PM Frequencies of Major CYPs in Asians and Caucasians

Mizutani, Takaharu

doi:10.1081/dmr-120023681

Cited by 221 publications

(143 citation statements)

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“…For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10]. Polymorphic studies have revealed that the IM allele CYP2D6*10 is predominant in Asian populations with frequencies ranging from 30% to 50% [7,11].…”

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confidence: 99%

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Dai

Geng

Wang

et al. 2015

Basic Clin Pharma Tox

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Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs related to genetic polymorphisms and is responsible for one-quarter of the currently used clinical drugs. We previously detected 22 novel, non-synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP2D6 substrates. In this study, wild-type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild-type enzyme. Our in vitro functional data can be useful for CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China.As one of the most important drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) is responsible for approximately 25% of clinically used drugs including analgesics, antiarrhythmics, antiemetics, antipsychotics, antidepressants, beta-adrenergic blockers and chemotherapeutic/hormone replacement agents [1][2][3]. Similar to other P450 subfamily members, the CYP2D6 gene locus is also highly polymorphic across different ethnic populations and individuals [4]. To date, a total of 105 allelic variants are defined and described in the Human CYP Allele Nomenclature database (http://www.cypalleles.ki.se/cyp2d6.htm). These genetic variants can be associated with increased, decreased or abolished enzymatic functions, which results in differences of up to 30-to 40-fold changes in substrate drug clearance values. Consequently, these differences in CYP2D6 activity have been demonstrated to be prominent contributors to interindividual drug response variability [2,5,6].It has been reported that significant ethnic and geographic differences exist in CYP2D6 alleles [7,8]. For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10]. Polymorphic studies have revealed that the IM allele CYP2D6*10 is predominant in Asian populations with frequencies ranging from 30% to 50% [7,11]. In a recent large-scale, genetic screening study, we sequenced all nine exons of the CYP2D6 gene in 2129 unrelated Chinese individuals. As a result, 22 new nonsynonymous, mutated sites were found, and 12 of them were designated as novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee [12]. Considering the fact that there are more than 1.4 billion people living in the mainland ...

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confidence: 99%

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Dai

Geng

Wang

et al. 2015

Basic Clin Pharma Tox

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“…The low prevalence of mutant genotypes indicates relative infrequency of poor metabolizer in Han Chinese, which is in line with previously reported low-frequency of CYP3A4 poor metabolizer in Asians. 55 Haplotypes of CYP3A4 in Han Chinese Haplotypes were inferred with 11 detected SNPs by the PHASE program. Our reconstruction of haplotypes strengthened previous findings that a few common haplotypes of CYP3A4 occupy a huge proportion of the total chromosomes examined, 54 whereas a large subset of haplotypes carries low levels of variation.…”

Section: Resultsmentioning

confidence: 99%

Analysis of CYP3A4 genetic polymorphisms in Han Chinese

Zhou

Shu

et al. 2011

J Hum Genet

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Our study aimed to comprehensively investigate the genetic polymorphisms of CYP3A4 in Han Chinese. We sequenced the gene regions of CYP3A4, including its promoter, exons, surrounding introns and 3¢ untranslated region (3¢UTR), from 100 unrelatedhealthy Han Chinese individuals. We detected 11 SNPs, three of which are novel. According to in silico functional prediction of novel variants, 20148 A4G in exon 10, resulting in substitution of Tyr319 with Cys (CYP3A4*21), may induce dramatic alteration of protein conformation, and 26908 G4A in 3¢UTR may disrupt post-transcriptional regulation. We identified five alleles in Han Chinese, the allele frequencies of CYP3A4*1, *5, *6, *18 and *21 are 97, 0.5, 1, 1 and 0.5%, respectively. Haplotype inference revealed 14 haplotypes, of which the major haplotype CYP3A4*1A constitutes 59% of the total chromosomes. We also examined the possible role of natural selection in shaping the variation of CYP3A4 and confirmed a trend, consistent with the action of positive selection. We systematically screened the genetic polymorphisms of CYP3A4 in Han Chinese, highlighted possible functional impairment of the novel allele and summarized the distinct allele and haplotype frequency distribution, with an emphasis on detecting the footprint of recent positive selection on the CYP3A4 gene in Han Chinese.

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“…The frequency of CYP2B6*5 is as high as 11% in white and black populations, 3% in Hispanic populations, and 0.3 to 5% in Asian populations (10 -12). CYP2C19*2 is even more frequent at 15 to 17% in white and black patients and up to 30% in Asian patients (12)(13)(14). Patients with these CYP450 variants may be It is likely that both approaches will be used in combination to generate personalized medicine panels to individualize therapies.…”

Section: Therapy Based On Genetic Variants In Drug Metabolic Pathwaysmentioning

confidence: 99%

Can We Personalize Treatment for Kidney Diseases?

Rovin

McKinley

Birmingham

2009

Clinical Journal of the American Society of Nephrology

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The idea of individualizing therapies to obtain optimal clinical results is not new but has only recently been applied to kidney diseases. Nonetheless, kidney disorders present a variety of opportunities to personalize medicine. Here, the heterogeneity of kidney disorders is reviewed to provide a rationale for pursuing personalized medicine. Data on adjusting therapy on the basis of pharmacogenetics/genomics and pharmacodynamics are summarized to demonstrate where the field is, and biomarker studies that reflect the future of personalized medicine are discussed. The goal of this review is to demonstrate that we can personalize therapy for kidney diseases but that considerable investment in new research will be required for personalized medicine to be routinely used in nephrology clinics. Clin J Am Soc Nephrol 4: 1670 -1676. doi: 10.2215 T he phrase personalized medicine has been used with increasing frequency in the lay press, and academia has embraced this concept by forming centers of personalized medicine within their health systems. The goal of determining the right drug, for the right patient, at the right time is not new, however, and has been actively pursued for some time in oncology using genomic tools to look for gene mutations or variations in gene expression that may affect therapy. Other disciplines, including nephrology, have joined this endeavor, although the data on personalized therapies for kidney diseases are still very preliminary. This mini-review presents these data to provide a framework for expanding research into individualized therapies for kidney diseases. Building a Case for Personalized Medicine in Kidney DiseasesThere is ample evidence that kidney disorders that are characterized by a specific constellation of clinical signs and symptoms display the molecular and biochemical heterogeneity that lends itself to individualized medicine. For example, despite similar clinical and histologic phenotypes, pediatric allograft rejection could be divided into three molecular groups by microarray analysis of total renal biopsy RNA expression (1). One of these acute rejection molecular groups was enriched for expression of B cell genes, and by immunohistochemistry, abundant B cells were found to be present in renal biopsy tissue from this subset of patients. Although the numbers were small, recovery from rejection and steroid responsiveness were significantly better in the patients who did not have B cells infiltrating their allografts. These data suggest that determining the molecular subtype of acute rejection before treatment may be used to identify patients who are likely to be steroid resistant and who may benefit from a different antirejection protocol (2).Molecular heterogeneity is also found in primary and secondary glomerular diseases. Pediatric patients who had FSGS and displayed nephrotic-range proteinuria or renal insufficiency could be differentiated from patients who did not have nephrosis or renal insufficiency, respectively, on the basis of unique renal cortical RNA expression (3...

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PM Frequencies of Major CYPs in Asians and Caucasians

Cited by 221 publications

References 25 publications

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Analysis of CYP3A4 genetic polymorphisms in Han Chinese

Can We Personalize Treatment for Kidney Diseases?

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