Pharmacogenomics of antimalarial drugs

Malaria continues to be a major public health issue in sub-Saharan Africa, with significant variability in treatment outcomes among individuals, largely due to host pharmacogenomic factors. Nonetheless, there are substantial gaps in understanding the population-specific genetic factors that influence antimalarial drug responses in high-burden, underrepresented areas like Mali. This doctoral thesis aims to fill these gaps through a comprehensive pharmacogenomic approach, combining global analyses with targeted studies within the Malian population to better understand the genetic basis of differences in the effectiveness and safety of key artemisinin-based combination therapies. Initial worldwide analyses showed significant ethno-geographic differences in the distribution of pharmacogenes. A meta-analysis of the ethno-geographic differences of CYP2C8 revealed a high occurrence of the reduced-function CYP2C8*2 allele in Africa, while CYP2C8*3 was more common in Europeans. Additionally, studies of the UDP-glycosyltransferase (UGT) superfamily and the KCNH2 gene, which encodes the hERG channel, showed substantial population- specific variation, affecting drug metabolism and cardiotoxicity risk. The creation of the PharmFreq database highlighted these global disparities, emphasizing the notable underrepresentation of African populations in pharmacogenomic research. Whole-exome sequencing of 95 Malian individuals revealed a population-specific pharmacogenomic profile. Mali showed a high prevalence of functionally important pharmacogenetic alleles, including CYP2C8*2 (14.2%), CYP3A5*1 (74.7%), and CYP2B6*6 (12.6%), which influence metabolic responses to drugs such as amodiaquine, lumefantrine, and efavirenz. Additionally, significant frequencies of variants in GSTP1, NQO1, and G6PD contributed to a complex landscape of risks related to drug toxicity and effectiveness. Third, targeted clinical studies within the WANECAM trial cohort confirmed functional validation. The CYP2C8*2 allele was linked to a 67% increase in desethylamodiaquine levels after repeated artesunate-amodiaquine treatment, explaining gastrointestinal intolerance and treatment discontinuation during Seasonal Malaria Chemoprevention (SMC). Regarding dihydroartemisinin- piperaquine, common synonymous variants in KCNH2, such as rs1805121, were associated with longer QTc intervals, indicating population-specific genetic susceptibility to cardiotoxicity independent of piperaquine levels. Ultimately, the integration of genetic frequency data with national drug utilization provided insights into the public health impact. It was estimated that about 130,000 children in Mali's SMC program are poor metabolizers of amodiaquine. Additionally, more than 1.35 million malaria cases each year involve individuals with genetic traits that make them more likely to have suboptimal lumefantrine exposure. This risk is heightened when efavirenz is used simultaneously. In conclusion, this thesis fills an important knowledge gap between population genetics and antimalarial treatment outcomes in Mali. It shows that pharmacogenomic variation is organized and has significant clinical effects, offering a scientific basis for improving drug use with precision public health approaches. The results support incorporating pharmacogenomic data into malaria control efforts to improve effectiveness, safety, and equity in high-burden African regions List of scientific papers I. Camara MD, Zhou Y, Dara A, Tékété MM, Nóbrega de Sousa T, Sissoko S, Dembélé L, Ouologuem N, Hamidou Togo A, Alhousseini ML, Fofana B, Sagara I, Djimde AA, Gil PJ, Lauschke VM. Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy. Antimicrob Agents Chemother. 2024 May 2;68(5):e0139023. doi: https://doi.org/10.1128/aac.01390-23. Epub 2024 Mar 28. PMID: 38546223; PMCID: PMC11064487. II. Camara MD, Zhou Y, De Sousa TN, Gil JP, Djimde AA, Lauschke VM. Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences. Hum Genomics. 2024 Apr 22;18(1):40. doi: https://doi.org/10.1186/s40246-024-00610-y. PMID: 38650020; PMCID: PMC11034136. III. Camara MD, Tekete MM, Dama S, De Sousa TN, Djimde M, Dara A, Doumdo O, Lauschke VM, Borrmann S, Djimde AA, Gil PJ. Tentative title: CYP2C8*2 impacts desethylamodiaquine concentration upon repeated artesunate-amodiaquine treatment of uncomplicated malaria in Mali. [Manuscript] IV. González-Padilla D, Camara MD, Lauschke VM, Zhou Y. Population-scale variability of the human UDP- glycosyltransferase gene family. J Genet Genomics. 2024 Nov;51(11):1228-1236. doi: https://doi.org/10.1016/j.jgg.2024.06.018. Epub 2024 Jul 4. PMID: 38969258. V. Tremmel R, Zhou Y, Camara MD, Laarif S, Eliasson E, Lauschke VM. PharmFreq: a comprehensive atlas of ethnogeographic allelic variation in clinically important pharmacogenes. Nucleic Acids Res. 2025 Jan 6;53(D1):D1498-D1509. doi: https://doi.org/10.1093/nar/gkae1016. PMID: 39540424; PMCID: PMC11701539. VI. Camara MD, Zhou Y, Park Y, De Sousa TN, Tékété MM, Dara A, Sissoko S, Dembele L, Lauschke VM, Gil PJ, Djimde AA. Tentative title: Foundation for personalized medicine in Malian population. [Manuscript]