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https://www.arca.fiocruz.br/handle/icict/64316
META-ANALYSIS OF THE GLOBAL DISTRIBUTION OF CLINICALLY RELEVANT CYP2C8 ALLELES AND THEIR INFERRED FUNCTIONAL CONSEQUENCES.
Amodiaquine
Drug metabolism
Pharmacogenetics
Precision medicine
Seasonal malaria chemoprevention
Author
Affilliation
Department of Physiology and Pharmacology. Karolinska Institutet. Stockholm, Sweden/Malaria Research and Training Center. Department of Epidemiology of Parasitic Diseases. Faculty of Pharmacy. University of Science, Techniques and Technologies. Bamako, Mali.
Department of Physiology and Pharmacology. Karolinska Institutet. Stockholm, Sweden
Department of Microbiology and Tumor Cell Biology. Karolinska Institutet. Stockholm, Sweden/ Molecular Biology and Malaria Immunology Research Group. René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil.
Department of Microbiology and Tumor Cell Biology. Karolinska Institutet. Stockholm, Sweden/ Institute of Hygiene and Tropical Medicine. Global Health and Tropical Medicine. Nova University of Lisbon. Lisbon, Portugal.
Malaria Research and Training Center. Department of Epidemiology of Parasitic Diseases. Faculty of Pharmacy. University of Science, Techniques and Technologies. Bamako, Mali.
Department of Physiology and Pharmacology. Karolinska Institutet. Stockholm, Sweden/ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology. Stuttgart, Germany/University of Tübingen. Tübingen, Germany.
Department of Physiology and Pharmacology. Karolinska Institutet. Stockholm, Sweden
Department of Microbiology and Tumor Cell Biology. Karolinska Institutet. Stockholm, Sweden/ Molecular Biology and Malaria Immunology Research Group. René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil.
Department of Microbiology and Tumor Cell Biology. Karolinska Institutet. Stockholm, Sweden/ Institute of Hygiene and Tropical Medicine. Global Health and Tropical Medicine. Nova University of Lisbon. Lisbon, Portugal.
Malaria Research and Training Center. Department of Epidemiology of Parasitic Diseases. Faculty of Pharmacy. University of Science, Techniques and Technologies. Bamako, Mali.
Department of Physiology and Pharmacology. Karolinska Institutet. Stockholm, Sweden/ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology. Stuttgart, Germany/University of Tübingen. Tübingen, Germany.
Abstract
Background: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates.
Results: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals.
Conclusions: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.
Keywords
Allele frequencyAmodiaquine
Drug metabolism
Pharmacogenetics
Precision medicine
Seasonal malaria chemoprevention
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