Worldwide Distribution of Cytochrome P450 Alleles: A Meta‐analysis of Population‐scale Sequencing Projects

Zhou, Yitian; Ingelman‐Sundberg, Magnus; Lauschke, Volker M.

doi:10.1002/cpt.690

Cited by 466 publications

(451 citation statements)

References 49 publications

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“…The *2 variant is almost absent or present at low frequency among South‐East (0.7%) and East Asians (<0.1%). In contrast, it is reported at higher frequencies in Caucasians (11.7%), South Asians (4.6%) and Africans (2.4%) . In the present analysis, the most commonly found CYP2C9 alleles in SEEA populations are * 1 , *2 and *3 (Table ).…”

Section: Discussioncontrasting

confidence: 62%

CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South‐East and East Asian populations: A systematic review

2019

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Summary What is known and objective Genetic polymorphism is one of the most important factors responsible for interindividual and interethnic variability in drug response. Studies in major populations, ie, Caucasians, Asians, and Africans, have provided evidence of differences in the genotype frequencies of major drug‐metabolizing enzyme cytochrome P450 (CYP). This study aimed to review systematically, all relevant articles related to the genetic polymorphisms in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in South‐East and East Asian (SEEA) populations. Methods Articles that report genetic polymorphisms, genotype frequencies and allele frequencies in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 were retrieved from the PubMed database. Results and discussions A total of 86 studies that fulfilled the eligibility criteria representing different ethnic populations of SEEA, ie, Burmese, Chinese, Japanese, Karen ethnic minority, Korean, Malaysian, Philippino, Singaporean, Taiwanese, Thai, Indonesian, and Vietnamese, were included in the analysis. In general, the genotype frequencies across SEEA populations are comparable. The CYP2C9*1/*1 (69.3%‐99.1%), *1/*3 (2.3%‐20.1%) and *3/*3 (0%‐2.2%) genotypes are reported in most SEEA populations. Six major CYP2C19 genotypes, ie, *1/*1 (6.25%‐88.07%), *1/*2 (21.5%‐86.46%), *1/*3 (0.8%‐15.8%), *2/*2 (3.4%‐14.5%), *2/*3 (0%‐7.3%) and *3/*3 (0%‐10.2%), are reported in most SEEA populations. Major CYP2D6 genotypes include *10/*10 (0%‐69.6%), *1/*1 (0%‐61.21%) and *1/*10 (0%‐62.0%). Major CYP3A5 genotypes are *3/*3 (2.0%‐71.4%), *1/*3 (16.0%‐57.1%) and *1/*1 (0%‐82.0%). Genotyping of abnormal genotypes of CYP2C9 (*1/*3), CYP2C19 (*1/*2, *1/*3), CYP3A5 (*1/*3) and CYP2D6 (*5/*10) associated with IM (Intermediate metabolizer) status, may be clinically beneficial in SEEA populations. Similarly, with CYP2C19 (*2/*2, *2/*3), CYP2D6 (*5/*5 ) linked to PM (Poor metabolizer), CYP2D6 (*10/*10, *1/*5 and to lesser extent *1/*4, *2/*5, *10/*41, *10/*49, *10/*14) and CYP3A5 (*1/*1) associated with EM (extensive metabolizer). What is new and conclusion Sufficient number of studies has provided comparable results in general. This review suggests that comparable genotype frequencies of CYP2C9, CYP2C19, CYP2D6 and CYP3A5 exist among the SEEA populations. It is noted that more research data are reported from East Asians compared with South‐East Asians. Concerned efforts are required to establish partnerships among SEEA countries that will ensure sufficient data from South‐East Asian countries which will assist in establishing the databases for SEEA populations.

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Section: Discussioncontrasting

confidence: 62%

CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South‐East and East Asian populations: A systematic review

2019

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“…Multidrug resistance transporters bind to >100 clinically relevant drugs and affect their disposition and pharmacokinetics, which is of particular importance for cancer drug resistance . Our analyses of genomic data from 138,632 individuals indicate that the genetic complexity in these transporter genes is extensive and comparable to the variability in other highly variable pharmacogene families, such as CYPs , SLCOs and UGTs . While a multitude of reports have implicated germline variants in multidrug resistance transporters in differences in chemotherapy response and dose‐limiting toxicity, these studies interrogated only candidate polymorphisms and failed to incorporate the genetic complexity of these transporter genes into their associations, which might be insufficient for the functional interpretation of complex ABC genotypes.…”

Section: Discussionmentioning

confidence: 99%

Germline variant burden in multidrug resistance transporters is a therapy‐specific predictor of survival in breast cancer patients

Xiao

Zhou

Winter

et al. 2020

Intl Journal of Cancer

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Multidrug resistance due to facilitated drug efflux mediated by ATP‐binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease‐specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug‐specific for subgroups treated with the MRP1 substrates cyclophosphamide (log‐rank p = 0.0011) and doxorubicin (log‐rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log‐rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.

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“…Thus, while a variant may be rare globally, frequencies of a minor allele might be substantial in specific populations. One such example is the prevalence of the reduced functionality allele CYP2C8*2, which is not found in individuals of European or East Asian ancestry but is common in Africans (MAF = 15.9%) [7]. Similarly, the loss-of-function CYP3A4*20 allele causing increased risk of adverse reactions to, e.g., paclitaxel, was not found in Asian, African, South American, and most European populations but reached frequencies of 3.8% in specific regions of Spain [86].…”

Section: Rare Genetic Variants and Population-specificitymentioning

confidence: 99%

“…By revealing its molecular underpinnings and identifying clinically actionable variants that can be targeted by approved Data for CYP alleles is obtained from ref. [7]. Non-CYP variants with pharmacogenetic importance in SLCO1B1, TPMT, or DPYD were obtained from ExAC [84] or the 1000 Genomes project [85] EUR Europeans, AFR Africans, EAS East Asians, SAS South Asians, AMR ad mixed Americans drugs, this approach allows to tailor therapy to the specific tumor, opening new avenues for personalized oncology (Table 5).…”

Section: Genetic Biomarkers In the Somatic Cancer Genomementioning

confidence: 99%

“…Enzymes encoded by the cytochrome P450 (CYP) superfamily of genes are responsible for > 75% of phase 1 drug metabolism and thus constitute major modulators of drug response [6]. Importantly, CYP genes are highly polymorphic between individuals and across populations, which can have important implications for the bioactivation and/or detoxification of medications [7].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Lauschke

Milani

Ingelman‐Sundberg

2017

AAPS J

118

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Abstract.Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drugmetabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.

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Worldwide Distribution of Cytochrome P450 Alleles: A Meta‐analysis of Population‐scale Sequencing Projects

Cited by 466 publications

References 49 publications

CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South‐East and East Asian populations: A systematic review

CYP2C9, CYP2C19, CYP2D6 and CYP3A5 polymorphisms in South‐East and East Asian populations: A systematic review

Germline variant burden in multidrug resistance transporters is a therapy‐specific predictor of survival in breast cancer patients

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

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