{{Rsnum
|rsid=3892097
|Gene=CYP2D6
|Chromosome=22
|position=42524947
|Orientation=plus
|GMAF=0.1061
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|geno1=(A;A)
|geno2=(A;G)
|geno3=(G;G)
|Gene_s=CYP2D6
}}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|OA=1
}}

[[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}}

{{ neighbor
| rsid = 5030655
| distance = 139
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6*4; CYP2D6:1846G>A
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=PubMed ID:19444434
|Annotation=This study of 43 patients with systemic sclerosis and 129 healthy volunteers showed higher prevalence of the CYP2D6*4 mutated alleles in patients with systemic sclerosis and the obtained OR values (OR = 2.6; P = 0.0002) suggest that this mutation has the effect of increasing systemic sclerosis morbidity rate.
|Drugs=
|Drug Classes=
|Diseases=Sclerosis
|Curation Level=Curated
|PharmGKB Accession ID=PA164857024
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6*4; CYP2D6:1846G>A
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=Web Resource:http://www.pharmgkb.org/search/annotatedGene/cyp2d6/variant.jsp#ImportantVariantInformationforCYP2D6-555
|Annotation=Causes a splicing defect that results in a non-functional protein and is diagnostic for the CYP2D6*4 haplotype.
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=In-Depth
|PharmGKB Accession ID=PA161145187
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6:1846G>A
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=PubMed ID:16958828
|Annotation=This variant is diagnostic for the non-functional CYP2D6*4 haplotype. Individuals with CYP2D6 *6/*4 , *5/*4 or *6/*6 genotypes are poor metabolizers of venlafaxine and are more prone to drug-induced side effects such as nausea, vomiting and diarrhea. However, CYP2D6 genotype does not seem to influence venlafaxine efficacy.
|Drugs=venlafaxine
|Drug Classes=
|Diseases=Depression; Depressive Disorder; Depressive Disorder, Major; Diarrhea; Drug Toxicity; Nausea; Vomiting
|Curation Level=Curated
|PharmGKB Accession ID=PA162316614
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6*4
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=PubMed ID:16958828; PubMed ID:1782973; PubMed ID:18070221
|Annotation=The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. A number of studies show that poor metabolizer (PMs:*4/*4) reqiure a lower dose of drugs which get metabolized by CYP2D6.
|Drugs=clomipramine; codeine; desipramine; imipramine; nortriptyline; venlafaxine
|Drug Classes=
|Diseases=Drug Toxicity
|Curation Level=Curated
|PharmGKB Accession ID=PA162316594
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6:1846G>A, part of CYP2D6*4
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=PubMed ID:19037197; Web Resource:http://preview.pharmgkb.org/search/annotatedGene/cyp2d6/variant.jsp
|Annotation=This variant is diagnostic for the CYP2D6*4 PM haplotype. Plasma concentrations of metoprolol were shown to be were 4.9-fold higher in the PMs, with greater reductions in heart rate, diastolic blood pressure, and mean arterial pressure in PMs than in non-PMs.
|Drugs=metoprolol
|Drug Classes=
|Diseases=
|Curation Level=Curated
|PharmGKB Accession ID=PA162372822
}}

{{PharmGKB
|RSID=rs3892097
|Name_s=CYP2D6:1846G>A, part of CYP2D6*4
|Gene_s=CYP2D6
|Feature=Intron
|Evidence=PubMed ID:16361630; Web Resource:http://preview.pharmgkb.org/search/annotatedGene/cyp2d6/variant.jsp
|Annotation=In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tended to have a higher risk of disease relapse and a lower incidence of hot flashes.
|Drugs=tamoxifen
|Drug Classes=
|Diseases=
|Curation Level=Curated
|PharmGKB Accession ID=PA162372823
}}

{{PMID Auto
|PMID=18547414
|Title=Genotyping panel for assessing response to cancer chemotherapy.
|OA=1
}}

{{PMID Auto
|PMID=19537956
|Title=CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women.
|OA=1
}}

{{PMID Auto
|PMID=20174590
|Title=Response to serotonin reuptake inhibitors in OCD is not influenced by common CYP2D6 polymorphisms.
|OA=1
}}

{{PMID Auto
|PMID=20459744
|Title=Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study.
|OA=1
}}

{{PMID Auto
|PMID=21840870
|Title=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 Auto
|PMID=22638694
|Title=CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application.
|OA=1
}}

{{GET Evidence
|impact=pharmacogenetic
|qualified_impact=Insufficiently evaluated pharmacogenetic
|inheritance=unknown
|quality_scores=Array
|dbsnp_id=rs3892097
|overall_frequency_n=1583
|overall_frequency_d=10548
|overall_frequency=0.150076
|n_genomes=7
|n_genomes_annotated=0
|n_haplomes=7
|n_articles=2
|n_articles_annotated=0
|in_pharmgkb=Y
|autoscore=2
|webscore=N
|n_web_uneval=10
}}

{{PMID Auto
|PMID=22688145
|Title=Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters
}}

{{PMID Auto
|PMID=23130019
|Title=Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.
|OA=1
}}

{{PMID Auto
|PMID=23133420
|Title=Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.
|OA=1
}}

{{on chip | 23andMe v3}}
{{on chip | HumanOmni1Quad}}