In humans, the cyp2c19 protein is encoded by the cyp2c19 gene. Full text comparison of cyp2c9, cyp2c19, cyp2d6, abcb1, and. The frequencies of rs1799853, rs1057910 and rs72558189 variant alleles were calculated as 1. Apr 16, 2020 cyp2c9 is an important drugmetabolizing enzyme. Rq analysis was performed using copycaller software applied. Cyp2d62d7 hybrid gene targeted sequence analysis, mayo clinic, laboratory developed test. Cyp2c19 metabolizes 15% of all currently used drugs, whereas cyp2d6 enzymes metabolize approximately 2025%, and cyp2c9 metabolizes approximately 10%. Cyp2c9 allelic variants and frequencies in a pediatric. Cyp2c92 and cyp2c93 alleles confer a lower risk for. The genotypes for cyp2c92, cyp2c93 and por28 variants were obtained from existing genome. Genotyping analysis of cyp2c9, vkorc1, and cyp4f2 and comparison of instrument platforms in this study, allelic discrimination assays. In this study one snp rs408611 of cyp2c9 did not fulfil hwe and was excluded p 0.
The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating stateofthe art algorithms and industrystandard software solutions. Genotyping of the cyp2c9 vkorc1, and cyp4f2 genes to. Large scale pharmacogenomics analysis finds that 20% of patients had severe druggene interaction warnings for their current medications contacts translational software inc. These nonfunctional alleles have been described as a risk factor for various diseases. Wikigenes cyp2c9 cytochrome p450, family 2, subfamily.
The cyp2c9 gene is involved in the breakdown metabolism of warfarin and the vkorc1 gene helps regulate the ability of warfarin to prevent blood from clotting. Nov 10, 2015 warfarin is metabolized primarily via oxidation in the liver by cyp2c9, and exerts its anticoagulant effect by inhibiting the protein vitamin k epoxide reductase complex, subunit 1 vkorc1. Warfarin and pharmacogenetic testing cyp2c9 and vkorc1. Pdf polymorphism detection of vkorc1 and cyp2c9 genes. Association of cyp gene polymorphisms with breast cancer. Genotyping of the cyp2c9 vkorc1, and cyp4f2 genes to evaluate. Each volunteer was asked to give a dna sample from the cheek using a cheek swab. Recommendations for clinical cyp2c9 genotyping allele selection. Cyp2c9 cytochrome, the major determinant of swarfarin metabolism, has two main genetic variants cyp2c9 2 and cyp2c9 3 with reduced catalytic activity compared to the wild type gene cyp2c9 1. A systematic genetic polymorphism analysis of the cyp2c9 gene in four different. Finally allelic and genotypic frequencies as well as. Vkorc1 and novel cyp2c9 variation predict warfarin. The first one, known as cyp2c9 2, replaces the amino acid arginine with the amino acid cysteine at position 144, written as arg144cys or r144c.
The distribution of the percentage allele frequency of pharmacogenetic cyp2c92, cyp2c93 and. Available possible variants of vkorc1 gene were identified after alignment and data analysis. The two most common cyp2c9 gene polymorphisms change single protein building blocks amino acids in the cyp2c9 enzyme. Cytochrome p450 2c19 abbreviated cyp2c19 is an enzyme. This is an open access database and upon searching for ontology information for the cyp2c19 and cyp2c9 gene, not enough information was found to be registered in there. It was also shown that pediatric patients needing anticoagulation after a. By contrast, the wt 11 genotype was more abundant and dominant. Impact of cyp2c9, vkorc1 and cyp4f2 genetic polymorphisms on. We sought to assess the association between the human cyp2c9 gene and coronary artery disease cad in xinjiang han population of china. The cyp2c9 8, 11, and alleles were amplified by pcr, and interrogated using restriction fragment length polymorphism rflp assays as previously described. Some regions of the genes may be removed from the panel if specifically mentioned in the test limitations section above. New large scale pharmacogenomics analysis by translational.
This protein, a member of the cyp2c subfamily of the cytochrome p450 mixedfunction oxidase system, is involved in the metabolism of xenobiotics, including many proton pump inhibitors and antiepileptics. A systematic genetic polymorphism analysis of the cyp2c9. Genetic variations in cytochrome p450 2c9 cyp2c9 contribute to. Up to now, 41 genetic variants have been identified for the cyp2c9 gene in different populations. Genetic polymorphisms and in silico mutagenesis analyses of. Cyp2c98, cyp2c911, cyp2c914, cyp2c9 p279t, or ggcxg421a variant alleles were not present in the inr. The cyp2c92 polymorphism leads to a decrease in warfarin metabolism to such a. Usa on an applied biosystems 3730xl dna analyzer or using the ceq dtcs. Cyp2c9 cytochrome p450 family 2 subfamily c member 9 homo. The cyp2c9 gene has nine exons and is located on chromosome. For testing statistical significance of differences between the cyp2c9 genotypes, the jonckheereterpstra trend test was used to test for genedose. Three single nucleotide polymorphisms snps, two in the cyp2c9 gene and one in the vkorc1 gene, have been found to play key roles in determining the.
Pdf genetic polymorphisms and in silico mutagenesis. So just to give an idea to the readers of this post about how this source is useful for pathway analysis, cyp2d6 gene was. The reported allele frequency is for the variant allele, an alternative allele to the reference allele, which is defined by the global population. Cyp2c9 allelic variants and frequencies in a pediatric sickle. Read on to learn more about enzyme function, genetics, and factors that increase or decrease cyp2c9 activity. The raw results were first analysed using the quantstudio realtime pcr software v1. Cyp2c92, cyp2c93, and cyp2c914 variant allele distributions in indigenous pakistani populations. Cys substitution at residue 144 of the cyp2c9 molecule.
The cyp2c9 gene was successfully genotyped for rs1799853 cyp2c92 r144c, rs1799853 cyp2c92 r144c, and rs72558189 cyp2c914 r125h polymorphisms, and allele frequencies were calculated for them. Several variants of the cyp2c9 gene have been described, but the. Comparison of cyp2c9, cyp2c19, cyp2d6, abcb1, and slco1b1 genepolymorphism frequency in russian and nanai populations dmitrij alekseevitch sychev,1 grigorij nikolaevich shuev,1 salavat shejhovich suleymanov,2 kristina anatolevna ryzhikova,3 karin badavievich mirzaev,3 elena anatolevna grishina,3 natalia evgenievna snalina,3 zhannet alimovna sozaeva,3 anton. Cn105861739a cyp2c19, cyp2c9 and vkorc1 genotyping. Amplicons including gene position 3608 were digested with avaii and those containing position 42614 with nsii and kpni. The cyp2c19 gene provides instructions for making an enzyme that is found primarily in liver cells in a cell structure called the. Diplotypes of cyp2c9 gene is associated with coronary artery. Enzymes produced from cytochrome p450 genes are involved in the formation and breakdown metabolism of various molecules and chemicals within cells. Previous studies have focussed on the pathogenesis of liver cirrhosis developing into hcc, but the molecular mechanism remains unclear. Jul 05, 2016 since high statistical heterogeneity was found among some analyses of genes cyp2c9, cyp4f2, vkorc1 1173 c t and vkorc11639 g a, the software stata 12. The cyp2c9 enzyme also plays a major role in breaking down the drug warfarin, which thins the blood and prevents.
Cyp2c9 is 1 of several cyp2c genes clustered in a 500kb region on proximal 10q24 gray et al. Interaction between variants in the cyp2c9 and por genes. Full text comparison of cyp2c9, cyp2c19, cyp2d6, abcb1. Detection of gene polymorphism assay cyp2c9 2, ugt1a9 98tc and cyp2b6 516gt was performed using dna chain replication reactions followed by polymorphisms analysis of restriction fragment length polymerase chain reactionrestriction fragment length polymorphism, pcrrflp. In this study, based on largescale gene screening, we found that the frequency of cyp2c9 2 and cyp2c9 3 in the han chinese population was 0. Low clearances were even found in the homozygous carriers of the wild. Genotyping for cyp2c9 2 3608ct, position referring to gene genbank. Cyp2c9 gene variants, drug dose, and bleeding risk in. Genetic polymorphisms and in silico mutagenesis analyses. Studies on the effect of cytochrome p450 2c9 cyp2c9, vitamin k epoxide reductase complex subunit 1 vkorc1, and cytochrome p450 4f2 cyp4f2 polymorphisms on warfarin maintenance dose in. Impact of cyp2c9, vkorc1 and cyp4f2 genetic polymorphisms. Ethnic distributions of the cyp2c9 polymorphisms are clinically significant in anticoagulation therapy because cyp2c9 is the major p450 that inactivates the active senantiomer of warfarin. Recommendations for clinical cyp2c9 genotyping allele.
Full text the effect of ugt1a9, cyp2b6 and cyp2c9 genes. Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. Go to the top of the page help find tests for this gene in the nih genetic testing registry. Cyp2c9 2, cyp2c9 3, and cyp2c9 14 variant allele distributions in indigenous pakistani populations. Cyp2c9 variant genotypes have been associated with a significantly increased risk of serious bleeding events. Two common alleles of cyp2c9, cyp2c9 2 and cyp2c9 3, are associated with markedly reductions in swarfarin 79hydroxylation and a greater risk of bleeding. The most common being cyp2c92 430ct in exon 3, and cyp2c93 1075ac in exon 7. People who carry cyp2c9 variants may process such drugs differently snps in cyp2c9 include. Like other cyp450 genes, cyp2c9 is highly polymorphic, and variant cyp2c9 star alleles are frequently included in clinical pgx testing assays.
Cyp2c19 catalyzes the metabolism of many commonly used drugs, including omeprazole 11, phenytoin 12, and diazepam. Tfsitescan software based on the transcription factor binding sites. While another study found that chinese and malaysian patients required higher warfarin doses with a genetic variation in cyp2c9 11 genotype 93. Cyp2d6 cytochrome p450, family 2, subfamily d, polypeptide 6 eg, drug metabolism gene analysis, targeted sequence analysis ie, cyp2d72d6 hybrid gene cyp2d72d6 hybrid gene targeted sequence analysis, mayo clinic, laboratory developed. Cyp2c9 polymorphism analysis in han chinese populations. Cyp2c9 encodes for an enzyme cytochrome p450 2c9 and catalyzes reactions involved in. For cyp2d6 gene copy number analysis, relative quantitation rq analysis was performed using copycaller software applied biosystems. The amplification system comprises two forward primers and a reverse fluorescent primer of six snps single nucleotide polymorphisms respectively and can simultaneously amplify the six snps. Cyp gene panels testing for more than 1 cyp gene on same date of service is a single unit of service uos1. P450 cy p alle l e nome n clat u re data b ase h a s tra n sitio n e d to the p har m a c ogene. Cyp2c9 is a member of the iic subfamily of the cytochrome p450 genes, responsible for metabolizing numerous drugs, such as phenytoin, tamoxifen, warfarin, fluvastin, and many nonsteroidal antiinflammatory drugs such as aspirin, ibuprofen and naproxen. There was no deviation from hardyweinberg equilibrium for any polymorphism.
Cytochrome p450 2c9 gene polymorphism and warfarin. As both the cyp2c92 and the cyp2c93 allele lead to decreased enzyme activity, both genotype results were pooled for regression analysis. The cyp2c9 gene provides instructions for making an enzyme that is found in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. Cyp2d6 cytochrome p450, family 2, subfamily d, polypeptide 6 eg, drug metabolism gene analysis, targeted sequence analysis ie, cyp2d72d6 hybrid gene cyp2d72d6 hybrid gene targeted sequence analysis, mayo clinic, laboratory developed test. The major alleles detected include cyp2c93, cyp2c192. Cyp2c9 cytochrome p450 family 2 subfamily c member 9 gene. Pdf polymorphism detection of vkorc1 and cyp2c9 genes for. Dec 31, 2019 cyp2d62d7 hybrid gene targeted sequence analysis, mayo clinic, laboratory developed test. Cytochrome p450 gene and drug interaction analysis in. The cyp2c9 gene is highly polymorphic and is located on chromosome 10q24. Functional characterization of 32 cyp2c9 allelic variants the. The cyp2c9 enzyme breaks down metabolizes compounds including steroid hormones and fatty acids. The cyp2c9 2 polymorphism leads to a decrease in warfarin metabolism to such a.
Genotyping for cyp2c92 3608ct, position referring to gene genbank. The aims of the present study were to identify key genes related to the transformation of cirrhosis into hcc, and explore the associated. The cyp2c9 enzyme also plays a major role in breaking down the. The cyp2c9 gene has nine exons and is located on chromosome 10q23. Comparison of prevalence in the lebanese population with other populations 91 the comparative analysis using genotype groups of different populations showed differences among leba nese and other caucasians table 3. The cyp2c98, 11, and alleles were amplified by pcr, and interrogated using restriction fragment length polymorphism rflp assays as previously described. The first one, known as cyp2c92, replaces the amino acid arginine with the amino acid cysteine at position 144, written as arg144cys or r144c. Computer analysis of cyp2c9 gene promoter revealed the presence of two putative ap1 sites tgagtca at positions. Calculations revealed that a minimum of 120 sam ples is required for the genotype representation in the. Analysis of genetic variations in cyp2c9, cyp2c19, cyp2d6 and.
The cyp2c92 allele is the result of a ct transition in position 430 of the cyp2c9 gene, leading to an arg. Regulation of human cyp2c9 expression by electrophilic stress. These ap1 sites are highly conserved between the cyp2c9 and cyp2c19 promoters but were not found in the cyp2c8 promoter fig. Jan 15, 2016 the records of a pharmacogenetic testing laboratory were retrospectively analyzed to identify patients tested for polymorphisms of genes coding for five cyp isozymes important in drug metabolism cyp2d6, cyp2c9, cyp2c19, cyp3a4, and cyp3a5 over a 16month period. This protein localizes to the endoplasmic reticulum and its expression is induced by rifampin. The cyp19a1 gene encodes for the enzyme aromatase, the latter of which is targeted in bc therapy by aromatase inhibitors ai due to its critical role in estrogen biosynthesis 6. The distribution of the percentage allele frequency of pharmacogenetic cyp2c9 2, cyp2c9 3 and.
A systematic genetic polymorphism analysis of the cyp2c9 gene in. Eight articles with a combined total of 507 pediatric patients were included in the meta. Genetic polymorphisms of cyp2c9 significantly influence the. The year of publication, language of publication, location of patients, mean age of. Kohn and pelz 2000 studied the warfarinresistance locus of the rat, rw, and by homology of synteny concluded that the homolog is on mouse chromosome 7 and 1 of 3 human chromosomes, including 10q25. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. The allele frequency of cyp2c9 and vkorc1 in the southern.
Jan 30, 2020 hepatocellular carcinoma hcc is the most common type of liver tumour, and is closely related to liver cirrhosis. Cyp2c9 makes up about 18% of the cytochrome p450 protein in liver microsomes data only for antifungal. Tfsitescan software based on the transcription factor binding sites database. The invention discloses a cyp2c19, cyp2c9 and vkorc1 genotyping multiplex amplification system and detection kit. A meta analysis of 9 studies showed that just one copy of the cyp2c9 2 or cyp2c9 3 allele reduces the daily dose of warfarin by 17% or 37%, respectively, compared to the cyp2c9.
Since high statistical heterogeneity was found among some analyses of genes cyp2c9, cyp4f2, vkorc1 1173 c t and vkorc11639 g a, the software stata 12. In figure 1, the individual oral clearances are shown divided into groups according to the six allelic combinations of the cyp2c9 gene. The cyp2c9 gene was successfully genotyped for rs1799853 cyp2c9 2 r144c, rs1799853 cyp2c9 2 r144c, and rs72558189 cyp2c9 14 r125h polymorphisms, and allele frequencies were calculated for them. The cyp2c19 gene provides instructions for making an enzyme that is found primarily in liver cells in a cell structure called. It is responsible for the clearance of up to 1520% of clinical drugs, and cyp2c9 gene variants greatly affect the way we react to these drugs. In this study, based on largescale gene screening, we found that the frequency of cyp2c92 and cyp2c93 in the han chinese population was 0.
The most common being cyp2c9 2 430ct in exon 3, and cyp2c9 3 1075ac in exon 7. Comparison of cyp2c9, cyp2c19, cyp2d6, abcb1, and slco1b1 genepolymorphism frequency in russian and nanai populations dmitrij alekseevitch sychev,1 grigorij nikolaevich shuev,1 salavat shejhovich suleymanov,2 kristina anatolevna ryzhikova,3 karin badavievich mirzaev,3 elena anatolevna grishina,3 natalia evgenievna snalina,3 zhannet alimovna sozaeva,3 anton mikhailovich grabuzdov,4 irina. Cyp2c9, vkorc1, and cyp4f2 polymorphisms and pediatric. Analysis of genetic variation in cyp450 genes for clinical. Cyp2c19, cyp2d6, cyp2c9, and vkorc1 genetic testing lcd.
Cyp2c9 is an important cytochrome p450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. We studied a large cohort of healthy young adults 283. Several variants of the cyp2c9 gene have been described, but the most prevalent and most studied of them are the cyp2c92 and cyp2c93 polymorphisms. The effect of ugt1a9, cyp2b6 and cyp2c9 genes polymorphism. The cyp2c9 gene cyp2c9 3 and the vkorc1 gene, encoding the warfarin. A f ter m ore t h an 15 years t h e human cy t oc h ro m e. The cyp2c19 gene is a member of the cytochrome p450 gene family. Functional characterization of 32 cyp2c9 allelic variants. The dosage and administration of warfarin must be individualized for each patient according to the particular patients prothrombin time pt international normalized ratio inr.
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