Cross-ancestry genome-wide association study defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations
Cross-ancestry genome-wide association study defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations
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 (ρ = 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.
712-723
Khor, Chiea Chuen
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Winter, Stefan
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Sutiman, Natalia
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Mürdter, Thomas E
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Chen, Sylvia
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Lim, Joanne Siok Liu
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Li, Zheng
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Li, Jingmei
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Sim, Kar Seng
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Ganchev, Boian
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Eccles, Diana
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Eccles, Bryony
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Tapper, William
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Zgheib, Nathalie K
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Tfayli, Arafat
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Ng, Raymond Chee Hui
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Yap, Yoon Sim
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Lim, Elaine
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Wong, Mabel
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Wong, Nan Soon
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Ang, Peter Cher Siang
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Dent, Rebecca
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Tremmel, Roman
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Klein, Kathrin
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Schaeffeler, Elke
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Zhou, Yitian
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Lauschke, Volker M
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Eichelbaum, Michel
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Schwab, Matthias
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Brauch, Hiltrud B
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Chowbay, Balram
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Schroth, Werner
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March 2023
Khor, Chiea Chuen
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Winter, Stefan
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Sutiman, Natalia
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Mürdter, Thomas E
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Chen, Sylvia
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Lim, Joanne Siok Liu
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Li, Zheng
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Li, Jingmei
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Sim, Kar Seng
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Ganchev, Boian
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Eccles, Diana
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Eccles, Bryony
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Tapper, William
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Zgheib, Nathalie K
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Tfayli, Arafat
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Ng, Raymond Chee Hui
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Yap, Yoon Sim
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Lim, Elaine
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Wong, Mabel
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Wong, Nan Soon
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Ang, Peter Cher Siang
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Dent, Rebecca
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Tremmel, Roman
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Klein, Kathrin
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Schaeffeler, Elke
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Zhou, Yitian
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Lauschke, Volker M
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Eichelbaum, Michel
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Schwab, Matthias
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Brauch, Hiltrud B
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Chowbay, Balram
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Schroth, Werner
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Khor, Chiea Chuen, Winter, Stefan, Sutiman, Natalia, Mürdter, Thomas E, Chen, Sylvia, Lim, Joanne Siok Liu, Li, Zheng, Li, Jingmei, Sim, Kar Seng, Ganchev, Boian, Eccles, Diana, Eccles, Bryony, Tapper, William, Zgheib, Nathalie K, Tfayli, Arafat, Ng, Raymond Chee Hui, Yap, Yoon Sim, Lim, Elaine, Wong, Mabel, Wong, Nan Soon, Ang, Peter Cher Siang, Dent, Rebecca, Tremmel, Roman, Klein, Kathrin, Schaeffeler, Elke, Zhou, Yitian, Lauschke, Volker M, Eichelbaum, Michel, Schwab, Matthias, Brauch, Hiltrud B, Chowbay, Balram and Schroth, Werner
(2023)
Cross-ancestry genome-wide association study defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations.
Clinical Pharmacology and Therapeutics, 113 (3), .
(doi:10.1002/cpt.2846).
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 (ρ = 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.
Text
Clin Pharma and Therapeutics - 2023 - Khor - Cross‐Ancestry Genome‐Wide Association Study Defines the Extended CYP2D6 Locus
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Accepted/In Press date: 23 December 2022
e-pub ahead of print date: 11 January 2023
Published date: March 2023
Additional Information:
Funding Information:
This study was supported by the National Medical Research Council Singapore (NMRC/1159/2008, NMRCB1011, NRFCG1516, NMRCG13163, NMRC/CIRG/1423/2015 and MOH‐000377) grants and the National Research Foundation of Singapore grants (NRF‐NRFI2018‐01 and NRF‐NRFF2017‐02). Additional funding was provided by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore and the Horizon 2020‐PHC‐2015 grant U‐PGx 668353. German funding resources include: Robert Bosch Foundation, Stuttgart, Germany, German Federal Ministry of Education and Research (BMBF 01ZP0502); the German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 72074 Tübingen, Germany, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy‐EXC 2180‐390900677 and EXC 2064/1‐390727645 as well as the DFG grants SCHR 1323/2‐1 and MU 1727/2‐1, and the Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA) University of Tübingen.
Funding Information:
This study was supported by the National Medical Research Council Singapore (NMRC/1159/2008, NMRCB1011, NRFCG1516, NMRCG13163, NMRC/CIRG/1423/2015 and MOH-000377) grants and the National Research Foundation of Singapore grants (NRF-NRFI2018-01 and NRF-NRFF2017-02). Additional funding was provided by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore and the Horizon 2020-PHC-2015 grant U-PGx 668353. German funding resources include: Robert Bosch Foundation, Stuttgart, Germany, German Federal Ministry of Education and Research (BMBF 01ZP0502); the German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 72074 Tübingen, Germany, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2180-390900677 and EXC 2064/1-390727645 as well as the DFG grants SCHR 1323/2-1 and MU 1727/2-1, and the Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA) University of Tübingen. Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Identifiers
Local EPrints ID: 475204
URI: http://eprints.soton.ac.uk/id/eprint/475204
ISSN: 0009-9236
PURE UUID: 40edd222-c37a-4afa-9754-91006e3c1ef1
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Date deposited: 14 Mar 2023 17:33
Last modified: 15 Aug 2024 01:36
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Contributors
Author:
Chiea Chuen Khor
Author:
Stefan Winter
Author:
Natalia Sutiman
Author:
Thomas E Mürdter
Author:
Sylvia Chen
Author:
Joanne Siok Liu Lim
Author:
Zheng Li
Author:
Jingmei Li
Author:
Kar Seng Sim
Author:
Boian Ganchev
Author:
Bryony Eccles
Author:
Nathalie K Zgheib
Author:
Arafat Tfayli
Author:
Raymond Chee Hui Ng
Author:
Yoon Sim Yap
Author:
Elaine Lim
Author:
Mabel Wong
Author:
Nan Soon Wong
Author:
Peter Cher Siang Ang
Author:
Rebecca Dent
Author:
Roman Tremmel
Author:
Kathrin Klein
Author:
Elke Schaeffeler
Author:
Yitian Zhou
Author:
Volker M Lauschke
Author:
Michel Eichelbaum
Author:
Matthias Schwab
Author:
Hiltrud B Brauch
Author:
Balram Chowbay
Author:
Werner Schroth
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