Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians

被引:65
作者
Borgiani, Paold
Ciccacci, Cinzia
Forte, Vittorio
Romano, Silvia
Federici, Giorgio
Novelli, Giuseppe
机构
[1] Univ Roma Tor Vergata, Dept Biopathol & Diagnost Imaging, Sch Med, Genet Sect, I-00133 Rome, Italy
[2] Univ Roma Tor Vergata, Ctr Pharmaceut Biotechnol, Sch Med, I-00133 Rome, Italy
[3] Azienda Ospedaliera, Policlin Tor Vergata, Ctr Haemostasis & Thrombosis, Rome, Italy
[4] Azienda Ospedaliera, Policlin Tor Vergata, Dept Lab Med, Rome, Italy
关键词
D O I
10.2217/14622416.8.11.1545
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
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页码:1545 / 1550
页数:6
相关论文
共 23 条
  • [1] Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P4502C9 gene polymorphisms on warfarin dose requirements
    Aquilante, CL
    Langaee, TY
    Lopez, LM
    Yarandi, HN
    Tromberg, JS
    Mohuczy, D
    Gaston, KL
    Waddell, CD
    Chirico, MJ
    Johnson, JA
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2006, 79 (04) : 291 - 302
  • [2] A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance
    Bodin, L
    Horellou, MH
    Flaujac, C
    Loriot, MA
    Samama, MM
    [J]. JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2005, 3 (07) : 1533 - 1535
  • [3] Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose:: a prospective study
    Carlquist, John F.
    Horne, Benjamin D.
    Muhlestein, Joseph B.
    Lappe, Donald L.
    Whiting, Bryant M.
    Kolek, Matthew J.
    Clarke, Jessica L.
    James, Brent C.
    Anderson, Jeffrey L.
    [J]. JOURNAL OF THROMBOSIS AND THROMBOLYSIS, 2006, 22 (03) : 191 - 197
  • [4] Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing
    Chen, LY
    Eriksson, N
    Gwilliam, R
    Bentley, D
    Deloukas, P
    Wadelius, M
    [J]. BLOOD, 2005, 106 (10) : 3673 - 3674
  • [5] A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
    D'Andrea, G
    D'Ambrosio, RL
    Di Perna, P
    Chetta, M
    Santacroce, R
    Brancaccio, V
    Grandone, E
    Margaglione, M
    [J]. BLOOD, 2005, 105 (02) : 645 - 649
  • [6] VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation
    Geisen, C
    Watzka, M
    Sittinger, K
    Steffens, M
    Daugela, L
    Seifried, E
    Müller, CR
    Wienker, TF
    Oldenburg, J
    [J]. THROMBOSIS AND HAEMOSTASIS, 2005, 94 (04) : 773 - 779
  • [7] A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy
    Hamberg, A-K
    Dahl, M-L
    Barban, M.
    Scordo, M. G.
    Wadelius, M.
    Pengo, V.
    Padrini, R.
    Jonsson, E. N.
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2007, 81 (04) : 529 - 538
  • [8] Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range
    Hirsh, J
    Dalen, JE
    Anderson, DR
    Poller, L
    Bussey, H
    Ansell, J
    Deykin, D
    [J]. CHEST, 2001, 119 (01) : 8S - 21S
  • [9] Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin
    Kamali, F
    Khan, TI
    King, BP
    Frearson, R
    Kesteven, P
    Wood, P
    Daly, AK
    Wynne, H
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 2004, 75 (03) : 204 - 212
  • [10] Warfarin dose related to apolipoprotein E (APOE) genotype
    Kohnke, H
    Sörlin, K
    Granath, G
    Wadelius, M
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 2005, 61 (5-6) : 381 - 388