Malaria genetic diversity and selection

13.2.1 Inherited factors and resistance to malaria

Malaria is one of the most important infectious diseases in the world and a leading cause of death, particularly among children. Genetic variation in man is an important determinant of disease susceptibility but has to be considered as part of a remarkably complex multifactorial disorder involving diversity in the mosquito vector, parasites, and environment as well as our own immune response (Box 13.1). The complexity of the relationship between parasite and host, involving multiple points of attack and defence, has left evidence in the human genome of the profound selective pressure malaria has exerted on human populations at risk of the disease living in tropical and subtropical regions of the world. Inherited factors providing a selective advantage are thought to have driven specific human alleles to high frequency in malaria endemic regions providing some of the clearest examples of genomic 'signatures of selection' (Section 10.2) as well as being manifest in the observed global distribution of monogenic diseases such as thalassaemia (Section 13.2.2) and sickle cell disease (Section 13.2.3).

Particular ethnic groups are also seen to have different inherent levels of resistance to malaria in the same geographic location, as seen among the Tharu in Nepal (Section 13.2.2) and Fulani people of West Africa (see Box 13.3). Specific genetic variants associated with malaria resistance are found in some cases to be localized to particular regions. For example there is evidence that a recent mutation of HBB resulting in haemoglobin C (Hb C) has risen to relatively high allele frequency in a particular region of central West Africa where, among the Dogon people for example, it is associated with protection from malaria due to P. falciparum (Section 13.2.3).

Other variants such as a single nucleotide substitution in the DARC gene associated with the Duffy antigen receptor have become more widely established: the variant confers complete resistance to P. vivax malaria and is at or near fixation in most West and Central African populations but very rare outside Africa (Section 13.2.4). Malaria has had a relationship with man since prehistory; indeed similar parasite species are found among reptiles and birds as well as other primates. However, malaria is thought to have become a major human pathogen only over the last 10 000 years when a sudden increase in the African malaria parasite population was found to have occurred, concurrent with the development of resident agricultural societies (Kwiatkowski 2005).

The contribution of human genetic diversity to the risk of malarial infection and severe illness is only one of many interrelated factors, which also include the intensity and nature of disease transmission and exposure, genetic variation in the parasite, and the virulence of the particular strain. Other factors include the ecology of the mosquito vector and acquired immunity developed by an individual living in a malaria endemic region, as well as coinfection and multiple environmental factors of which socioeconomic status is very important. A large longitudinal study of mild clinical malarial illness and disease requiring hospital admission among children in the Kilifi District of coastal Kenya has shown that genetic factors account for approximately one-quarter of the variation observed between children in their susceptibility to malaria, equal to the proportion of variability explained by household factors such as spatial distribution in mosquito breeding sites, and use of insecticide and insect repellents (Mackinnon et al. 2005). Such a study to estimate the heritability of malarial infection was possible due to careful epidemiological analysis within and between households of individuals of varying genetic relatedness. The estimate of genetic factors accounting for 25% of variation in the incidence of malaria among an African population of children living in a malaria endemic area was broadly similar to that observed among a mainly adult population in Sri Lanka, where disease transmission and incidence was significantly lower, and P. vivax as well as P. falciparum contributed to the clinical cases (Mackinnon et al. 2000).

In the following sections examples of the relationship between genetic variation and malaria are described to

Box 13.1 Malaria

Malaria is the most important parasitic disease of man. The figures are stark. There were an estimated 515 million episodes of clinical malaria due to Plasmodium falciparum in 2002 and more than 1 million deaths globally per annum (Snow et al. 2005). Some 2.37 billion people were estimated to be at risk of P. falciparum transmission in 2007 (Fig. 13.1) (Guerra et al. 2008). The major disease burden falls in Africa where 70% of clinical events are thought to occur, with the majority of deaths among children (Snow et al. 2005). P. falciparum is one of four different Plasmodium species known to infect man, the others being P. vivax, P. ovale, and P. malariae. The species differ in their virulence, length of life cycle, and red blood cell preferences. The major mosquito vector of P. falciparum in sub-Saharan Africa is Anopheles gambiae. Transmission of the sporozoite stage of the parasite to the human host occurs by the bite of an infected mosquito; this is followed by invasion and replication in liver cells and the release of merozoites, which invade red blood cells and multiply with fever and vital organ damage. Gametocytes from infected red cells may then be taken up during a blood meal by a mosquito where they multiply and complete the life cycle of the parasite by developing into sporozoites (Fig. 13.2). The most severe manifestations of malaria are seen with P. falciparum where cerebral malaria, severe malarial anaemia, and respiratory distress may result, in some cases with fatal results. It is, however, only a small minority of individuals who develop the life threatening forms of the disease. Major advances have been achieved through malaria control programmes but malaria remains a major global public health problem with ongoing efforts to coordinate and intensify such work, for example through the Roll Back Malaria Partnership launched in 1998 (www.rbm.who.int).

Figure 13.1 Plasmodium falciparum global distribution and malaria risk. Stable transmission refers to a P. falciparum annual parasite incidence of 0.1 cases per thousand people per annum; unstable are areas of extremely low transmission (<0.1 per thousand per annum). Reprinted with permission from the Malaria Atlas Project (www.map.ox.ac.uk) (Hay and Snow 2006; Guerra et al 2007, 2008).

Figure 13.1 Plasmodium falciparum global distribution and malaria risk. Stable transmission refers to a P. falciparum annual parasite incidence of 0.1 cases per thousand people per annum; unstable are areas of extremely low transmission (<0.1 per thousand per annum). Reprinted with permission from the Malaria Atlas Project (www.map.ox.ac.uk) (Hay and Snow 2006; Guerra et al 2007, 2008).

Figure 13.2 Life cycle of human malaria parasites. (1) During the blood meal of the female Anopheles mosquito, sporozoites are injected into the human capillaries. (2) Sporozoites can be found in the blood for about 30 minutes, most are destroyed but some invade the cells of the liver. (3) After about a week, infected liver cells containing mature schizonts burst releasing thousands of tiny merozoites into the blood. (4) Merozoites invade red blood cells and develop over 48-72 hours to produce more merozoites. (5) After several generations, some merozoites develop into sexually differentiated forms (gametocytes). (6) Male and female gametocytes are taken up by the mosquito when feeding, gametes fuse in the mosquito gut, and the zygote (ookinete) penetrates the gut wall to form an oocyst. Ten to 14 days later thousands of sporozoites are released from the oocyst and travel to the salivary glands. Redrawn from Rosenthal (2008), copyright 2008 Massachusetts Medical Society. All rights reserved.

Figure 13.2 Life cycle of human malaria parasites. (1) During the blood meal of the female Anopheles mosquito, sporozoites are injected into the human capillaries. (2) Sporozoites can be found in the blood for about 30 minutes, most are destroyed but some invade the cells of the liver. (3) After about a week, infected liver cells containing mature schizonts burst releasing thousands of tiny merozoites into the blood. (4) Merozoites invade red blood cells and develop over 48-72 hours to produce more merozoites. (5) After several generations, some merozoites develop into sexually differentiated forms (gametocytes). (6) Male and female gametocytes are taken up by the mosquito when feeding, gametes fuse in the mosquito gut, and the zygote (ookinete) penetrates the gut wall to form an oocyst. Ten to 14 days later thousands of sporozoites are released from the oocyst and travel to the salivary glands. Redrawn from Rosenthal (2008), copyright 2008 Massachusetts Medical Society. All rights reserved.

highlight how this relationship has been explored and the remarkable insights it has afforded (Fig. 13.3). A large number of variants relate to the red blood cell where malaria has exerted powerful selective pressures, notably involving the a and p globin gene loci with structural variants of haemoglobin such as Hb S, Hb C, and Hb E as well as the thalassaemias providing resistance to infection. Genetic variation involving receptors for parasite entry to red cells and red cell metabolism have also provided substrate on which selection has acted. Diversity in major histocompatibility complex (MHC) molecules involved in the presentation of parasite proteins in liver cells, and polymorphism of immune genes and of receptors involved in the process of cytoadherence of infected red cells, provide further examples of the complexity of the relationship between parasite and host, and the points at which advantage may be gained through the possession of particular variants. A number of excellent reviews address the role of genetic factors in malaria in more detail (Kwiatkowski 2005; Williams 2006; Weatherall 2008).

13.2.2 Thalassaemia, natural selection and malaria

Thalassaemias are inherited disorders causing defective and imbalanced synthesis of globin, first described in the 1920s among children of Mediterranean origin with severe anaemia. This group of disorders are now recognized as the most common single gene diseases found in man, whose consequences range from being asymptomatic to lethal. In Section 1.3 the nature and molecular basis of a and p thalassaemia were reviewed. The name thalassaemia derives from the Greek for the sea ('thalassa1) and blood ('a/ma'), reflecting the high frequency of thalassaemia in Italian and Greek coastal populations. The occurrence of thalassaemia is however much more extensive, being found in the Middle East, Africa, India, and South East Asia. A correlation between the geographic distribution of thalassaemia and the incidence of malarial infection was noted (Fig. 13.4), with Haldane proposing that heterozygotes may have a selective advantage compared to those without the variant (Haldane 1949). Haldane noted that the red blood cells of carriers of thalassaemia might be more resistant to malarial infection, with the resulting heterozygote advantage leading to increased frequency of thalassaemia gene variants in the population balanced by the selective disadvantage of the homozygous state (Haldane 1949; Weatherall 2008). Evidence to support the concepts of balanced polymorphism and the malaria hypothesis continue to accumulate with further elegant examples, as will be described for the structural haemoglobin variant, sickle haemoglobin (Section 13.2.3).

Individuals with a+ thalassemia have reduced production of a chains due to one of the two HBA genes in the a globin locus on chromosome 16p13.3 being deleted or inactivated by specific mutations. At a molecular level such individuals are either heterozygotes or homozygotes for deletion events (denoted -a/aa and -a/-a respectively) or particular mutations (aTa/aa and aTa/ aTa); the haematological phenotype associated with this varies from being clinically silent (heterozygotes) to mild anaemia (homozygotes) although is more severe in non-deletional forms of a+ thalassaemia. In a0 thalassaemia there are no a chains produced from a given chromosome as both linked genes are deleted; affected individuals may be either heterozygous --/aa or homozygous --/-- for a0 thalassaemia and this is associated with a severe or fatal phenotype (Box 1.15). (Section 1.3) (Weatherall 2008). In the mountains and swamps of Papua New Guinea, and the islands of the southwest Pacific, a clear relationship was found between the endemicity of malaria and the frequency of deletional forms of a+ thalassemia (Flint et al. 1986). In Papua New Guinea, rates of malaria were low above 1500 m and the frequency of a+ thalassemia dropped ten-fold from northern coastal areas into the highlands. Moreover, a clear progressive reduction in malarial endemicity was observed on progressing south and east from coastal Papua New Guinea until the disease was absent in New Caledonia and Fiji (Fig. 13.5). This was mirrored by the frequency of a+ thalassemia, which fell from almost 70% in the northern coastal regions of Papua New Guinea to less than 10% in New Caledonia in the southeast.

In the southern lowlands of the Terasi region of Nepal, rates of malarial infection were so high that it was considered for a long time uninhabitable by most Nepalese. The Tharu people, however, appeared to be naturally immune and had lived there for generations. As malaria control measures improved and other ethnic groups settled in the area, the prevalence of cases of residual malaria were noted to be seven times higher in the non-Tharu population (Terrenato et al. 1988). Genetic studies showed almost all Tharu people have a+ thalassemia in the heterozygous or homozygous state, with most homozygous (-a/-a), among whom morbidity from malaria was estimated to

Common erythrocyte variants that affect resistance to malaria

Gene Protein

Reported genetic associations with malaria

FY Duffy antigen

G6PD Glucose-6-phosphate dehydogenase

GYPA Glycophorin A HBA a globin ß globin Haptoglobin

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