It may seem remarkable that so many genetic variants are associated with resistance to malaria but this is considered to reflect the remarkably strong selective pressure exerted by malaria over recent human history. The enzyme glucose-6-phosphate dehydrogenase (G6PD) provides protection for the cell against oxidative damage, for example as a result of iron accumulating on the breakdown of haemoglobin by malaria parasites. Inherited deficiency of G6PD is commonly seen (Box 13.2) and a striking correlation between the frequency of deficiency and malarial endemicity was noted when comparing different geographic regions worldwide (Allison 1960; Luzzatto 1979; Ganczakowski et al. 1995). Patients with G6PD deficiency have been found to have fewer malaria parasites in their blood due to inhibition of parasite growth (Luzzatto et al. 1969; Roth et al. 1983).
Box 13.2 Glucose-6-phosphate dehydrogenase deficiency (OMIM 305900)
G6PD deficiency is the commonest enzymopathy known in man, affecting more than 400 million people worldwide, predominantly in tropical and subtropical regions of Africa and Asia (Fig. 13.8). Most people with G6PD deficiency are asymptomatic but the consequences can be severe. These include jaundice in the newborn and haemolytic anaemia, in which the red cells of people with the enzyme deficiency break down in response to the oxidative stress associated with infection, drugs, or other precipitants including eating fava beans (Cappellini and Fiorelli 2008). The G6PD gene lies on the long arm of the X chromosome at Xp28 near to the genes responsible for colour blindness and haemophilia A.
G6PD is remarkably polymorphic: over 400 biochemical variants have been described with more than 140 mutations resulting in variable degrees of enzyme deficiency (Cappellini and Fiorelli 2008). Most are missense mutations, with enzyme stability most commonly affected. A database of mutations involving G6PD is available online (www.bioinf. org.uk/g6pd) (Kwok et al. 2002). 'A' and 'B' variants are distinguished by an asparagine to aspartic acid substitution at position 126 arising due to an A to G single nucleotide substitution in exon 5; the 'A-' variant carries a further amino acid substitution of valine for methionine at position 68 due to a G to A nucleotide substitution in exon 4. The A—' variant accounts for about 90% of G6PD deficiency in tropical Africa (Cappellini and Fiorelli 2008).
There have been several studies investigating G6PD deficiency and susceptibility to malaria. The location of the G6PD locus on the X chromosome adds to the complexities of analysis as in men there will only be one copy while in women there will be two, and variable X chromosome inactivation adds significant genetic heterogeneity. Protection from seizures and coma in severe malaria was found among children in Nigeria (Gilles et al. 1967). More recently two large studies of over 2000 children found that the common form of G6PD deficiency found in Africa (due to the 'A-' variant) (Box 13.2) was associated with about a 50% reduction in risk of severe malaria in female heterozygotes and male hemizygotes (Ruwende et al. 1995). The evidence suggests that, like Hb S, the genetic variability at the G6PD gene locus represents an elegant example of a balanced polymorphism. Here, the selective advantage conferred by resistance to malaria appears counterbalanced by a selective disadvantage of blood disorders associated with the enzyme deficiency.
The evolutionary history of genetic variation at the G6PD locus has been studied using highly polymorphic microsatellite markers and restriction fragment length polymorphisms (RFLPs) in geographically diverse populations (Tishkoff et al. 2001). Analysis of the malaria susceptibility associated 'A-' and 'Med' mutations (the latter is common around the Mediterranean, involving substitution of phenylalanine for serine at position 188) suggests they have arisen independently within the last 3840-11 760 years and 1600-6640 years, respectively. The recent origins of such mutations are consistent with the hypothesis that malaria has had a major impact on human populations only since the introduction of agriculture within the last 10 000 years. Signatures of recent selection are seen involving G6PD, for example on haplotypic analysis with extended haplotypes of high frequency observed (Section 9.2.2).
The mechanism of protection conferred by G6PD deficiency is thought to relate to the susceptibility of parasitized G6PD deficient red blood cells to oxidative stress with earlier phagocytosis (Cappadoro et al. 1998). Remarkably, there is evidence that the P. falciparum counters this by manufacturing G6PD itself (Usanga and Luzzatto 1985). In G6PD deficient cells, adaptive changes were seen in the parasite over time on culture of P. falciparum with induction of a novel G6PD encoded by the parasite genome. The malaria parasite is an active player in its war of attrition with man, having its own genetic arsenal with which to combat variation in the host environment - as further illustrated with the diversity seen in parasite 'var' genes involved in evading the immune response (Section 13.2.6).
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