The Glucose-6-phosphate Dehydrogenase Mahidol Variant Protects Against Uncomplicated Plasmodium Vivax Infection and Reduces Disease Severity in a Kachin Population from Northeast Myanmar

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common red cell disorders in the world. The aim of this study was to investigate whether the G6PD Mahidol variant and haplotype 1311 T/93C, which are prevalent in the Kachin ethnic population along the China-Myanmar border area, offer protection against Plasmodium vivax infection. Malaria was monitored in nine villages near the Laiza township, Kachin State, Myanmar, where 258 cases of uncomplicated P. vivax were identified in 2013-2017. From the same villages, 250 unrelated, malaria-free participants were recruited to serve as the control cohort. Quantitative enzyme activity analysis in 100 healthy individuals identified that both male hemizygotes and female heterozygotes of the G6PD Mahidol variant had on average ~40% lower enzyme activity relative to the wild-type individuals. Compared with the overall prevalence of 25.2% in the control cohort, the G6PD Mahidol variant had a significantly lower prevalence (7.0%) among the 258 vivax patients (P <  .0001, χ test). Logistic regression analysis of G6PD genotypes stratified by sex showed that the individuals with the Mahidol 487A allele had dramatically reduced odds of having acute vivax malaria (adjusted odds ratio = 0.213 for male 487A hemizygotes, P < .0001, and 0.248 for female 487GA heterozygotes, P < .001). Furthermore, both 487A hemizygous male and 487GA heterozygous female patients had significantly lower asexual parasitemias than the wild-type patients, suggesting a potential effect on alleviating disease severity. In contrast, the silent mutation haplotype 1311 T/93C was highly prevalent (49.6%) in the study population, but it was not associated with altered G6PD enzymatic activities nor did it seem to provide protection against vivax infection or disease severity. Taken together, this study provided evidence that the Mahidol G > A mutation offers protection against P. vivax infection and potentially reduces disease severity in a Kachin population.