haplotype structure in European American warfarin patients and association with clinical outcomes

Veenstra, David L.; Blough, David K.; Higashi, Mitchell K.; Farin, Frederico M.; Srinouanprachan, Sengkeo; Rieder, Mark J.; Rettie, Allan E.

doi:10.1016/j.clpt.2005.01.019

Cited by 100 publications

(86 citation statements)

References 19 publications

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“…13 The five haplotypes in our population corresponded well to these five haplotype groups despite using different polymorphisms. The haplotypes H9 and H10, including CYP2C9*2 and CYP2C9*3, have been termed groups 2 and 3 by Veenstra et al (Figure 3).…”

Section: Discussionsupporting

confidence: 53%

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

et al. 2006

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In 97 unselected volunteers and two additional homozygous carriers of CYP2C9*3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9*3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl-and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9*3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9*3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r 2 ¼ 82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9*3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.

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Section: Discussionsupporting

confidence: 53%

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

et al. 2006

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“…However, most of these efforts have focused on populations of European descent. [11][12][13][14][15][16][17][18]Herein we report CYP2C9 allele frequencies among European American and African American patients and evaluate the influence of CYP2C9 on warfarin dose stratified by race. We detail genotyping methodology and describe study design and cohort characteristics at enrollment.…”

Section: Introductionmentioning

confidence: 99%

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Limdi

Goldstein

Blaisdell

et al. 2007

Personalized Medicine

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Background-Cytochrome P4502C9 (CYP2C9) plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European American and African American patients. We also identify two new mutations; one in the coding region and one in the non-coding region of the CYP2C9 gene.

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“…CYP2C9 is largely responsible for the metabolic clearance of (S)-warfarin, the more active of the two CYP2C9 isoforms [36], accounting for 60 -70% of warfarin's overall anticoagulant activity [37]. Two variants within CYP2C9, designated * 2 and * 3, are clearly associated with lower warfarin dose requirements in Caucasian populations and increased bleeding risk [38][39][40][41][42][43][44][45]. However, their effect is less clear in other populations, particularly African Americans [44,46].…”

Section: Reasons For Difficulty With Warfarin Therapymentioning

confidence: 99%

Warfarin therapy: in need of improvement after all these years

Kimmel

2008

Expert Opinion on Pharmacotherapy

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Background-Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal.Objective-To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy.Results-Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions.Conclusion-Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes.

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haplotype structure in European American warfarin patients and association with clinical outcomes

Cited by 100 publications

References 19 publications

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

Influence of CYP2C9 Genotype on Warfarin Dose Among African–Americans and European–Americans

Warfarin therapy: in need of improvement after all these years

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