The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement

Abstract

The degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G > A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose. The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p = 0.032). Common polymorphism (6484C > T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95-6.45), 3.49 (3.07-3.90) and 2.11 (1.80-2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p < 0.001). In contrast, 9041G > A polymorphism in 3'UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58- 3.60), 4.26 (3.69-4.82) and 5.86 (4.53-7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p < 0.001). With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9, VKORC1), age and body-surface-area. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.

Evaluation of Genetic Factors for Warfarin Dose Prediction

“…Polymorphisms in these genes have been previously suggested as contributors to stable dose variation. 18,19,[30][31][32][33][34][35] However, in each of the previous publications, the individual genes accounted for a very small amount (<5%) of the predictive value for warfarin dose. Given the low explanatory value of these genes and differences between our patient population and the Japanese, Italian and Swedish populations used in the previous studies, it is not surprising that these variants do not contribute to our model.…”

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

“…12 Among the other non-functional alleles, CYP2C19*3 is very rare in Caucasians and as confirmed by our previous study, also very rare (0.4% allele frequency) in Slovenian population. 11 All the 11 patients with CYP2C19*1/*17 genotype, that could possibly lead to an increased CYP2C19 metabolic capacity for substrate hydroxylation, 8 had SW-21OHD. Among 17 patients with other CYP2C19 genotypes leading to normal (*1/*1 and *2/*17) or decreased (*1/*2) CYP2C19 enzyme activity, 15 had SW-21OHD, one had SV-21OHD and one had NC-21OHD.…”

“…CYP2C19*2 allele accounts for 93% of the alleles that code for a non-functional enzyme in the Caucasians and in the Slovene population. 10,11 A novel variant allele, CYP2C19*17 was reported to lead to ultra-rapid metabolism of some CYP2C19 substrates. It is characterized by two SNPs in the promoter region, -3402C>T and -806C>T, the latter is associated with increased transcriptional activity that leads to ultra-rapid metabolism of some CYP2C19 substrates.…”

Warfarin therapy: in need of improvement after all these years

“…Several recent studies have developed and tested dosing algorithms that incorporate genotype as well as clinical characteristics (Table 1) [31,40,84,[88][89][90][91][92][93]. Most algorithms share in common the inclusion of age, measures of body size (such as body surface area or weight), and CYP2C9 variants.…”