TY  - JOUR
AU  - Khor, Chiea Chuen
AU  - Winter, Stefan
AU  - Sutiman, Natalia
AU  - Mürdter, Thomas E
AU  - Chen, Sylvia
AU  - Lim, Joanne Siok Liu
AU  - Li, Zheng
AU  - Li, Jingmei
AU  - Sim, Kar Seng
AU  - Ganchev, Boian
AU  - Eccles, Diana
AU  - Eccles, Bryony
AU  - Tapper, William
AU  - Zgheib, Nathalie K
AU  - Tfayli, Arafat
AU  - Ng, Raymond Chee Hui
AU  - Yap, Yoon Sim
AU  - Lim, Elaine
AU  - Wong, Mabel
AU  - Wong, Nan Soon
AU  - Ang, Peter Cher Siang
AU  - Dent, Rebecca
AU  - Tremmel, Roman
AU  - Klein, Kathrin
AU  - Schaeffeler, Elke
AU  - Zhou, Yitian
AU  - Lauschke, Volker M
AU  - Eichelbaum, Michel
AU  - Schwab, Matthias
AU  - Brauch, Hiltrud B
AU  - Chowbay, Balram
AU  - Schroth, Werner
TI  - Cross-ancestry GWAS defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations.
JO  - Clinical pharmacology & therapeutics
VL  - 113
IS  - 3
SN  - 0009-9236
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DKFZ-2023-00080
SP  - 712-723
PY  - 2023
N1  - 2023 Mar;113(3):712-723
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - pmid:36629403
DO  - DOI:10.1002/cpt.2846
UR  - https://inrepo02.dkfz.de/record/186728
ER  -