Frequency of CYP2D6 alleles affecting drug metabolism

Prediction of CYP2D6 phenotype from genotype across world populations – Genet Med. 2017 Jan; – free full-text PMC article

Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes.

CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations.

I’ve added a glossary of genetic terms at the end of this post. 

However, there is no standard approach to translate diplotypes into predicted phenotype.

Conclusions:

This comprehensive study summarizes allele frequencies, diplotypes, and predicted phenotype across major populations, providing a rich data resource for clinicians and researchers. Challenges of phenotype prediction from genotype data are highlighted and discussed.

CYP2D6 is a member of the cytochrome P450 gene superfamily, which constitutes many important phase I drug metabolizing enzymes and contributes to the metabolism of up to 25% of clinically used drugs. 

As reviewed by He et al., CYP2D6 is the predominant pathway for the elimination or bioactivation of many centrally acting drugs, including tricyclic antidepressants, serotonin-selective reuptake inhibitors, opioids, and antiemetics, but also antiarrythmics, β-blockers, antihistamines, and antiviral agents.

In addition, CYP2D6 also plays a role in the metabolism of drugs of abuse and has been shown to bioactivate a number of procarcinogens and neurotoxins.

CYP2D6 allele frequencies have been shown to vary substantially among world populations. Some allelic variants are present across populations at similar frequencies, whereas others are observed at vastly different frequencies or have only been detected in a certain ethnic group. Polymorphic expression of CYP2D6 is the most important single factor impacting variable activity within and among populations.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) develops guidelines that enable the translation of genetic laboratory test results into actionable prescribing decisions for specific drugs (https://www.pharmgkb.org/page/cpic and https://cpicpgx.org)

Since its inception in 2009, 22 guidelines and updates have been published, including three involving CYP2D6 (CYP2D6/codeine; CYP2D6 and CYP2C19/tricyclic antidepressants; and CYP2D6 and CYP2C19/ selective serotonin reuptake inhibitors).

In the supplemental materials of the CYP2D6 guidelines, allele frequencies across populations have been systematically captured and updated with each new guideline or update.

To our knowledge, this is the most comprehensive and up-to-date resource for CYP2D6 allele-frequency information.

It is freely available through the PharmGKB at http://www.pharmgkb.org/download.action?filename=CYP2D6_Frequency_Table_and_Legend_R3.pdf.


 

Glossary

Note: for a more comprehensive glossary, visit NIH’s Genetics Home Reference Glossary

Gene: An area along a chromosome typically encompassing the information necessary to encode one protein.

Allele: Traditional definition: alternate forms of a gene, composed of one or more SNPs. More loosely: a SNP. For example, at a given position along a chromosome, most people might have the DNA base “A”. A few might have an alternative sequence. Each defined type is an allele.

Single Nucleotide Polymorphism (SNP; pronounced snip): A precise position along a chromosome where the DNA of different people may vary. Generally two alternate alleles are found at a particular SNP. At least 2,000,000 SNPs are now known and there may be over 30,000,000 in the human genome. The SNPs that have medical or health consequences for you and your loved ones are the focus of SNPedia.

Haplotype: A specific combination of SNPs all occurring on the same chromosome (i.e. all occurring on the chromosome inherited from Dad, or, inherited from Mom). Human autosomal chromosomes normally come in pairs, and the combination in one individual of these two haplotypes is referred to as a diplotype.

Diplotype: What genotype is to allele, diplotype is to haplotype; a specific combination of two haplotypes.

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5 thoughts on “Frequency of CYP2D6 alleles affecting drug metabolism

  1. meb

    The pharmgkb link doesn’t seem to correct, “Resource Not Found

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    1. Zyp Czyk Post author

      I agree! The CDC guideline has resulted in a deadly policy. They won’t give my 88-yr-old mother more than 2 Vicodin daily, ostensibly to prevent some junkie shooting up and dying, but there is NO connection between a senior who need pain control and young people who succumb to addiction out of despair.

      Now pain patients are in even more despair, so it’s no wonder suicides are becoming more frequent. We die of painful misery, addicts overdose due to psychological despair. Despair defines the whole situation for both patients and doctors.

      I keep dreaming of waking up from this nightmare. If this is how we are expected to live in America, those suffering from these barbaric policies are making a logical decision to leave – not just the country, but life itself.

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