Strong gene dose dependent protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against <i>Plasmodium vivax</i> malaria

Background X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PDd Med) is common across Europe and Asia. Epidemiological studies investigating the potential protective effect of G6PD deficiency against malaria have yielded conflicting results. Methods G6PDd Med genotyping was performed in Pashtun patients in Afghanistan with acute Plasmodium vivax malaria and Pashtun subjects attending the same study centres with unrelated conditions or for routine vaccinations. A Bayesian statistical model assuming Hardy-Weinberg equilibrium was used to estimate the potential protective effects of G6PDd Med on vivax malaria, and was fitted to all available data from this and previous studies. Findings In patients with vivax malaria 1.6% (5 of 308) of males were G6PD Med hemizygotes compared with 8.2% (28 of 342) of controls (risk ratio; 95% confidence interval: 0.198 [0.078 to 0.507]), and 6.8% (31 of 458) of female patients were heterozygotes compared with 11.2% (40 of 358) of controls (RR 0.606 [0.387 to 0.948]). From all available data, the estimated allele frequency of G6PDd Med in the Pasthun is 8.8% (95% credible interval, 7.5-10.2). In hemizygous males and homozygous females, G6PDd Med confers a strong protective effect against symptomatic P. vivax malaria reducing the incidence by 73% (95% C.I. 53-87). In heterozygous females the estimated protective effect was 56% (95% C.I. 40-69). The protective effect in heterozygous females is 0.78 (95% CI, 1.09-0.53) of that observed in hemizygous males and homozygous females. Interpretation The G6PD Mediterranean genotype confers a very large and gene dose proportional protective effect against vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by epidemiological studies in healthy subjects.