{"entity": "publication", "iuid": "28a34a109dc24e86a66f6d9edaed4d04", "timestamp": "2026-11-06T19:21:45.341Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/28a34a109dc24e86a66f6d9edaed4d04.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/28a34a109dc24e86a66f6d9edaed4d04"}}, "title": "Cross-Ancestry Genome-Wide Association Study Defines the Extended CYP2D6 Locus as the Principal Genetic Determinant of Endoxifen Plasma Concentrations.", "authors": [{"family": "Khor", "given": "Chiea Chuen", "initials": "CC"}, {"family": "Winter", "given": "Stefan", "initials": "S"}, {"family": "Sutiman", "given": "Natalia", "initials": "N"}, {"family": "M\u00fcrdter", "given": "Thomas E", "initials": "TE"}, {"family": "Chen", "given": "Sylvia", "initials": "S", "orcid": "0000-0002-0445-6502", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5310f9983f7c447b8ccd17d80cb2d4a3.json"}}, {"family": "Lim", "given": "Joanne Siok Liu", "initials": "JSL"}, {"family": "Li", "given": "Zheng", "initials": "Z", "orcid": "0000-0002-7060-2213", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a014baeffa7c4317af45a704a24d17c9.json"}}, {"family": "Li", "given": "Jingmei", "initials": "J", "orcid": "0000-0001-8587-7511", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6027dea1185b4a00a77a6bca138eab20.json"}}, {"family": "Sim", "given": "Kar Seng", "initials": "KS", "orcid": "0000-0002-3822-7759", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7f1c9943279444bfad3e051f04296a71.json"}}, {"family": "Ganchev", "given": "Boian", "initials": "B"}, {"family": "Eccles", "given": "Diana", "initials": "D"}, {"family": "Eccles", "given": "Bryony", "initials": "B"}, {"family": "Tapper", "given": "William", "initials": "W"}, {"family": "Zgheib", "given": "Nathalie K", "initials": "NK", "orcid": "0000-0002-0571-768X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/191f804995e74a6d91b2c3a150be69ee.json"}}, {"family": "Tfayli", "given": "Arafat", "initials": "A"}, {"family": "Ng", "given": "Raymond Chee Hui", "initials": "RCH"}, {"family": "Yap", "given": "Yoon Sim", "initials": "YS"}, {"family": "Lim", "given": "Elaine", "initials": "E"}, {"family": "Wong", "given": "Mabel", "initials": "M"}, {"family": "Wong", "given": "Nan Soon", "initials": "NS"}, {"family": "Ang", "given": "Peter Cher Siang", "initials": "PCS"}, {"family": "Dent", "given": "Rebecca", "initials": "R"}, {"family": "Tremmel", "given": "Roman", "initials": "R", "orcid": "0000-0003-1564-0433", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5dcfb9d17c9340d69ea2c5fcbd06aeec.json"}}, {"family": "Klein", "given": "Kathrin", "initials": "K"}, {"family": "Schaeffeler", "given": "Elke", "initials": "E"}, {"family": "Zhou", "given": "Yitian", "initials": "Y", "orcid": "0000-0003-3066-5444", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c4e92db79d554ad283927ad7e6e54e8d.json"}}, {"family": "Lauschke", "given": "Volker M", "initials": "VM", "orcid": "0000-0002-1140-6204", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/82048d4da61547d08aa9d2bb3bae12dd.json"}}, {"family": "Eichelbaum", "given": "Michel", "initials": "M"}, {"family": "Schwab", "given": "Matthias", "initials": "M", "orcid": "0000-0002-9984-075X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a671991e1b85463e8a7bbad2e29fb1bd.json"}}, {"family": "Brauch", "given": "Hiltrud B", "initials": "HB", "orcid": "0000-0001-7531-2736", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d50df7befe8b45989a8b81d3051004b5.json"}}, {"family": "Chowbay", "given": "Balram", "initials": "B", "orcid": "0000-0003-4775-9877", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a4b56e6cd97f40cd88668603d7c510f6.json"}}, {"family": "Schroth", "given": "Werner", "initials": "W", "orcid": "0000-0003-1412-4592", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/30be50cbd1474b8ebe8a0b31c5b47c91.json"}}], "type": "journal article", "published": "2023-03-00", "journal": {"title": "Clin. Pharmacol. Ther.", "issn": "1532-6535", "volume": "113", "issue": "3", "pages": "712-723", "issn-l": "0009-9236"}, "abstract": "The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (\u03c1 = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.", "doi": "10.1002/cpt.2846", "pmid": "36629403", "labels": {"DDLS Fellow": null, "Yitian Zhou": null}, "xrefs": [], "notes": [], "created": "2026-11-06T09:32:58.404Z", "modified": "2026-11-06T09:32:59.085Z"}