ABSTRACT Warfarin therapy is complicated by a narrow therapeutic index and substantial interpatient variability in dose response. The cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genes have recently been determined to be associated with warfarin dose requirements, with reduced doses of this drug being required in patients with the variant CYP2C9*2, CYP2C9*3, or VKORC1 -1639A allele. The combination of genotype and clinical factors explains approximately 50 to 60% of the variance in warfarin dose requirements in Caucasians and Asians, but only 25 to 40% among African Americans. Racial differences in the association between genotype and a patient's response to warfarin treatment may be caused by racial differences in the frequencies of the variant CYP2C9*2, CYP2C9*3, and VKORC1 -1639A alleles or by the influence of non-genetic factors. Genotype also influences the time required to attain therapeutic anticoagulation and the risk for over-anticoagulation and hemorrhage. Although the incorporation of genotype information improves the accuracy of dose prediction, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been demonstrated. Therefore, the routine use of CYP2C9 and VKORC1 genotyping is not supported by currently available evidence. The results of ongoing or future multicenter clinical trials are expected to clarify the role of pharmacogenomics in the management of warfarin therapy.
- SourceAvailable from: Christina G Perry[Show abstract] [Hide abstract]
ABSTRACT: Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy.Current Cardiology Reports 07/2013; 15(7):381.
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ABSTRACT: Background: Managing individual-based anti-coagulant therapy with warfarin is an important goal for bleeding prevention in personalized medicine. Objectives: The purpose of the present study was to evaluate the allelic frequency of VKORC1 (C1173T, G1639A) and CYP2C9 (CYP2C9*2 and CYP2C9*3) polymorphic genes with SimpleProbe® real-time PCR as a fast, accurate and easy-to-handle method. Patients and Methods: One hundred unrelated patients under warfarin therapy were recruited as the study population. Real-time PCR was performed with SimpleProbe® for single-nucleotide polymorphisms (SNP) detection of CYP2C9 and VKORC1 genes. Results: The allelic frequencies for VKORC1 C1173T (CC, CT, TT) were 25%, 51% and 24%, respectively and for VKORC1 G1639A (-GG, GA, AA) were 27%, 51% and 22%, respectively. Despite a significant association between allelic polymorphisms in VKORC1 and warfarin dose (P < 0.001), it was not statistically significant for CYP2C9*2 and CYP2C9*3, most probably due to the low rate of CYP2C9*2 and CYP2C9*3 SNPs observed. Conclusions: SimpleProbe® real-time PCR is a fast and accurate technique qualified to detect VKORC1 and CYP2C9 SNPs. These results encourage taking further steps towards using VKORC1 and CYP2C9 allelic screening to prevent clinical complications due to resistance or sensitivity to warfarin as well as anti-coagulant dose adjustment.Thrita. 02/2014; 3(1):e14033.
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ABSTRACT: Myocardial remodeling is pivotal in the progression and complication of chronic heart failure (HF). We assessed serial measurement of five biomarkers with biologic links to remodeling (biglycan, secreted frizzled-related protein 3, endostatin, insulin-like growth factor binding protein 7 [IGFBP7], mimecan) in 142 patients with HF followed through 882 office visits. IGFBP7 and mimecan were most associated with events; in fully adjusted models, lower IGFBP7 concentrations across visits independently predicted fewer events (odds ratio [OR] = 0.83; 95 % confidence interval [CI] = 0.73-0.95, p = 0.01). Subjects with rising mimecan had greater decrease in left ventricular end diastolic (p = 0.07) and systolic (p = 0.01) volumes, greater increase in ejection fraction (p = 0.02), and had lowest event rates. Statistical models suggested several HF medications might lead to changes in both IGFBP7 and mimecan values. The results suggest serial measurement of IGFBP7 provides prognostic information, while changes in mimecan provide unique information regarding myocardial remodeling.Journal of Cardiovascular Translational Research 12/2013; · 3.06 Impact Factor