Genetic diversity of the Duffy antigen/receptor for chemokines gene and its susceptibility to zoonotic malaria in non-human primates and Indonesian populations

Background and Aim: Zoonotic malaria caused by Plasmodium knowlesi presents a growing public health challenge in Southeast Asia. Host genetic factors, particularly polymorphisms in the Duffy antigen/receptor for chemokines (DARC), may influence susceptibility to zoonotic transmission. Indonesia’s vast ethnic and ecological diversity offers a unique context to explore the genetic interface between human and non-human primate (NHP) hosts and zoonotic malaria. This study aimed to investigate the genetic diversity of the DARC gene in sympatric human and NHP populations across Indonesia and its potential role in modulating susceptibility to zoonotic malaria. Materials and Methods: A cross-sectional survey was conducted in Sabang (Aceh), Palangkaraya (Central Kalimantan), and North Buton (Southeast Sulawesi). Dried blood spots were collected from 68 NHPs and 363 humans. DARC promoter and coding regions were amplified through polymerase chain reaction, sequenced, and analyzed using bioinformatic tools. Phylogenetic analyses and allele-specific comparisons were performed to assess cross-species genetic similarity and regional variation in DARC alleles. Results: No −46T>C promoter single-nucleotide polymorphism associated with Duffy negativity was found in either humans or NHPs. Three genotypic forms – FYA, FYB, and FYA/FYB – were observed in human populations, with FYA being predominant in Kalimantan and Sulawesi. Notably, individuals with the FYA allele in Aceh, a region with high P. knowlesi incidence, were less likely to have an infection, suggesting a potential protective role. All NHPs carried the FY*B allele. Comparative analyses revealed high DARC sequence homology between humans and NHPs, particularly Macaca fascicularis and Macaca brunnescens, implicating molecular compatibility in zoonotic transmission dynamics. Conclusion: This is the first comprehensive study to assess DARC gene polymorphisms in both human and NHP populations in Indonesia within the context of zoonotic malaria. The findings underscore the significance of host genetic variation in mediating susceptibility to P. knowlesi and highlight regional allele profiles as potential markers for risk stratification. These insights provide a genomic framework to inform surveillance and control strategies in malaria-endemic regions vulnerable to zoonotic transmission. Keywords: DARC gene, genetic polymorphism, host-pathogen interaction, Indonesia, malaria susceptibility, nonhuman primates, Plasmodium knowlesi, zoonotic malaria.