G6PD variants but not Filipino beta-thalassemia are associated with reduced risk of Plasmodium knowlesi infection in Sabah, Malaysia

BACKGROUND: The emergence of Plasmodium knowlesi as the predominant cause of malaria in Malaysian Borneo raises important questions about protective genetic factors in endemic populations. This study investigates two common erythrocyte polymorphisms, glucose-6-phosphate dehydrogenase (G6PD) deficiency and Filipino β-thalassemia, for association with P. knowlesi infection risk. METHODS: A retrospective case-control study compared 106 PCR-confirmed P. knowlesi cases with 89 controls from Sabah, Malaysia. Genotyping used multiplex PCR (8 major Southeast Asian G6PD variants) and gap-PCR (Filipino β-thalassemia deletions). Statistical analysis employed Fisher's exact tests and logistic regression models to evaluate associations with infection risk, including controlling for age, sex, ethnicity and district site. RESULTS: G6PD deficiency genetic variants were present in 4/106 (3.8%, 95%CI 1.0-9.4%) P. knowlesi cases compared to 11/89 (12.4%, 95%CI 6.3-21.0%) controls (OR = 0.28, 95%CI 0.09-0.91; p = 0.034). The Viangchan variant (871G>A) was predominant (71%), with Coimbra and Mediterranean variants also present. No relationship with G6PD variants and severe malaria or sex was detected, although analysis was constrained by small numbers. Filipino β-thalassemia demonstrated no association. CONCLUSIONS: G6PD deficiency related variants confer substantial protection against P. knowlesi susceptibility, while β-thalassemia appears neutral. Findings have implications for zoonotic malaria transmission risk in Southeast Asia.