title: Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin.
abstract: American College of Medical Genetics statements and guidelines are designed primarily as an educational resource for medical geneticists and other health care professionals to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These statements and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the health care professional should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these standards and guidelines. 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.
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Dennis
authors.initials: D
authors.lastname: O'Kane
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.forename: Michael S
authors.initials: MS
authors.lastname: Watson
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Brian
authors.initials: B
authors.lastname: Gage
authors.forename: Roy
authors.initials: R
authors.lastname: Gandolfi
authors.forename: Richard
authors.initials: R
authors.lastname: King
authors.forename: Elaine
authors.initials: E
authors.lastname: Lyon
authors.forename: Robert
authors.initials: R
authors.lastname: Nussbaum
authors.forename: Dennis
authors.initials: D
authors.lastname: O'Kane
authors.forename: Kevin
authors.initials: K
authors.lastname: Schulman
authors.forename: David
authors.initials: D
authors.lastname: Veenstra
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.forename: Michael S
authors.initials: MS
authors.lastname: Watson
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D013923:Thromboembolism / Q000188:drug therapy*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases