CYP2D6*36 gene arrangements within the cyp2d6 locus: association of CYP2D6*36 with poor metabolizer status.
Article Details
- CitationCopy to clipboard
Gaedigk A, Bradford LD, Alander SW, Leeder JS
CYP2D6*36 gene arrangements within the cyp2d6 locus: association of CYP2D6*36 with poor metabolizer status.
Drug Metab Dispos. 2006 Apr;34(4):563-9. Epub 2006 Jan 13.
- PubMed ID
- 16415111 [ View in PubMed]
- Abstract
Unexplained cases of CYP2D6 genotype/phenotype discordance continue to be discovered. In previous studies, several African Americans with a poor metabolizer phenotype carried the reduced function CYP2D6*10 allele in combination with a nonfunctional allele. We pursued the possibility that these alleles harbor either a known sequence variation (i.e., CYP2D6*36 carrying a gene conversion in exon 9 along the CYP2D6*10-defining 100C>T single-nucleotide polymorphism) or novel sequences variation(s). Discordant cases were evaluated by long-range polymerase chain reaction (PCR) to test for gene rearrangement events, and a 6.6-kilobase pair PCR product encompassing the CYP2D6 gene was cloned and entirely sequenced. Thereafter, allele frequencies were determined in different study populations comprising whites, African Americans, and Asians. Analyses covering the CYP2D7 to 2D6 gene region established that CYP2D6*36 did not only exist as a gene duplication (CYP2D6*36x2) or in tandem with *10 (CYP2D6*36+*10), as previously reported, but also by itself. This "single" CYP2D6*36 allele was found in nine African Americans and one Asian, but was absent in the whites tested. Ultimately, the presence of CYP2D6*36 resolved genotype/phenotype discordance in three cases. We also discovered an exon 9 conversion-positive CYP2D6*4 gene in a duplication arrangement (CYP2D6*4Nx2) and a CYP2D6*4 allele lacking 100C>T (CYP2D6*4M) in two white subjects. The discovery of an allele that carries only one CYP2D6*36 gene copy provides unequivocal evidence that both CYP2D6*36 and *36x2 are associated with a poor metabolizer phenotype. Given a combined frequency of between 0.5 and 3% in African Americans and Asians, genotyping for CYP2D6*36 should improve the accuracy of genotype-based phenotype prediction in these populations.
DrugBank Data that Cites this Article
- Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Metoprolol Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
ADR Inferred Increased risk of slow heart rate (bradycardia) Details Venlafaxine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, nausea, vomiting and diarrhea Details Codeine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements Details Amitriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Imipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Dextromethorphan Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements Details Nortriptyline Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Tamoxifen Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor response to drug treatment, shorter time to relapse Details Desipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Clomipramine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for adverse side effects Details Atomoxetine Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635CYP2D6*36 Not Available - 100C>T (rs1065852)
- -1426C>T
- variable number of A’s in the region -1258 to -1237a
Effect Inferred Poor drug metabolizer, increased side effects. Details