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

Manuela Vecsler; Ronen Loebstein; Shlomo Almog; Daniel Kurnik; Boleslav Goldman; Hillel Halkin; Eva Gak

doi:10.1160/TH05-06-0446

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2006; 95(02): 205-211
DOI: 10.1160/TH05-06-0446

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Autoren

Manuela Vecsler

¹Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel

³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Ronen Loebstein

²Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
Shlomo Almog

²Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Daniel Kurnik

²Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel
Boleslav Goldman

¹Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel

³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Hillel Halkin

²Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel

³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Eva Gak

¹Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel

³Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Abstract

Summary

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), γ-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G₁₅₄₂C VKORC1 polymorphism was associated with decreased warfarin doses in the heteroand 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 excep tionally high warfarin dose (20mg/day) and the prevalence of heterozygous ₁₁A 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 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. 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 anticoagulation.

Keywords

warfarin (coumarin) sensitivity - vitamin K cycle - single nucleotide polymorphisms (SNPs) - combined genotype - pharmacogenetics

Volltext

Referenzen

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