How CYP2D6 polymorphism modulates the community-wide risk of Plasmodium vivax infection: a panel study in Amazonian Brazil

The CYP2D6 enzyme plays a critical role in the metabolism of primaquine, the most widely used drug for the radical cure of Plasmodium vivax malaria. Impaired CYP2D6 activity has been associated with an increased risk of relapse. However, the overall impact of CYP2D6 on infection dynamics is still not fully understood. We hypothesized that individuals with impaired CYP2D6 activity develop partial immunity more rapidly due to the ineffective clearance of hypnozoites. To test this hypothesis, we conducted a community-based study involving approximately 1,300 individuals genotyped for CYP2D6 and assessed repeatedly for P. vivax using molecular diagnosis. This approach allowed us to detect and monitor submicroscopic and asymptomatic infections over a 4-year follow-up period. In our cohort, children with impaired CYP2D6 activity exhibited a higher frequency of P. vivax infections compared to those with normal enzyme activity. This pattern changed during the second decade of life, as the prevalence of P. vivax infection increased in adolescents with normal enzyme activity (P = 0.0008, Generalized additive mixed model). Consistent with this, parasite densities were lower in adults with impaired CYP2D6 activity compared with younger individuals with normal enzyme activity (P = 0.0383, Linear mixed model). These findings underscore the potential role of CYP2D6 in shaping infection dynamics and malaria immunity in endemic areas.