Malaria-Related Host Genetic Variation in an Endemic Population of Southern Senegal

Host genetic variation is a key determinant of malaria susceptibility, particularly in endemic regions where intense transmission has driven strong selective pressures on red blood cell-related genes. However, Senegalese and other African populations remain underrepresented in genomic studies, limiting population-specific inference. We analyzed malaria-related host genetic variants in 140 febrile patients from southern and south-eastern Senegal, focusing on key loci (ACKR1, Dantu blood group, HBB and G6PD) and on composite Multilocus Genotype Profiles (MGPs). We described the co-occurrence of the variants within individuals, allowing exploratory assessment of combined genetic architectures. We identified both well-established malaria-protective variants, including the Duffy-negative Fy(a-b-) phenotype (observed in all individuals), G6PD key variants (e.g., G202A with an allelic frequency of ~3%, A376G at ~40%, T968C at ~1%), and HBB variants (HbS at ~7% and HbC at ~1%), as well as some rare and less characterized polymorphisms. To the best of our knowledge, this study provides the first description in the Senegalese population of the Dantu variant (rs186873296) and the rare ACKR1 rs577808287 variant, each observed in 2 distinct individuals. Five major composite MGPs across the four loci were predominantly observed and together represented more than 75% of individuals. Excluding Duffy status, most of these profiles included at least one variant previously reported in the literature as malaria-protective, a pattern consistent with the hypothesis of malaria-driven balancing selection, despite the presence of potentially deleterious alleles. This study highlights substantial genetic heterogeneity in malaria-relevant host genes in Senegal and demonstrates the value of integrating composite genetic architectures into malaria research. These findings provide population-specific data that are critical for improving malaria risk assessment, clinical interpretation, and public health strategies in endemic regions. Moreover, the relatively high frequencies of some variants may reflect balancing selection, possibly partially driven by the adaptive benefits they confer in populations exposed to malaria.