Genetic relatedness of Cambodian Plasmodium falciparum isolates is driven by geography and occupation

Abstract

Background: Cambodia is nearing Plasmodium falciparum elimination, but targeted interventions are needed to prevent resurgence. Identity-by-descent (IBD)-based methods offer insight into parasite relatedness and transmission dynamics.

Methods: We estimated pairwise genetic relatedness between 107 P. falciparum isolates collected from military personnel and farmers in Cambodia between 2014 and 2016. All isolates underwent whole genome sequencing. Relatedness was defined as the proportion of the genome shared IBD between isolates. We evaluated associations between relatedness and epidemiologic factors, including occupation, location, time, age, and sex. Infomap community detection was used to identify clusters of highly related parasites and their association with covariates.

Results: Mean IBD sharing was high (40%), with greater relatedness among isolates from Oddar Meanchey than from Kratie province (p<2.2e-16). Within Oddar Meanchey, isolates from individuals with different occupations shared 7.2% less of their genome IBD than farmer pairs (probability of direction (pd)=99.9), after adjusting for age. Highly related clusters (>90% IBD) were associated with occupation, K13 mutation (C580Y vs. R539T), and PfCRT mutation (p= 0.0025, 0.0001, and 0.0001, respectively). Isolates from mixed-occupation pairs had lower odds of high relatedness (>90% IBD) than pairs from farmers (pd=0.958).

Conclusions: High overall IBD sharing may reflect a combination of recent elimination efforts and expansion of drug-resistant lineages. Substantial differences in relatedness between provinces underscore the role of geography in shaping relatedness patterns. Lower relatedness among mixed-occupation pairs compared to farmer pairs suggests potential occupation-specific transmission sources and supports tailoring interventions to local micro-epidemiologic factors.

Figure 1.

Highly Related Parasite Clusters and Associated Epidemiologic and Genetic Factors in Oddar Meanchey Province (0.90 IBD Threshold). Infomap network analysis identifies seven highly related parasite populations in Oddar Meanchey Province ranging from 2–22 members. A. The network graph shows parasite clusters, with colored nodes representing clonal populations and grey nodes representing unclustered isolates. (B–F) Bar plots show cluster membership among isolates in clusters with ≥2 isolates (panel A grey isolates excluded) by: B. Occupation, C. Transmission season, D. K13 resistance marker, E. Pfpm2 copy number classification, and F. PfCRT mutation. Each bar color corresponds to a cluster. p-values were calculated using MCMC approximate Fisher’s exact tests.