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Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We profiled the genetic landscape of <jats:italic>CYP2C8<\/jats:italic> 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 <jats:italic>CYP2C8*2<\/jats:italic> was most common in West and Central Africa with frequencies of 16\u201336.9%, whereas it was rare in Europe and Asia (&lt;\u20092%). In contrast, <jats:italic>CYP2C8*3<\/jats:italic> and <jats:italic>CYP2C8*4<\/jats:italic> were common throughout Europe and the Americas (6.9\u201319.8% for <jats:italic>*3<\/jats:italic> and 2.3\u20137.5% for <jats:italic>*4<\/jats:italic>), but rare in African and East Asian populations. Importantly, we observe pronounced differences (&gt;\u20092.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20\u201360% of individuals in Africa and Europe carry at least one <jats:italic>CYP2C8<\/jats:italic> 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\u2009&lt;\u20092% of East Asian and 8.3\u201312.8% of South and West Asian individuals.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Combined, the presented analyses mapped the genetic and inferred functional variability of <jats:italic>CYP2C8<\/jats:italic> with high ethnogeographic resolution. These results can serve as a valuable resource for <jats:italic>CYP2C8<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40246-024-00610-y","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T08:02:03Z","timestamp":1713772923000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences"],"prefix":"10.1186","volume":"18","author":[{"given":"Mahamadou D.","family":"Camara","sequence":"first","affiliation":[]},{"given":"Yitian","family":"Zhou","sequence":"additional","affiliation":[]},{"given":"Ta\u00eds N\u00f3brega","family":"De Sousa","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 P.","family":"Gil","sequence":"additional","affiliation":[]},{"given":"Abdoulaye A.","family":"Djimde","sequence":"additional","affiliation":[]},{"given":"Volker M.","family":"Lauschke","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"key":"610_CR1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.clpt.2004.12.267","volume":"77","author":"RA Totah","year":"2005","unstructured":"Totah RA, Rettie AE. 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