INTRODUCTION: Warfarin is currently considered to be the anticoagulant of choice in the long-term treatment and prevention of thromboembolic events. However, it presents a narrow therapeutic range and a great interindividual dose variability. We investigated the influence of variants of the VKORC1 and CYP2C9 loci on the mean weekly warfarin dose (MWWD) required to reach stabilized therapeutic international normalized ratio, in order to confirm and to estimate the contribution of common genetic variability of these two genes in an Italian population and to search for novel rare VKORC1 alleles. METHODS: A total of 148 patients were followed for 6 months and analyzed for VKORC1 and CYP2C9 gene variants. Analysis of variance and multiple linear regression analysis were used to study the contribution of each genetic factor to MWWD requirement. RESULTS: The complete sequencing of the VKORC1 coding region did not reveal the presence of exonic variants, while two common noncoding SNPs were highly associated: the T allele of VKORC1 1173C>T SNP (tag-SNP of H1-H2 haplotypes) is highly associated with low MWWD (p < 0.0001), while the A allele of VKORC1 3730G>A SNP (tag-SNP of H9 haplotype) is associated with high MWWD (p = 0.001). Also, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) variant alleles were significantly associated with low MWWD (p = 0.003 and 0.027, respectively). According to a multiple linear regression model including, besides VKORC1 and CYP2C9 SNPs, also age and weight, this percentage reaches 56% (gender is not significant). DISCUSSION: Our results clearly indicate VKORC1 as the gene with the largest contribution to MWWD. Analyzing only one tag SNP of VKORC1 gene (1173C>T), it is possible to foresee 20% of the total variability. Our results may contribute to give useful indications for clinicians especially in the initiation of therapy so as to avoid the risk of adverse events.
INTRODUCTION:Warfarin is currently considered to be the anticoagulant of choice in the long-term treatment and prevention of thromboembolic events. However, it presents a narrow therapeutic range and a great interindividual dose variability. We investigated the influence of variants of the VKORC1 and CYP2C9 loci on the mean weekly warfarin dose (MWWD) required to reach stabilized therapeutic international normalized ratio, in order to confirm and to estimate the contribution of common genetic variability of these two genes in an Italian population and to search for novel rare VKORC1 alleles. METHODS: A total of 148 patients were followed for 6 months and analyzed for VKORC1 and CYP2C9 gene variants. Analysis of variance and multiple linear regression analysis were used to study the contribution of each genetic factor to MWWD requirement. RESULTS: The complete sequencing of the VKORC1 coding region did not reveal the presence of exonic variants, while two common noncoding SNPs were highly associated: the T allele of VKORC1 1173C>T SNP (tag-SNP of H1-H2 haplotypes) is highly associated with low MWWD (p < 0.0001), while the A allele of VKORC1 3730G>A SNP (tag-SNP of H9 haplotype) is associated with high MWWD (p = 0.001). Also, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) variant alleles were significantly associated with low MWWD (p = 0.003 and 0.027, respectively). According to a multiple linear regression model including, besides VKORC1 and CYP2C9 SNPs, also age and weight, this percentage reaches 56% (gender is not significant). DISCUSSION: Our results clearly indicate VKORC1 as the gene with the largest contribution to MWWD. Analyzing only one tag SNP of VKORC1 gene (1173C>T), it is possible to foresee 20% of the total variability. Our results may contribute to give useful indications for clinicians especially in the initiation of therapy so as to avoid the risk of adverse events.
Authors: Nita A Limdi; Mia Wadelius; Larisa Cavallari; Niclas Eriksson; Dana C Crawford; Ming-Ta M Lee; Chien-Hsiun Chen; Alison Motsinger-Reif; Hersh Sagreiya; Nianjun Liu; Alan H B Wu; Brian F Gage; Andrea Jorgensen; Munir Pirmohamed; Jae-Gook Shin; Guilherme Suarez-Kurtz; Stephen E Kimmel; Julie A Johnson; Teri E Klein; Michael J Wagner Journal: Blood Date: 2010-03-04 Impact factor: 22.113
Authors: Helene Puehringer; Ralph M Loreth; Gudrun Klose; Brigitte Schreyer; Walter Krugluger; Barbara Schneider; Christian Oberkanins Journal: Eur J Clin Pharmacol Date: 2010-04-08 Impact factor: 2.953
Authors: Thomas P Moyer; Dennis J O'Kane; Linnea M Baudhuin; Carmen L Wiley; Alexandre Fortini; Pamela K Fisher; Denise M Dupras; Rajeev Chaudhry; Prabin Thapa; Alan R Zinsmeister; John A Heit Journal: Mayo Clin Proc Date: 2009-12 Impact factor: 7.616
Authors: Nita A Limdi; T Mark Beasley; Michael R Crowley; Joyce A Goldstein; Mark J Rieder; David A Flockhart; Donna K Arnett; Ronald T Acton; Nianjun Liu Journal: Pharmacogenomics Date: 2008-10 Impact factor: 2.533