Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin

被引:133
作者
Vecsler, M
Loebstein, R
Almog, S
Kurnik, D
Goldman, B
Halkin, H
Gak, E [1 ]
机构
[1] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Head Mol Genet Unit, IL-52621 Tel Hashomer, Israel
[2] Chaim Sheba Med Ctr, Inst Clin Pharmacol, IL-52621 Tel Hashomer, Israel
[3] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
关键词
warfarin (coumarin) sensitivity; vitamin K cycle; single nucleoticle polymorphisms (SNPs); combined genotype; pharmacogenetics;
D O I
10.1160/TH05-06-0446
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001).Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2)= 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an excep-tionally high warfarin dose (20mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 and VKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n=9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3mg/day; n=18; p < 0.01). The odds ratio for doses < 3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anti coagulation.
引用
收藏
页码:205 / 211
页数:7
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