RESUMEN
CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.
Asunto(s)
Antihipertensivos/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Losartán/uso terapéutico , Anciano , Antihipertensivos/farmacocinética , Hidrocarburo de Aril Hidroxilasas/química , Hidrocarburo de Aril Hidroxilasas/metabolismo , Pueblo Asiatico/genética , Cristalografía , Citocromo P-450 CYP2C9 , Resistencia a Medicamentos/genética , Femenino , Variación Genética , Humanos , Hipertensión/etnología , Losartán/farmacocinética , Masculino , Persona de Mediana Edad , Mutación Missense , Polimorfismo de Nucleótido Simple , Estructura Terciaria de ProteínaAsunto(s)
Oxigenasas de Función Mixta/genética , Farmacogenética/métodos , Warfarina/administración & dosificación , Anciano , Secuencia de Aminoácidos , Femenino , Haplotipos , Humanos , Japón , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/fisiología , Datos de Secuencia Molecular , Fenotipo , Polimorfismo de Nucleótido Simple , Homología de Secuencia de Aminoácido , Vitamina K Epóxido ReductasasRESUMEN
The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.
Asunto(s)
Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Ligasas de Carbono-Carbono/genética , Oxigenasas de Función Mixta/genética , Warfarina/administración & dosificación , Anciano , Citocromo P-450 CYP2C9 , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Modelos Biológicos , Farmacogenética , Polimorfismo de Nucleótido Simple , Análisis de Regresión , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/genética , Vitamina K Epóxido ReductasasRESUMEN
gamma-Glutamyl carboxylation, a reaction essential for the activity of vitamin K-dependent proteins, requires the concerted actions of gamma-glutamyl carboxylase (GGCX), vitamin K 2, 3-epoxide reductase complex 1 (VKORC1), and the chaperone calumenin (CALU). We evaluated the contribution of genetic polymorphisms in VKORC1, GGCX, and CALU to interindividual variation in the activities of plasma protein C and protein S. We sequenced these 3 genes in 96 Japanese individuals and geno-typed 9 representative single-nucleotide polymorphisms in 3655 Japanese individuals representative of the general population. The mean activity of protein C in women bearing the GG genotype of GGCX 8016G>A (130.8% +/- 1.5%, n = 156) was significantly greater (P = .002) than that of individuals with either the AG (126.8% +/- 0.7%, n = 728) or the AA (125.4% +/- 0.6%, n = 881) genotype, after adjusting for confounding factors. The GGCX 8016G>A change leads to the substitution of Gin for Arg at amino acid residue 325 (Arg 325 Gln). This effect was comparable to that of a previously defined polymorphism in the protein C promoter. Mean protein S activity was influenced by the VKORC1 3730G>A and CALU 20943T>A genotypes, after adjusting for confounding factors. Thus, polymorphisms in genes involved in the vitamin K-dependent gamma-carboxylation reaction influence interindividual variation in the activities of protein C and protein S in the general population.