Testing a biochemical model of human genetic resistance to falciparum malaria by the analysis of variation at protein and microsatellite loci

We recently proposed a biochemical model of genetic resistance to falciparu m malaria based on the role of oxidant stress (of parasitic origin) in indu cing the irreversible oxidation of hemoglobin and its binding to the erythr ocyte membrane (Destro-Bisol et al. 1996). To test the model, we analyzed t he relationships between the polymorphisms at the hemoglobin beta chain (HB B) and red cell glutathione peroxidase (GPX1) loci in 18 populations that h ad been subjected to endemic malaria (Cameroon and Central African Republic ). The erythrocytes of GPX1*2 heterozygotes should be more efficient in she ltering the cell membrane from irreversible oxidation and binding of hemogl obin caused by the oxidant stress exerted by Plasmodium falciparum. Accordi ng to our model, the GPX1*2 allele has an epistatic effect on the HBB*A/*S genotype by lowering its protection against falciparum malaria, In turn, th is should decrease the fitness of the HBB*A/*S-GPX1*2/*1 genotype. Our pred ictions were confirmed, in fact, we observed a clear trend toward a dissoci ation between the HBB*A/*S and GPX1*2/*1 genotypes in the overall data. To test alternative hypotheses, we also analyzed the genetic variation at 9 pr otein and 10 autosomal microsatellite loci at both the single- and the 2-lo cus level, We also discuss the possible relevance of an alternative biochem ical pathway, The results further support the conclusions of our study beca use the dissociation between the GPX1*2/*1 and HBB*A/*S genotypes does not appear to be related either to a general decrease in heterozygosity or to a n increased risk of sudden death in HBB*A/*S individuals.