%0 Journal Article
%A Khor, Chiea Chuen
%A Winter, Stefan
%A Sutiman, Natalia
%A Mürdter, Thomas E
%A Chen, Sylvia
%A Lim, Joanne Siok Liu
%A Li, Zheng
%A Li, Jingmei
%A Sim, Kar Seng
%A Ganchev, Boian
%A Eccles, Diana
%A Eccles, Bryony
%A Tapper, William
%A Zgheib, Nathalie K
%A Tfayli, Arafat
%A Ng, Raymond Chee Hui
%A Yap, Yoon Sim
%A Lim, Elaine
%A Wong, Mabel
%A Wong, Nan Soon
%A Ang, Peter Cher Siang
%A Dent, Rebecca
%A Tremmel, Roman
%A Klein, Kathrin
%A Schaeffeler, Elke
%A Zhou, Yitian
%A Lauschke, Volker M
%A Eichelbaum, Michel
%A Schwab, Matthias
%A Brauch, Hiltrud B
%A Chowbay, Balram
%A Schroth, Werner
%T Cross-ancestry GWAS defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations.
%J Clinical pharmacology & therapeutics
%V 113
%N 3
%@ 0009-9236
%C Hoboken, NJ
%I Wiley-Blackwell
%M DKFZ-2023-00080
%P 712-723
%D 2023
%Z 2023 Mar;113(3):712-723
%X 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 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-Mb region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and 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
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36629403
%R 10.1002/cpt.2846
%U https://inrepo02.dkfz.de/record/186728