Katarzyna Drozda1, Shan Wong, Shitalben R Patel, Adam P Bress, Edith A Nutescu, Rick A Kittles, Larisa H Cavallari. 1. Departments of aPharmacy Practice bPharmacy Systems, Outcomes and Policy cCenter for Pharmacoepidemiology and Pharmacoeconomic Research dDepartment of Medicine, Section of Hematology and Oncology, University of Illinois at Chicago, Chicago, Illinois eDepartment of Pharmacotherapy and Translational Research, University of Florida at Gainesville, Gainesville, Florida, USA.
Abstract
OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. METHODS: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. RESULTS: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. CONCLUSION: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.
OBJECTIVES: Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype affects performance of dosing algorithms in African Americans. METHODS: In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G > A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. RESULTS: The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02-2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6-2.8) mg/day in rs12777823 variant homozygotes (P = 0.004), and 2.2 (0.5-2.9) mg/day in carriers of a CYP2C9 variant (P < 0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P < 0.001) and overdosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P = 0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P < 0.01) or IWPC (P < 0.01) algorithm. CONCLUSION: These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.
Authors: Nita A Limdi; Donna K Arnett; Joyce A Goldstein; T Mark Beasley; Gerald McGwin; Brian K Adler; Ronald T Acton Journal: Pharmacogenomics Date: 2008-05 Impact factor: 2.533
Authors: Mitchell K Higashi; David L Veenstra; L Midori Kondo; Ann K Wittkowsky; Sengkeo L Srinouanprachanh; Fred M Farin; Allan E Rettie Journal: JAMA Date: 2002-04-03 Impact factor: 56.272
Authors: Mia Wadelius; Leslie Y Chen; Jonatan D Lindh; Niclas Eriksson; Mohammed J R Ghori; Suzannah Bumpstead; Lennart Holm; Ralph McGinnis; Anders Rane; Panos Deloukas Journal: Blood Date: 2008-06-23 Impact factor: 22.113
Authors: Gregory M Cooper; Julie A Johnson; Taimour Y Langaee; Hua Feng; Ian B Stanaway; Ute I Schwarz; Marylyn D Ritchie; C Michael Stein; Dan M Roden; Joshua D Smith; David L Veenstra; Allan E Rettie; Mark J Rieder Journal: Blood Date: 2008-06-05 Impact factor: 22.113
Authors: Andrea R Redman; Leslie J Dickmann; Robert S Kidd; Joyce A Goldstein; Denise M Ritchie; Yuen Yi Hon Journal: Clin Appl Thromb Hemost Date: 2004-04 Impact factor: 2.389
Authors: N A Limdi; G McGwin; J A Goldstein; T M Beasley; D K Arnett; B K Adler; M F Baird; R T Acton Journal: Clin Pharmacol Ther Date: 2007-07-25 Impact factor: 6.875
Authors: B F Gage; C Eby; J A Johnson; E Deych; M J Rieder; P M Ridker; P E Milligan; G Grice; P Lenzini; A E Rettie; C L Aquilante; L Grosso; S Marsh; T Langaee; L E Farnett; D Voora; D L Veenstra; R J Glynn; A Barrett; H L McLeod Journal: Clin Pharmacol Ther Date: 2008-02-27 Impact factor: 6.875
Authors: Victoria M Pratt; Larisa H Cavallari; Andria L Del Tredici; Houda Hachad; Yuan Ji; Ann M Moyer; Stuart A Scott; Michelle Whirl-Carrillo; Karen E Weck Journal: J Mol Diagn Date: 2019-05-08 Impact factor: 5.568
Authors: K Kubo; M Ohara; M Tachikawa; L H Cavallari; M T M Lee; M S Wen; M G Scordo; E A Nutescu; M A Perera; A Miyajima; N Kaneko; V Pengo; R Padrini; Y T Chen; H Takahashi Journal: Pharmacogenomics J Date: 2016-08-09 Impact factor: 3.550
Authors: Matthew G McDonald; Lindsay M Henderson; Sutapa Ray; Catherine K Yeung; Amanda L Johnson; John P Kowalski; Helmut Hanenberg; Constanze Wiek; Kenneth E Thummel; Allan E Rettie Journal: J Pharmacol Exp Ther Date: 2020-05-18 Impact factor: 4.030
Authors: Laura K Wiley; Jacob P Vanhouten; David C Samuels; Melinda C Aldrich; Dan M Roden; Josh F Peterson; Joshua C Denny Journal: Pac Symp Biocomput Date: 2017
Authors: Victoria M Pratt; Larisa H Cavallari; Andria L Del Tredici; Houda Hachad; Yuan Ji; Lisa V Kalman; Reynold C Ly; Ann M Moyer; Stuart A Scott; Michelle Whirl-Carrillo; Karen E Weck Journal: J Mol Diagn Date: 2020-05-04 Impact factor: 5.568
Authors: Karen E Wells; Sonia Cajigal; Edward L Peterson; Brian K Ahmedani; Rajesh Kumar; David E Lanfear; Esteban G Burchard; L Keoki Williams Journal: J Allergy Clin Immunol Date: 2016-03-22 Impact factor: 10.793
Authors: Minami Ohara; Yasuhiko Suzuki; Saki Shinohara; Inna Y Gong; Crystal L Schmerk; Rommel G Tirona; Ute I Schwarz; Ming-Shien Wen; Ming Ta Michael Lee; Kiyoshi Mihara; Edith A Nutescu; Minoli A Perera; Larisa H Cavallari; Richard B Kim; Harumi Takahashi Journal: Clin Pharmacokinet Date: 2019-08 Impact factor: 6.447