Rs3892097

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is asnp
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dbSNPrs3892097
hapmaprs3892097
hgdprs3892097
ensemblrs3892097
gopubmedrs3892097
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hgvbaseg2prs3892097
medrefsnprs3892097
23andMers3892097
SNP Nexus

GeneCYP2D6
Chromosome22
Orientationminus
Position42524947
ReferenceGRCh37 37.1/131
GenotypeEffect
rs3892097(A;A)CYP2D6 poor metabolizer; many associations related to drug metabolism
rs3892097(A;G)extensive metabolizer (usually)
rs3892097(G;G)extensive metabolizer


Genotypes Magnitude Summary
Rs3892097(A;A) 33 CYP2D6 poor metabolizer; many associations related to drug metabolism
Rs3892097(A;G) extensive metabolizer (usually)
Rs3892097(G;G) extensive metabolizer
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]

Neighborrs5030655
Distance139
PharmGKBPA161145187
NameCYP2D6*4, CYP2D6:1846G>A
AnnotationCauses a splicing defect that results in a non-functional protein and is diagnostic for the CYP2D6*4 haplotype.
GeneCYP2D6
FeatueIntron
EvidenceWeb Resource:http://www.pharmgkb.org/search/annotatedGene/cyp2d6/variant.jsp#ImportantVariantInformationforCYP2D6-555
Drugs
Diseases
Curation LevelIn-Depth