Are Individuals With Flavin-Deficient Erythrocytes Protected From Malaria?

Studies from the 1980s and 1990s hypothesised that individuals with flavin deficient erythrocytes (FDE) from certain regions of Italy (where malaria was once endemic) are partially protected from malaria. This hypothesis has never been tested. Using a glutathione reductase (a flavo-enzyme) activity assay, we screened for individuals with FDE at two study sites. We screened a total of 150 people in Ferrara, Italy and 169 in Huye, Rwanda and found the incidence of FDE to be 23% and 13%, respectively. None of the individuals with FDE had a dietary riboflavin deficiency. Importantly, FDE from individuals in Ferrara were less capable of supporting in vitro proliferation of P. falciparum. Supporting this observation, we also found that erythrocytes depleted of riboflavin in vitro cannot support parasite proliferation. As the presence of FDE has been suggested to be familial, we sequenced the coding regions of FAD synthetase and flavokinase (the enzymes involved in flavin generation) of the 22 individuals with FDE from Huye, and detected mutations in four individuals; three had mutations in FAD synthetase and one had a mutated flavokinase. Whether these mutations, and potentially mutations in other genes, play a role in FDE and protection from malaria, requires further investigation.