AUMENTATA SENSIBILITA’ GENETICA AL WARFARIN

Major bleeding caused by warfarin in a genetically susceptible patient.
Pharmacotherapy 221,97-101, 2002

Un’alterazione genetica del gene che codifica CYP2C9 determina una ridotta clearance dell’S warfarin con il rischio di gravi emorragie. In questi pz sono necessari dosaggi più bassi.
La frequenza di questi alleli varia nelle diverse popolazioni ed è pari al 6-10% nelle popolazioni caucasiche. La clearance del farmaco è molto rallentata.
Anche dopo la riduzione della dose qs pz hanno un rischio aumentato di emorragie maggiori di 3,68 volte rispetto ai pz senza l’alterazione dell’allele.

The potential clinical and economic outcomes of pharmacogenetics-oriented management of warfarin therapy- a decision analysis.
Thromb Haemost 2004, 92,590-7
Un trattamento orientato farmacogeneticamente con un modesto costo aggiuntivo è potenzialmente più efficace nel prevenire le emorragie.

CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnettrade mark systematic review and meta-analysis.
Sanderson S, Emery J- Genet Med 2005, Feb 7(2) 97-104
Due comuni alleli varianti del citocroma CYP2C9 (CYP2C9*2 e CYP2C9*3) determinano un ridtotto metabolismo del warfarin. Metaanalisi  su 3029 pazienti.
20% avevano alleli varianti
CYP2C9*2 12%- riduzione dose del 17%- Rischio relativo emorragico 1,91
CYP2C9*3   8%- riduzione dose del 37   - Rischio relativo emorragico 1,77
In conclusione i pazienti portatori di questa variante hanno necessità di una dose minore di warfarin e un rischio doppio di emorragie.

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.
Blood 2005, 24 March- Bodin L

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.
Rieder MJ, Reiner . Department of Genome Sciences, University of Washington, Seattle, USA.
N Engl J Med. 2005 Jun 2;352(22):2285-93.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level. Copyright 2005 Massachusetts Medical Society.

 

 

  Settembre  2005