Review
Copy number variants in pharmacogenetic genes

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Variation in drug efficacy and toxicity remains an important clinical concern. Presently, single nucleotide polymorphisms (SNPs) only explain a portion of this problem, even in situations where the pharmacological trait is clearly heritable. The Human CNV Project identified copy number variations (CNVs) across approximately 12% of the human genome, and these CNVs were considered causes of diseases. Although the contribution of CNVs to the pathogenesis of many common diseases is questionable, CNVs play a clear role in drug-related genes by altering drug metabolizing and drug response. In this review, we provide a comprehensive evaluation of the clinical relevance of CNVs to drug efficacy, toxicity, and disease prevalence in world populations, and discuss the implication of using CNVs as a diagnostic tool in clinical intervention.

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).

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      Single nucleotide polymorphism (SNPs) in genes, specifically belongs to PK and PD of any drug, act as one of the main genetic factor accountable for individual drug response (Katara, 2014). A copy number variation (CNV) is another factor which considerably takes part in variable response, i.e., CYP2D6 and CYP2C19 genes (He et al., 2011; Santos et al., 2018). On the basis of features some time CNV also considered as copy number polymorphism (CNPs) and those genes which show such polymorphism are known as CNP-genes (Bailey et al., 2008).

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