{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:17:57Z","timestamp":1784780277329,"version":"3.55.0"},"reference-count":52,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,4]]},"abstract":"\n Pharmacogenomic research has historically focused on individuals of European ancestry, leading to the underrepresentation of genetic variants common in non\u2010European populations. This bias is exemplified by\n CYP3A5<\/jats:italic>\n *6, a functionally consequential variant common in individuals of African ancestry (MAF: 11\u201319%) but virtually absent in Europeans (MAF: 0.15%). We conducted a retrospective, longitudinal cohort study using real\u2010world data from 1,461 adult kidney transplant recipients across 67 countries, analyzing 4,293 dose\u2010normalized 24\u2010hour area\u2010under\u2010the\u2010curve (AUC\n 0\u201024<\/jats:sub>\n ) measurements of tacrolimus. Patients with\n CYP3A5*<\/jats:italic>\n 1\/*1 were excluded. Linear mixed\u2010effects models (LME) were used to assess the association between\n CYP3A5*<\/jats:italic>\n 6 carriage and tacrolimus exposure, adjusting for clinical factors and ancestry using both HLA\u2010based principal components and country of birth.\n CYP3A5<\/jats:italic>\n *6 carriers had a 17% lower dose\u2010normalized AUC\n 0\u201024<\/jats:sub>\n than\n CYP3A5<\/jats:italic>\n *3 carriers (\n P<\/jats:italic>\n \u2009=\u20090.015). Sensitivity analyses using dose\u2010normalized trough concentrations (C\n 0<\/jats:sub>\n ) confirmed these findings, with a 20% lower exposure in\n CYP3A5<\/jats:italic>\n *6 carriers (\n P<\/jats:italic>\n \u2009=\u20090.011). An interval\u2010based analysis demonstrated persistently lower tacrolimus exposure across the first post\u2010transplant year. All\n CYP3A5<\/jats:italic>\n *6\u2010containing genotypes showed significantly lower dose\u2010normalized AUC\n 0\u201024<\/jats:sub>\n compared to\n CYP3A5<\/jats:italic>\n *3\/*3, the most common genotype in European populations, with the largest reductions observed in\n CYP3A5<\/jats:italic>\n *1\/*6 (\u221239%;\n P<\/jats:italic>\n \u2009<\u20090.001) and\n CYP3A5<\/jats:italic>\n *3\/*6 (\u221218%;\n P<\/jats:italic>\n \u2009=\u20090.006). African origin, defined by country of birth, was independently associated with a 23% higher AUC\n 0\u201024<\/jats:sub>\n (\n P<\/jats:italic>\n \u2009<\u20090.001). This is the first study to demonstrate a differential effect on tacrolimus exposure between the\n CYP3A5<\/jats:italic>\n *6 and\n CYP3A5<\/jats:italic>\n *3 loss\u2010of\u2010function alleles. Our results may help bridge the ethnicity gap, advance the applicability of pharmacogenomic findings, and promote health equity.\n <\/jats:p>","DOI":"10.1002\/cpt.70162","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T06:56:38Z","timestamp":1766472998000},"page":"942-952","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lower Dose\u2010Normalized Tacrolimus Exposure in\n CYP3A5<\/i>\n *6 vs. *3 Loss\u2010of\u2010Function Allele Carriers: A Longitudinal Retrospective Real\u2010World Study in Kidney Transplant Recipients"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-4693","authenticated-orcid":false,"given":"Amar D.","family":"Levens","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3219-253X","authenticated-orcid":false,"given":"Dirk Jan A. R.","family":"Moes","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick","family":"Boer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-3595","authenticated-orcid":false,"given":"Aiko P. J.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Transplant Center Leiden University Medical Center Leiden The Netherlands"},{"name":"Transplant Center Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2206-3929","authenticated-orcid":false,"given":"Dorottya K.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Transplant Center Leiden University Medical Center Leiden The Netherlands"},{"name":"Department of Surgery, Transplant Center Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8227-3998","authenticated-orcid":false,"given":"Danny","family":"van der Helm","sequence":"additional","affiliation":[{"name":"Transplant Center Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7694-8381","authenticated-orcid":false,"given":"Soufian","family":"Meziyerh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Transplant Center Leiden University Medical Center Leiden The Netherlands"},{"name":"Transplant Center Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-1193","authenticated-orcid":false,"given":"Dave L.","family":"Roelen","sequence":"additional","affiliation":[{"name":"Department of Immunology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9108-9212","authenticated-orcid":false,"given":"Stefan","family":"B\u00f6hringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"},{"name":"Department of Medical Statistics and Bioinformatics Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5980-6947","authenticated-orcid":false,"given":"Teun","family":"Van Gelder","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-5552","authenticated-orcid":false,"given":"Jesse J.","family":"Swen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00572-8"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14983"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-024-00794-y"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01672-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1491"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-121323-104008"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.78"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.113"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(03)00168-1"},{"key":"e_1_2_9_10_1","first-page":"23","article-title":"CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment","volume":"11","author":"Chen L.","year":"2018","journal-title":"Pharmgenomics Pers Med."},{"key":"e_1_2_9_11_1","unstructured":"Royal Dutch Pharmacists Association (KNMP).CYP3A5: Royal Dutch Pharmacists Association (KNMP) (2020)."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1016"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000640"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41397-024-00349-8"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/14622416.2024.2370761"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.63.s83.25.x"},{"key":"e_1_2_9_17_1","first-page":"119","article-title":"Kidney diseases in Africa: aetiological considerations, peculiarities and burden","volume":"41","author":"Okunola O.","year":"2012","journal-title":"Afr. 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