Variability in CYP2C9 allele frequency: A pilot study of its predicted impact on warfarin response among healthy South and North Indians

Nahar, Risha; Deb, Roumi; Saxena, Renu; Puri, Ratna Dua; Verma, Ishwar C.

doi:10.1016/s1734-1140(13)70977-0

Cited by 31 publications

(35 citation statements)

References 26 publications

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“…A higher frequency for CYP2C9*3 in Spain has also been suggested [7] , but this is not evident from the analysis of 1000 genomes data. It is clear that CYP2C9*3 is a relatively common allele in South Asians and the frequency is comparable to or higher than that reported for the UK, but CYP2C9*2 is less common, especially for the South Indian population, in line with a previous report [45] .…”

Section: Cyp2c9supporting

confidence: 88%

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Daly

2015

Drug Metabolism and Personalized Therapy

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Data on frequency of pharmacogenetic polymorphisms in the UK population are limited. However, availability of whole genome sequencing data on 94 UK controls of European ethnicity from the 1000 genomes project together with similar data on other populations provides a valuable new source of data in this area and allows direct comparison of allele frequencies with those for other European populations. The ethnic diversity of the UK population also needs to be considered, and 1000 genomes includes data on South Asians, the most common ethnic group in the UK after White Europeans. Allele frequencies for polymorphisms in genes relevant to phase I and phase II drug metabolism for UK, Finnish, Spanish and South Asian populations were obtained from the literature and 1000 genomes. Generally there was good agreement between the literature and 1000 genomes reports. CYP2D6*4, the most common CYP2D6 poor metabolizer allele among Europeans, appears more common in the UK than in Spain and Finland, whereas, as suggested previously, CYP2C19*2 and CYP2C9*2 appear more common in Finland and Spain, respectively, than in the UK. South Asians show low frequencies of CYP2C9*2 and CYP2C19*17 but higher frequencies of CYP2C19*2 compared with UK residents of European ethnicity. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs.

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Section: Cyp2c9supporting

confidence: 88%

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Daly

2015

Drug Metabolism and Personalized Therapy

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“…One limitation of genotyping, no matter the method used, includes allele drop out events, due to the presence of variations besides the one of interest. These events have been described for genotyping assays across multiple genes [14, 15, 21-24]. While the majority of these interfering variations are usually rare, they can severely alter accurate prediction of the metabolizing phenotype within a particular individual.…”

Section: Discussionmentioning

confidence: 99%

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Scantamburlo¹,

Tziolia

Zopf³

et al. 2017

Cell Physiol Biochem

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Background/Aim: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its genotype for phenotype prediction is essential. Methods: A cohort of 365 patient samples was genotyped for CYP2D6 using Sanger sequencing (as the gold standard), hydrolysis probe assays or pyrosequencing. Results: A discrepant result between the three genotyping methods for the loss of function CYP2D6*3 (g.2549delA, rs35742686) genetic variant was found in one of the samples. This sample also contained the CYP2D6 g.2470T>C (rs17002852) variation, which had an allele frequency of 2.47% in our cohort. Redesign of the CYP2D6*3 pyrosequencing and hydrolysis probe assays to avoid CYP2D6 g.2470 corrected the anomaly. Conclusion: To evidence allele drop out and increase the accuracy of genotyping, intra-patient validation of the same genetic variation with at least two separate methods should be considered.

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“…Coumarin-based drugs prevent the production of vitamin K-dependent coagulation factors and thereby reduce the risk of blood clots formation (1). Warfarin is the main member of coumarin family and is the most prescribed oral anticoagulant drug across the world (123).…”

Section: Introductionmentioning

confidence: 99%

“…Warfarin is the main member of coumarin family and is the most prescribed oral anticoagulant drug across the world (123). Studies show that one patient out of every 100 patients taking warfarin encounters fatal bleeding annually (4) and up to 15% of patients experience mild bleeding (5).…”

Section: Introductionmentioning

confidence: 99%

The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population

et al. 2017

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The genetic factors are determinants in required dosage changes of warfarin among which are polymorphisms of CYP2C9 and VKORC1 genes. The present study aimed to determine the allele and genotype frequency of CYP2C9 and VKORC1 genes in Birjand population. This study was conducted on 120 individuals who referred to Imam Reza and Vali-Asr hospitals for PT/INR test. After extracting the genomic DNA, the considered sequences were amplified by PCR, and restriction fragment length polymorphism analysis was done by AvaII and KpnI enzymes to determine allele polymorphisms. Moreover, related sequences of VKORC1, after amplification, were sequenced for determining the genotype. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium, observed heterozygosity, expected heterozygosity, and polymorphism information content were calculated by PowerMarker V 3.25 software. Amongst 120 individuals in this study with the mean age of 58.12 ± 12.7 years, 80.8%, 9.1%, and 10% exhibited the alleles of 1, 2, and 3 CYP2C9 gene, respectively. The genotype frequencies of 1/1, 1/2, 2/2, 3/1, 3/2, and 3/3 of this gene were found to be 64.1, 15.8, 0, 17.5, 2.5, and 0 %, respectively. In -1639 G>A region, VKORC1 had normal homozygote genotype (GG) and in 1173 C>T region, heterozygote (CT) with the frequency of 48.7% and 45.9% had the most prevalence. Compared with other populations, there is a considerable difference between the allele frequency of CYP2C9 and VKORC1 genetic variance. Since 35.8% of the selected populations carry an abnormal allele causing sensitivity to warfarin, the specialists at medical centers must be informed about the genotypes of patients before prescribing warfarin.

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Variability in CYP2C9 allele frequency: A pilot study of its predicted impact on warfarin response among healthy South and North Indians

Abstract: Genotype frequency of CYP2C9 and VKORC1 SNPs is variable among the two ethno-geographically distinct Indian populations. This could translate into diverse warfarin response among the Indian population.

Cited by 31 publications

References 26 publications

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population

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