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


CONCLUSIONS
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.
Tor Vergata University, Department of Biopathology and Diagnostic Imaging, Section of Genetics, School of Medicine, Via Montpellier 1, 00133 Rome, Italy. borgiani@uniroma2.it
Paola
P
Borgiani
Cinzia
C
Ciccacci
Vittorio
V
Forte
Silvia
S
Romano
Giorgio
G
Federici
Giuseppe
G
Novelli
D000367:Age Factors; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001835:Body Weight; D065729:Cytochrome P-450 CYP2C9; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007558:Italy; D016014:Linear Models; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000925:Anticoagulants; D014859:Warfarin; D004247:DNA; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases