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@ARTICLE{Khor:186728,
      author       = {C. C. Khor and S. Winter and N. Sutiman and T. E. Mürdter
                      and S. Chen and J. S. L. Lim and Z. Li and J. Li and K. S.
                      Sim and B. Ganchev and D. Eccles and B. Eccles and W. Tapper
                      and N. K. Zgheib and A. Tfayli and R. C. H. Ng and Y. S. Yap
                      and E. Lim and M. Wong and N. S. Wong and P. C. S. Ang and
                      R. Dent and R. Tremmel and K. Klein and E. Schaeffeler and
                      Y. Zhou and V. M. Lauschke and M. Eichelbaum and M. Schwab
                      and H. B. Brauch$^*$ and B. Chowbay and W. Schroth},
      title        = {{C}ross-ancestry {GWAS} defines the extended {CYP}2{D}6
                      locus as the principal genetic determinant of endoxifen
                      plasma concentrations.},
      journal      = {Clinical pharmacology $\&$ therapeutics},
      volume       = {113},
      number       = {3},
      issn         = {0009-9236},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DKFZ-2023-00080},
      pages        = {712-723},
      year         = {2023},
      note         = {2023 Mar;113(3):712-723},
      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 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
                      $66\%$ of associated, mostly intergenic variants to be
                      significantly correlated with hepatic CYP2D6 activity or
                      expression (rho=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 to 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
                      non-genetic factors may account for the unexplained portion
                      of variability.},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36629403},
      doi          = {10.1002/cpt.2846},
      url          = {https://inrepo02.dkfz.de/record/186728},
}