How Duffy Blood Group (FY) Polymorphism and Age Modulate Vivax Malaria Risk at the Community Level: A Population-based Retrospective Cohort Study in the Amazon

Background A promoter variant commonly found in sub-Saharan Africans and their descendants disrupts Duffy antigen (Fy) expression on erythrocytes, leading to the Fy-negative phenotype, and confers partial resistance to blood-stage Plasmodium vivax infection. In addition, the 125G→A substitution, rare in Africans, defines the Fy^a/Fy^b polymorphism that can modulate vivax malaria risk in Amazonians. The combined effect of these FY polymorphisms on P. vivax infection risk remains little explored at the population level. Methods We studied a household-based random sample of 1737 Amazonians, with a well-balanced distribution of FY alleles, who were exposed to P. vivax transmission and contributed 7878.9 person-years of follow-up. We fitted a multivariable zero-inflated negative binomial model to incidence data, assuming that zero counts could arise from individuals at risk who remained uninfected over 5 years of follow-up ("sampling zeroes") or from not-at-risk individuals ("structural zeroes"). Results Plasmodium vivax infections were heterogeneously distributed in the population, with 0 to 11 cases per person (average incidence, 25.8 cases/100 person-years at risk). We show that Fy-negativity remains a major malaria resistance trait in Amazonians and contributes significantly to the "structural zeroes"observed in P. vivax incidence data. Moreover, the differences in P. vivax infection risk associated with the Fy^a/Fy^b polymorphism observed among young participants were attenuated with increasing age, most likely because more susceptible Fy(b+) individuals develop clinical immunity faster than less susceptible Fy(a+) individuals. Conclusions FY polymorphism appears to modulate the rate at which immunity to P. vivax develops in Amazonians, with clear clinical and public health implications.