Esteban J Parra1, Mariana R Botton2, Jamila A Perini3, S Krithika1, Stephane Bourgeois4, Todd A Johnson5, Tatsuhiko Tsunoda5, Munir Pirmohamed6, Mia Wadelius7, Nita A Limdi8, Larisa H Cavallari9, James K Burmester10, Allan E Rettie11, Teri E Klein12, Julie A Johnson9, Mara H Hutz2, Guilherme Suarez-Kurtz3. 1. Department of Anthropology, University of Toronto at Mississauga, ON, Canada. 2. Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 3. Pharmacology Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. 4. William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, UK. 5. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Japan. 6. Department of Molecular & Clinical Pharmacology, University of Liverpool, UK. 7. Department of Medical Sciences, Clinical Pharmacology & Science for Life Laboratory, Uppsala University, Sweden. 8. Department of Neurology, University of Alabama at Birmingham, AL, USA. 9. University of Florida, Department of Pharmacotherapy & Translational Research, FL, USA. 10. Clinical Research Center, Marshfield Clinic Research Foundation, WI, USA. 11. Department Medicinal Chemistry, School of Pharmacy, University of Washington, WA, USA. 12. Department of Genetics, Stanford University School of Medicine, CA, USA.
Abstract
AIM: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. METHODS: Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. RESULTS: Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. CONCLUSION: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.
AIM: Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. METHODS: Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. RESULTS: Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. CONCLUSION: We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.
Authors: P Lenzini; M Wadelius; S Kimmel; J L Anderson; A L Jorgensen; M Pirmohamed; M D Caldwell; N Limdi; J K Burmester; M B Dowd; P Angchaisuksiri; A R Bass; J Chen; N Eriksson; A Rane; J D Lindh; J F Carlquist; B D Horne; G Grice; P E Milligan; C Eby; J Shin; H Kim; D Kurnik; C M Stein; G McMillin; R C Pendleton; R L Berg; P Deloukas; B F Gage Journal: Clin Pharmacol Ther Date: 2010-04-07 Impact factor: 6.875
Authors: Stephen E Kimmel; Benjamin French; Scott E Kasner; Julie A Johnson; Jeffrey L Anderson; Brian F Gage; Yves D Rosenberg; Charles S Eby; Rosemary A Madigan; Robert B McBane; Sherif Z Abdel-Rahman; Scott M Stevens; Steven Yale; Emile R Mohler; Margaret C Fang; Vinay Shah; Richard B Horenstein; Nita A Limdi; James A S Muldowney; Jaspal Gujral; Patrice Delafontaine; Robert J Desnick; Thomas L Ortel; Henny H Billett; Robert C Pendleton; Nancy L Geller; Jonathan L Halperin; Samuel Z Goldhaber; Michael D Caldwell; Robert M Califf; Jonas H Ellenberg Journal: N Engl J Med Date: 2013-11-19 Impact factor: 91.245
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: Andrea L Jorgensen; Sameh Al-Zubiedi; Jieying Eunice Zhang; Andrew Keniry; Anita Hanson; Dyfrig A Hughes; Diane van Eker; Lisa Stevens; Karen Hawkins; Cheng H Toh; Farhad Kamali; Ann K Daly; David Fitzmaurice; Alison Coffey; Paula R Williamson; Brian Kevin Park; Panos Deloukas; Munir Pirmohamed Journal: Pharmacogenet Genomics Date: 2009-10 Impact factor: 2.089
Authors: W Hernandez; E R Gamazon; K Aquino-Michaels; E Smithberger; T J O'Brien; A F Harralson; M Tuck; A Barbour; L H Cavallari; M A Perera Journal: J Thromb Haemost Date: 2017-03-25 Impact factor: 5.824
Authors: Karla Claudio-Campos; Aurora Labastida; Alga Ramos; Andrea Gaedigk; Jessicca Renta-Torres; Dariana Padilla; Giselle Rivera-Miranda; Stuart A Scott; Gualberto Ruaño; Carmen L Cadilla; Jorge Duconge-Soler Journal: Front Pharmacol Date: 2017-06-07 Impact factor: 5.810
Authors: Esteban J Parra; Andrew Mazurek; Christopher R Gignoux; Alexandra Sockell; Michael Agostino; Andrew P Morris; Lauren E Petty; Craig L Hanis; Nancy J Cox; Adan Valladares-Salgado; Jennifer E Below; Miguel Cruz Journal: PLoS One Date: 2017-02-28 Impact factor: 3.240