G6PD A- Deficiency and Severe Malaria in The Gambia: Heterozygote Advantage and Possible Homozygote Disadvantage

Abstract

Abstract. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is frequent in Africa, because it confers resistance to Plasmodium falciparum malaria; however, the nature of the protection and the genotypes associated with it have been controversial. In 1972, Bienzle and others described protection from malaria in West African females heterozygous for G6PD A-. They determined that G6PD A-heterozygotes had lower parasite counts than A-homozygotes, hemizygous males, and normal individuals. However, other studies have reached different conclusions about the protective genotypes. DNA samples from 135 children with severe malaria and 146 children with mild malaria from The Gambia were genotyped for the G6PD A-mutation that is most frequent among Gambians (G6PD 968 T-C); there was a marked deficiency of heterozygotes and an excess of homozygotes with severe malaria, producing a strong deviation from Hardy-Weinberg equilibrium. Our results support the protective effect in G6PD A-heterozygous females and suggest that homozygotes might be more susceptible to severe malaria attacks.Glucose-6-phosphate dehydrogenase (G6PD) deficiency is widespread across Africa, because it confers resistance to Plasmodium falciparum (and possibly, P. vivax) malaria, but despite this evidence and the previous evidence that G6PD is under strong natural selection, the nature of the protection and genotypes associated with it has been controversial.

Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk

“…Over-dominance refers to heterozygous ''advantage'' related to a single locus and signifies that the phenotype of heterozygous may lie outside the phenotypical range of both wild-type homozygous and wild-type mutants. Examples in humans include G6PD A-deficiency and severe malaria [23] and HLA-DRB1 heterozygosity and protection against HCV [24]. Genes exert pleiotropic effects, and the biologic effect of PT G20210A cannot be explained on the sole basis of prothrombin expression and activity but may rely upon parallel activation/suppression of other related genes and pathways to thrombosis [25].…”

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

“…This is partly due to the genetic complexity of the locus, being X-linked with multiple deficiency alleles with the result that it has extensive allelic and phenotypic heterogeneity, and also to the fact that clinical and epidemiological studies have appeared to give conflicting results. An early study concluded that G6PD deficiency protects against P. falciparum malaria in heterozygous females (Bienzle et al, 1972) and this is supported by a number of more recent studies (Manjurano et al, 2012; Sirugo et al, 2014; Luzzatto, 2015; Manjurano et al, 2015; Uyoga et al, 2015). However other studies have indicated that the protective effect is present in both heterozygous females and hemizygous males (Ruwende et al, 1995; Clark et al, 2009; Shah et al, 2016) or that it is confined to hemizygous G6PD-deficient males (Guindo et al, 2007), or that there are no protective effects at all (Johnson et al, 2009; Toure et al, 2012).…”

Assessing risk for Mendelian disorders in a Bronx population

“…; Sirugo et al. ). The panel also included alleles for some conditions with rare prevalence among one of these populations for which testing would have clinical utility.…”