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Manuela Vecsler, Ronen Loebstein, Shlomo Almog, Daniel Kurnik, Boleslav Goldman, Hillel Halkin, Eva Gak
Combined genetic profiles of components and regulators of the vitamin K-dependent -carboxylation system affect individual sensitivity to warfarin
Keywords: warfarin (coumarin) sensitivity,vitamin K cycle,single nucleotide polymorphisms (SNPs),combined genotype,pharmacogenetics
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), -glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G1542C 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 r2 = 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 G11A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous 11A allele carriers in the upper 10th dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 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 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.918.4) 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 anticoagulation.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 95
Pages: 205 - 211