Multivariate Statistical Analysis of the Genetic Diversity of <i>Plasmodium </i><i>falciparum</i> Isolates from Individuals Carrying the Major or Minor Sickle Cell Trait (HBAA, HBAS, and HBSS) in Abidjan (Côte d&#

In malaria-endemic areas, the relatively high probability of hemoglobinopathies, especially sickle cell disease, raises important questions regarding the evolutionary interactions between host hemoglobin genotype and adaptive dynamics of Plasmodium falciparum. In fact, while the protection provided by heterozygous genotypic HbAS against malaria-resistant forms is now well established, the impact on the genetic structuring of parasitic populations remains relatively poorly understood. To do this, we carried out, as part of an exploratory approach, a population genomics analysis on 30 clinical isolates of P. falciparum from individuals of the HbAA, HbAS and HbSS genotypes in Côte d’Ivoire. Next-generation sequencing (NGS) data were analyzed using principal component analysis (PCA), permuted analysis of variance (PERMANOVA), and Jost differentiation index (JOST’D) to assess genetic deviations. Coding and non-coding SNPs were then functionally annotated to identify evolutionary adaptation signatures. Genetic analyses show a significant structuring of isolates according to the hemoglobin genotype of the host, with moderate to strong differentiation between parasites from HbAS compared to those from homozygotes HbAA and HbSS. Discriminating SNPs are contained in genes associated with erythrocyte invasion, immune escape (clag3.2, acs7, rh5, var2csa, PfEMP1), as well as intergenic regions potentially involved in transcriptional regulation. Thus, this study validates an exploratory method to identify differentially expressed mutations according to sickle cell traits and supports the idea of the genetic adaptation of the parasite, controlled by the hemoglobin status of the patient. Moreover, the impact of the erythrocyte environment on the variability of the P. falciparum genome has been highlighted. The data here opens the door to a suite of studies aimed at deepening the functional assessment of mutations and justifying the integration of hemoglobinopathies into the malaria control strategy in endemic regions. The results of this exploratory study will be consolidated by a larger print run of the DREPAL project (DREpanocytosis PALudism), promoted by the paludology mycology unit of the Institut Pasteur de Côte d’Ivoire.