Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed mutations of 7 vitamin K-dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr-->Met of the factor II gene, -402G-->A, (37-bp repeat)n, and -746T-->C of the factor VII gene, and (CAA repeat)n of the gamma-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G-->A, (CAA repeat)n, CYP2C9*3, and 165Thr-->Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses.
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PMID:Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. 1465 80

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.
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PMID:The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. 1667 68