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From SNPedia

Geno Mag Summary
(A;A) 3 CYP2D6 poor metabolizer; many associations related to drug metabolism
(A;G) extensive metabolizer (usually)
(G;G) 0 extensive metabolizer
ReferenceGRCh38 38.1/142
GeneCYP2D6, LOC102723722, LOC107987465, LOC107987481
is asnp
is mentioned by
dbSNP (classic)rs3892097
1000 genomesrs3892097
23andMe allrs3892097
GWAS Ctlgrs3892097
Merged fromRs1800716
Max Magnitude3

The normal (or wild type) form of this SNP is a (G). The (A) form disrupts proper mRNA formation, resulting in a nonfunctional CYP2D6 protein. The associated allele is also known as CYP2D6*4. The CYP2D6*4 allele is the most common nonfunctioning variant of CYP2D6.

If two copies of this (or similar) changes are inherited, poor metabolism ('PM') of debrisoquine [PMID 2211621] is observed. Many other drugs are typically first metabolized by CYP2D6 including dextromorphan, sparteine, metoprolol, nortriptyline and many other antidepressants and codeine. Of course, sometimes the active form of a drug is the one post-CYP2D6 metabolism; an example of this is tamoxifen, where the active form (endoxifen) is formed primarily via CYP2D6 metabolism; less functioning CYP2D6 can mean less benefit from taking the drug.

The CYP2D6*4 allele (i.e. rs3892097(A)) has been postulated by researchers over the years to have many potential consequences, both positive and negative.

On the positive side: this allele may reduce the risk of certain cancers, such as bladder and lung [PMID 1978251], and it may correlate with somwhat less severe neurodegeneration in Alzheimer's [PMID 7574463].

On the other hand, at least two studies [PMID 14991823, PMID 15174030] have concluded that the risk of developing Parkinson's disease upon exposure to pesticides is increased from 3 to 8 fold among carriers of CYP2D6*4 alleles. The risk to CYP2D6*4 carriers appears proportional to the degree of pesticide exposure, with no additional risk of developing Parkinson's seen for CYP2D6*4 carriers with no pesticide exposure, and the highest increased risk of developing Parkinson's seen for CYP2D6*4 carriers with frequent exposure to pesticides.

Patients prescribed tricyclic antidepressants (TCA) who are homozygous for the CYP2D6*4 allele metabolize these drugs more slowly, which puts them at higher risk for adverse side effects. A study of ~1100 Dutch patients reports: (1) 6 fold more side effects upon switching antidepressants for CYP2D6*4 homozygotes, but not for heterozygotes, and (2) that the effective and maintenance doses of antidepressants for CYP2D6*4 homozygotes are lower than for patients with one or more higher metabolizing CYP2D6 alleles. [PMID 18070221OA-icon.png]

rs3892097(A;A) patients taking a beta blocker drug such as metoprolol are at ~4x increased risk for bradycardia, based on a study of 1,533 patients in the Rotterdam Study. These CYP2D6 *4/*4 homozygotes have the 'poor metabolizer' (PM) phenotypes, and had adjusted heart rates that were 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (p < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio of 3.86, CI: 1.68-8.86, p = 0.0014).[PMID 18784654]

[PMID 18547414OA-icon.png] Genotyping panel for assessing response to cancer chemotherapy.

[PMID 19537956OA-icon.png] CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women.

[PMID 20174590OA-icon.png] Response to serotonin reuptake inhibitors in OCD is not influenced by common CYP2D6 polymorphisms.

[PMID 20459744OA-icon.png] Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study.

[PMID 21840870] Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy.

[PMID 22638694OA-icon.png] CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application.

[PMID 22688145] Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters

[PMID 23130019OA-icon.png] Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.

[PMID 23133420OA-icon.png] Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.

Risk Rs3892097(A;A)
Alt Rs3892097(A;A)
Reference Rs3892097(G;G)
Significance Other
Disease Debrisoquine doxepin response - Dosage antidepressants response - Dosage trimipramine response - Dosage imipramine response - Dosage clomipramine response - Dosage tamoxifen response - Efficacy amitriptyline response - Dosage nortriptyline response - Dosage desipramine response - Dosage not provided
Variation info
Gene CYP2D6
CLNDBN Debrisoquine, poor metabolism of doxepin response - Dosage, Toxicity/ADR antidepressants response - Dosage, Toxicity/ADR trimipramine response - Dosage, Toxicity/ADR imipramine response - Dosage, Toxicity/ADR clomipramine response - Dosage, Toxicity/ADR tamoxifen response - Efficacy, Toxicity/ADR amitriptyline response - Dosage, Toxicity/ADR nortriptyline response - Dosage, Toxicity/ADR desipramine response - Dosage, Toxicity/ADR not provided
Reversed 1
HGVS NC_000022.10:g.42524947C>T
CLNSRC OMIM Allelic Variant PharmGKB Clinical Annotation
CLNACC RCV000018385.23, RCV000211167.1, RCV000211174.1, RCV000211232.1, RCV000211292.1, RCV000211293.1, RCV000211307.1, RCV000211390.1, RCV000211415.1, RCV000211422.1, RCV000342450.1,

[PMID 28343093] Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy.