A Rapid-ACCE review of CYP2C9 and VKORC1 allele testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding

Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island 02903, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 03/2008; 10(2):89-98. DOI: 10.1097/GIM.0b013e31815bf924
Source: PubMed


Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding.
Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications.
Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing.
The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues.

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    • "In this study, even though there has been an established interpretation guideline for warfarin dosing ( [9–11], DNAGPS Optimus does not interpret the results properly; consequently the dosing results of DNAGPS were opposite to those of 23andMe. What is worse is that Hellogene tested inapposite gene (GGCX gene) for warfarin dosing. "
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    ABSTRACT: Introduction: Genetic testing services for disease prediction, drug responses, and traits are commercially available by several companies in Korea. However, there has been no evaluation study for the accuracy and usefulness of these services. We aimed to compare two genetic testing services popular in Korea with 23andMe service in the United States. Materials and methods: We compared the results of two persons (one man and one woman) serviced by Hellogene Platinum (Theragen Bio Institute), DNAGPS Optimus (DNAlink), and 23andMe service. Results: Among 3 services, there were differences in the estimation of relative risks for the same disease. For lung cancer, the range of relative risk was from 0.9 to 2.09. These differences were thought to be due to the differences of applied single nucleotide polymorphisms (SNPs) in each service for the calculation of risk. Also, the algorithm and population database would have influence on the estimation of relative disease risks. The concordance rate of SNP calls between DNAGPS Optimus and 23andMe services was 100% (30/30). conclusions: Our study showed differences in disease risk estimations among three services, although they gave good concordance rate for SNP calls. We realized that the genetic services need further evaluation and standardization, especially in disease risk estimation algorithm.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "This is because most laboratories cannot perform warfarin genotyping and report findings in a timely manner, and because no reliable prospective study has yet shown that genotyping analysis can reduce the frequency of serious bleeding [3]. Ideally, the results of warfarin genotyping tests should be reported before the initial dose of warfarin is given or at least before stabilization of international normalized ratio (INR) (thus within 3 days after the start of treatment) [3] [8] to be clinically effective. Although Fig. 2. Reaction platform of the real-time PCR method for warfarin dose genotyping. "
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    ABSTRACT: Introduction: Thiopurine drugs are metabolized via S-methylation and catalyzed by thiopurine S-methyltransferase (TPMT). Patients with very low TPMT activity are at high risk of fatal bone marrow toxicity when standard doses of thiopurine drugs are administered. TPMT genotyping can predict TPMT activity and is not affected by transfusion or red blood cell defects. Here, we report a new allele-specific real-time polymerase chain reaction (PCR) system for thiopurine methyltransferase genotyping that is validated in Korean population. Materials and methods: Three major TPMT single-nucleotide polymorphisms (TPMT 2, 3B, and 3C) were genotyped using real-time PCR with the allele-specific primers and probes. Internal positive controls were included in each well, and an automatic interpretative algorithm was applied. This system was validated using 244 clinical samples and 2 commercial DNA samples that had been previously genotyped using PCR-direct sequencing. Results. All of the obtained results are concordant with those of the reference method. All of the internal positive control reactions were successful. The allele frequency of TPMT 3C was 2.05% (10 of 488 alleles). All of the patients with variant alleles were heterozygotes, and no homozygotes were detected. No TPMT 2, 3A, or 3B alleles were observed in this Korean population. Conclusion: This rapid, accurate, and user-friendly genotyping system can be readily used to improve the efficacy and safety of thiopurine treatments in clinical practice.
    Full-text · Article · Feb 2013
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    • "Recent studies have analyzed genetic variations in patients taking warfarin and identified several single nucleotide polymorphisms (SNPs) that affect warfarin dosing. Two SNPs have been shown by many investigators to affect warfarin dosage, one in the vitamin K 2,3-epoxide reductase complex: VKORC1-1639 G > A, and the other involving the liver cytochrome P450 2C9 isozyme: CYP2C9 rs1057910 [6-9]. More recently, a SNP in another P450 isozyme, CYP4F2 rs2108622-1347 C > T, has been shown to be responsible for differences in warfarin dosage for many individuals [10-12]. "
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    ABSTRACT: Background Individuals with implanted mechanical valve prostheses require lifelong anticoagulation therapy with warfarin. The narrow therapeutic index of warfarin makes it difficult to dose and maintain proper anticoagulation. A number of single nucleotide polymorphisms (SNPs) affecting vitamin K or warfarin metabolism have been shown to affect warfarin dosing. Our aim was to study the effect of the CYP4F2 rs2108622-1347 (C > T) variant on warfarin dosing in Chinese patients. Methods We studied 352 patients after heart valve replacement surgery. Warfarin dosing for patients was adjusted to achieve 1.8 ≤ INR ≤ 2.5. We determined the presence of SNPs in CYP4F2 in these patients and investigated their association with warfarin dosing. Results We found the frequency of the CYP4F2 rs2108622 C allele was 79.5% and T-allele frequency was 20.5%. The warfarin dose requirement for CC individuals was significantly lower than that for CT or TT individuals (P < 0.05). TT-homozygous individuals required a 0.56 mg/day higher dose of warfarin than their CC counterparts. Conclusions This study demonstrates that CYP4F2 rs2108622 significantly affects the warfarin dose requirement to achieve adequate anticoagulant activity in Chinese individuals. Genotyping of this SNP may allow clinicians to determine the initiation dose for patients following valve-replacement surgery in China.
    Full-text · Article · Sep 2012 · Journal of Cardiothoracic Surgery
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