy Antigen/Receptor for Chemokines (DARC) gene mutation are mostly distributed in the areas where *P. falciparum* malaria is endemic. These genes expression have high levels of prevalence in malaria endemic areas which is considered to be the consequence of their protective role against *P. falciparum* [101]. In this context, malaria can be defined as an infectious disease that has pronouncedely higher selective pressure on the human genome in comparison with all other infectious diseases [101]. Polymorphysms of the above-mentioned genes are typical examples

time, typical features of malaria clinical picture develop [97, 98].

thalassemia births throughout national screening programs [68].

**156**

of Haldane's idea of balanced polymorphism. According to this author, balanced polymorphism exists when certain genes have fixed high frequency in susceptible populations since enhanced fitness encompanied with heterozygotes multiple times overweights morbidity and mortality associated with homozygotes and compound heterozygotes [102].
