Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

被引:168
作者
Flockhart, David A. [2 ]
O'Kane, Dennis [3 ]
Williams, Marc S. [4 ]
Watson, Michael S. [1 ]
Flockhart, David A. [2 ]
Gage, Brian [5 ]
Gandolfi, Roy [4 ]
King, Richard [6 ]
Lyon, Elaine [7 ]
Nussbaum, Robert [8 ]
O'Kane, Dennis [3 ]
Schulman, Kevin [9 ]
Veenstra, David [10 ]
Williams, Marc S. [4 ]
Watson, Michael S. [1 ]
机构
[1] Amer Coll Med Genet Fdn, 9650 Rockville Pike, Bethesda, MD 20814 USA
[2] Indiana Univ, Sch Med, Indianapolis, IN USA
[3] Mayo Clin, Rochester, MN USA
[4] Intermountain Hlthcare, Salt Lake City, UT USA
[5] Washington Univ, Sch Med, St Louis, MO USA
[6] Univ Minnesota Hlh Ctr, Minneapolis, MN USA
[7] Univ Utah, ARUP Labs, Salt Lake City, UT USA
[8] Univ Calif San Francisco, San Francisco, CA 94143 USA
[9] Duke Univ, Res Inst, Durham, NC USA
[10] Univ Washington, Seattle, WA 98195 USA
关键词
pharmacogenetics; warfarin; coumadin; CYP2CP; VKORC1; thromboembolism; hypercoagulation;
D O I
10.1097/GIM.0b013e318163c35f
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Warfarin (Coumadin) is a potent drug that when used judiciously and monitored closely, leads to substantial reductions in morbidity and mortality from thromboembolic events. However, even with careful monitoring, initiation of warfarin dosing is associated with highly variable responses between individuals and challenges achieving and maintaining levels within the narrow therapeutic range that can lead to adverse drug events. Variants of two genes, CYP2C9 and VKORC1, account for 30-50% of the variability in dosing of warfarin; thus, many believe that testing of these genes will aid in warfarin dosing recommendations. Evidence about this test is evolving rapidly, as is its translation into clinical practice. In an effort to address this situation, a multidisciplinary expert group was organized in November 2006 to evaluate the role of CYP2C9 and VKORC1 testing in altering warfarin-related therapeutic goals and reduction of adverse drug events. A recently completed Rapid-ACCE (Analytical, Clinical Validity, Clinical Utility, and Ethical, Legal, and Social Implications) Review, commissioned to inform this work group, was the foundation for this analysis. From this effort, specific recommendations for the appropriate use of CYP2C9 and VKORC1 testing were developed and are presented here. The group determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin. However, there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients. Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing. Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in determining the cause of unusual therapeutic responses to warfarin therapy.
引用
收藏
页码:139 / 150
页数:12
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