Trends in Molecular Medicine
ReviewCopy number variants in pharmacogenetic genes
Section snippets
Pharmacogenetics
Pharmacogenetics aims to study the gene variants associated with drug metabolism enzymes, transporters, drug receptors and to relieve the burden of sickness caused by interindividual differences in drug response or vulnerabilities to drug toxicity 1, 2. Since the completion of the Human Genome Project in 2000, there has been a burst in the number of pharmacogenetic research studies published, with some of the findings now being introduced into clinical practice. To practice pharmacogenetics
What is a copy number variant?
Human DNA has one copy of autosomal regions on each chromosome. However, as discovered by the Human Genome Project, many genetic regions display a variation in the number of copies (more or less than two copies). Alleles containing 0–13 gene copies have been reported across the human population [13]. These genetic variants are termed CNVs and are defined as DNA segments ranging in size from one kilobase to several megabases among individuals owing to deletion, insertion, inversion, duplication,
CYP2D6
CYP2D6 is predominantly expressed in human liver, and it metabolizes over 25% of drugs currently used in the clinic [19]. CYP2D6 is highly polymorphic and its variants account for the majority of the variation in enzyme activity that is observed within and between populations. To date, more than 75 CYP2D6 alleles have been documented in the Human Cytochrome P450 (CYP) Allele Nomenclature database (http://www.cypalleles.ki.se/cyp2d6.htm). Alleles comprise a combination of polymorphisms,
CYP2D6
Codeine is a widely used analgesic and antitussive agent in the clinic. It is activated by CYP2D6 to a strong central nervous system (CNS) sedative, morphine. Kirchheiner and colleagues found that after a single 30 mg dose of codeine, the plasma concentrations of morphine are significantly higher in CYP2D6 UMs than EMs [45]. High plasma concentrations of morphine can lead to several fatal effects including hypotension and respiratory depression, especially in pediatric patients. A healthy
Prevalence of CNVs in drug-related genes in human populations
Understanding the prevalence of major genetic variations related to drug efficacy and toxicity is crucial for both health providers and patients. Both the Ministry of Health in each nation and physicians in clinics can use this knowledge to maximize benefit and minimize harm for patients prior to and during drug therapy [61], which is widely accepted as the base for personalized genomic medicine [62].
The frequency of CNVs is shown in Table 1. These data can help each population to select the
Which drugs should be labeled with CNV markers?
Since 2008, the FDA has released a list of valid genomic biomarkers in the context of approved drug labels [5]. The term “valid biomarkers” has been described in the previously released “Guidance for Industry: Pharmacogenomic Data Submissions” [4] as a “biomarker that is measured in an analytical test system with well established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicological,
Concluding remarks
The translation of CNV knowledge into clinic intervention remains a big challenge, with a growing number of pharmacogenetics studies providing robust evidence for the impact of CNVs on the efficacy and toxicity of drug therapy [18]. However, few comparative effectiveness studies have been conducted in this field, which has limited the expansion of genetic testing of CNVs into primary healthcare systems. In addition, investigations on the cost versus benefits of genetic testing have been
Conflicts of interest
Dr McLeod is a consultant to Medco Health Solutions, Gentris Corporation and Myriad Genetics.
Acknowledgments
The authors are supported by the National Institutes of Health Pharmacogenetics Research Network (U01 GM63340), the University Cancer Research Fund and UL1RR025747 from the National Center for Research Resources. This research is part of the Pharmacogenetics for Every Nation Initiative (www.pgeni.org).
References (95)
Pharmacogenetics and adverse drug reactions
Lancet
(2000)Metabolic activity of dextromethorphan O-demethylation in healthy Japanese volunteers carrying duplicated CYP2D6 genes: duplicated allele of CYP2D6*10 does not increase CYP2D6 metabolic activity
Clin. Chim. Acta
(2004)A multiplex real-time PCR method for detection of GSTM1 and GSTT1 copy numbers
Clin. Biochem.
(2009)- et al.
GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis
Eur. J. Cancer
(2010) Glutathione-S-transferase genotypes influence the risk of chemotherapy-related toxicities and prognosis in Korean patients with diffuse large B-cell lymphoma
Cancer Genet. Cytogenet
(2010)- et al.
The array CGH and its clinical applications
Drug. Discov. Today
(2008) Genetic polymorphisms of glutathione S-transferase and risk of vitiligo in the Chinese population
J. Invest. Dermatol.
(2009)Cytochrome P450 1A1, glutathione S-transferases M1 and T1 polymorphisms in Ovambos and Mongolians
Leg. Med. (Tokyo)
(2009)Association of glutathione S-transferase gene polymorphisms (GSTM1 and GSTT1) of vitiligo in Korean population
Life Sci.
(2007)Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis
Am. J. Hum. Genet.
(2008)
Pharmacogenomics and individualized drug therapy
Annu. Rev. Med.
The AmpliChip CYP450 genotyping test: integrating a new clinical tool
Mol. Diagn. Ther.
Implications for KRAS status and EGFR-targeted therapies in metastatic CRC
Nat. Rev. Clin. Oncol.
A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs
Pharmacogenet Genomics
Genetic determinants of response to warfarin during initial anticoagulation
N. Engl. J. Med.
Pharmacogenomics of anti-TB drugs-related hepatotoxicity
Pharmacogenomics
Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use
Pharmacotherapy
Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication
Anesth. Analg.
Inheritance and drug response
N. Engl. J. Med.
Global variation in copy number in the human genome
Nature
Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH)
J. Med. Genet.
Common deletion polymorphisms in the human genome
Nat. Genet.
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
Nature
CNVs of human genes and their implication in pharmacogenetics
Cytogenet. Genome Res.
Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I
Clin. Pharmacokinet.
CYP2D6 and tamoxifen: DNA matters in breast cancer
Nat. Rev. Cancer
Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity
Pharmacogenomics J.
CYP2D6*36 gene arrangements within the cyp2d6 locus: association of CYP2D6*36 with poor metabolizer status
Drug Metab. Dispos.
Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology
Pharmacogenetics
CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure
Pharmacogenet. Genomics
Evolution of detoxifying systems: the role of environment and population history in shaping genetic diversity at human CYP2D6 locus
Pharmacogenet. Genomics
Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population
Pharmacogenetics
CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants
Pharmacogenomics
Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes
Clin. Pharmacol. Ther.
10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes
Clin. Pharmacol. Ther.
Genome-wide pharmacogenetics of antidepressant response in the GENDEP project
Am. J. Psychiatry.
Endometrial profile of tamoxifen and low-dose estradiol combination therapy
Clin. Cancer Res.
Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer
Br. J. Pharmacol.
Pharmacogenomics of tamoxifen and aromatase inhibitors
Cancer
Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6
J. Pharmacol. Exp. Ther.
Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen
Breast Cancer Res. Treat.
Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment
Clin. Pharmacol. Ther.
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