Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements

Aquilante, Christina L.; Langaee, Taimour; Lopez, Larry M.; Yarandi, Hossein; Tromberg, Jennifer; Mohuczy, Dagmara; Gaston, K.; Waddell, Cassandra D.; Chirico, Mark J.; Johnson, Julie A.

doi:10.1016/j.clpt.2005.11.011

Cited by 248 publications

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“…The ultimate goal was to improve our understanding of the worldwide allele frequency distribution of these polymorphisms and to discuss the results in light of the known effect of these markers on warfarin dosing and the differences in average warfarin dosing that have been reported The VKORC1 gene is believed to be the most important individual predictor of warfarin dose. 29,38 Previous research has shown that the derived T allele of the rs9923231 polymorphism, which is located in the promoter region of the gene, is associated with lower warfarin dose requirements. Moreover, there is evidence indicating that the rs9923231 T allele is associated with a reduction of VKORC1 mRNA levels of up to 70%, in comparison to the wild-type allele.…”

Section: Discussionmentioning

confidence: 99%

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

et al. 2010

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“…Dose variance explained by VKORC1 and CYP2C9 was 25% and 9%, respectively, confirming and refining previous estimates. 10,19 Genotype imputation using data from the European HapMap (CEPH European) SNPs and additional variants from approximately 1000 selected candidate genes 26,27 expanded our tests of association in the index population to more than 3 million SNPs across the human genome. However, no significant SNPs outside of those previously described gave robust signals for association.…”

Section: Replication Resultsmentioning

confidence: 99%

“…This patient set has previously been studied for the effects of VKORC1 and other candidate genes on stabilized warfarin dosing. 19 Stable warfarin dose was defined by less than 10% variability between clinic visits and an INR within the target range at more than 3 visits. Exclusion criteria for these patients were liver cirrhosis, advanced malignancy, hospitalization within 4 weeks before the index visit, or febrile/diarrheal illness within 2 weeks of the index visit.…”

Section: Study Setting and Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…17 Generally, dose associations with other candidate genes have shown small statistical effects or fail to replicate in independent populations. 15,18,19 It remains unclear whether additional common genetic variation outside of these candidate genes contribute significantly to the 45% to 55% of unexplained variance in warfarin dosing.The utility of prospective, pharmacogenetically guided warfarin dosing has been studied in a small patient set, 20 but a proposed large National Heart, Lung and Blood Institute (NHLBI)-funded randomized clinical trial should provide more definitive data addressing this (Request for Proposal NHLBI-HV-08-03). Although polymorphisms with small effect on warfarin dose would probably not be incorporated into this trial, knowledge of additional polymorphisms with a large effect would be extremely The online version of this article contains a data supplement.…”

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A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Cooper

Johnson

Langaee³

et al. 2008

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Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n ‫؍‬ 181) and 2 independent replication patient populations (n ‫؍‬ 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P ‫؍‬ 6.2 ؋ 10 ؊13 ) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ϳ 10 ؊4 ). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. IntroductionThe determination of safe yet effective doses of warfarin for individual patients is one of the most promising clinical applications of pharmacogenetics. [1][2][3] There are large variation in warfarin dose from patient to patient and significant clinical consequences of doses that produce insufficient or excessive pharmacologic effects. Thus, reducing uncertainty in establishing the therapeutic dose in individual patients could improve quality of care as well as expand the range of patients who could be treated. 4 In white patients, genetic factors are more strongly correlated with stabilized warfarin dose than all other known patient-related factors. Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awar...

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Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues

2014

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IMPORTANCE Significant variations in dose requirements of warfarin and its analogues (acenocoumarol and phenprocoumon) make selecting the appropriate dose for an individual patient difficult. Genetic factors account for approximately one-third of the variation in dose requirement. The clinical usefulness of genotype-guided dosing of warfarin has been previously assessed in randomized clinical trials that were limited by lack of power and inconsistent results.OBJECTIVE To compare genotype-guided initial dosing of warfarin and its analogues with clinical dosing protocols. MEDLINE (inception to December 31, 2013), EMBASE (inception to December 31, 2013), and the Cochrane Library Central Register of Controlled Trials (inception to December 31, 2013) were searched for randomized clinical trials comparing genotype-guided warfarin dosing vs clinical dosing for adults with indications for anticoagulation. DATA SOURCES AND STUDY SELECTION DATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently on trial design, baseline characteristics, and outcomes. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURESThe outcomes analyzed included the percentage of time that the international normalized ratio (INR) was within the therapeutic range, the percentage of patients with an INR greater than 4, and the incidence of major bleeding and thromboembolic events. Summary standardized differences in means (or Mantel-Haenszel risk ratios) were obtained using a random-effects model. RESULTSIn 9 trials, 2812 patients were randomized to receive warfarin, acenocoumarol, or phenprocoumon according to a genotype-guided algorithm or a clinical dosing algorithm. Follow-up ranged from 4 weeks to 6 months (median, 12 weeks). The standardized difference in means of the percentage of time that the INR was within the therapeutic range was 0.14 (95% CI, −0.10 to 0.39) in the genotype-guided dosing cohort (P = .25). The risk ratio for an INR greater than 4 was 0.92 (95% CI, 0.82 to 1.05) for genotype-guided dosing vs clinical dosing. The risk ratios for major bleeding and thromboembolic events were 0.60 (95% CI, 0.29 to 1.22) and 0.97 (95% CI, 0.46 to 2.05), respectively, for genotype-guided vs clinical dosing. CONCLUSIONS AND RELEVANCEIn this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms.

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Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements

Abstract: Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.

Cited by 248 publications

References 43 publications

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Genotype-Guided vs Clinical Dosing of Warfarin and Its Analogues

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