Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

Erik Fung; Nikolaos A. Patsopoulos; Steven M. Belknap; Daniel J. O'Rourke; John F. Robb; Jeffrey L. Anderson; Nicholas W. Shworak; Jason H. Moore

doi:10.1055/s-0032-1328891

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2012; 38(08): 893-904
DOI: 10.1055/s-0032-1328891

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

Erik Fung

¹Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

²Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

,

Nikolaos A. Patsopoulos

³Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

⁴Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

⁵Broad Institute of Harvard and MIT, Cambridge, Massachusetts

,

Steven M. Belknap

⁶Department of Medicine, Northwestern Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois

,

Daniel J. O'Rourke

¹Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

²Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

⁷Section of Cardiology, Veterans Affairs Medical Center, White River Junction, Vermont

,

John F. Robb

¹Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

²Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

,

Jeffrey L. Anderson

⁸Cardiovascular Department, Intermountain Medical Center, Murray, Utah

⁹University of Utah School of Medicine, Salt Lake City, Utah

,

Nicholas W. Shworak

¹Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

²Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

¹⁰Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

,

Jason H. Moore

²Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

¹¹Institute of Quantitative Biomedical Science, Dartmouth College, Hanover, New Hampshire

¹²Departments of Genetics and Community and Family Medicine, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire

› Author Affiliations

Abstract

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways.

Keywords

warfarin - pharmacogenetics - polymorphisms - personalized medicine

Full Text

References

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