|(A;A)||3||CYP2D6 poor metabolizer; many associations related to drug metabolism|
|(A;G)||extensive metabolizer (usually)|
|Gene||CYP2D6, LOC102723722, LOC107987465, LOC107987481|
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 18070221]
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 18547414] Genotyping panel for assessing response to cancer chemotherapy.
[PMID 19537956] CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women.
[PMID 20174590] Response to serotonin reuptake inhibitors in OCD is not influenced by common CYP2D6 polymorphisms.
[PMID 20459744] 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 22638694] 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 23130019] Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.
[PMID 23133420] Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.
|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|
|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|
|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.