CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction.

Article Details

Citation

Gaedigk A, Fuhr U, Johnson C, Berard LA, Bradford D, Leeder JS

CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction.

Pharmacogenomics. 2010 Jan;11(1):43-53. doi: 10.2217/pgs.09.133.

PubMed ID
20017671 [ View in PubMed
]
Abstract

AIMS: Allelic variants of cytochrome P450 CYP2D6 (CYP2D6), such as gene deletion, duplication, multiplication and conversion, contribute to the wide range of CYP2D6 activity. Novel gene arrangements were discovered and characterized. MATERIALS & METHODS: DNA from 32 Caucasian and 59 African-American duplication-positive subjects were analyzed by long-range PCR and genotyping to detect CYP2D7-2D6 hybrid tandem alleles. Novel allelic variants were sequenced and a strategy for the detection and analysis of hybrid genes was refined. RESULTS: CYP2D7-2D6 hybrid tandem alleles were identified in one African-American and four Caucasian subjects. Three novel hybrid genes were found on CYP2D6*1 and CYP2D6*2 duplication backgrounds and designated CYP2D6*76, *77 and *78. CYP2D7 to 2D6 conversion occurred in introns 1 and 4, and exon 9. All carried a T-insertion in exon 1 abolishing activity. In Caucasians, four out of 33 (12%) of the duplication-positive alleles were hybrid tandems, three CYP2D6*77 + *2 and one CYP2D6*78 + *2. By contrast, in African-Americans only one of 60 duplication-positive alleles was identified as a hybrid tandem. This allele was designated CYP2D6*76 + *1. CONCLUSION: Hybrid tandem alleles occur infrequently (<0.25%) in Caucasians, but may explain why not every subject with a CYP2D6 duplication presents with an ultrarapid metabolizer phenotype.

DrugBank Data that Cites this Article

Pharmaco-genomics
DrugInteracting Gene/EnzymeAllele nameGenotypesDefining change(s)Type(s)DescriptionDetails
MetoprololCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
ADR InferredIncreased risk of slow heart rate (bradycardia)Details
VenlafaxineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, nausea, vomiting and diarrheaDetails
CodeineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
AmitriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ImipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
DextromethorphanCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirementsDetails
NortriptylineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
TamoxifenCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor response to drug treatment, shorter time to relapseDetails
DesipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
ClomipramineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, lower dose requirements, higher risk for adverse side effectsDetails
AtomoxetineCytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
CYP2D6*13Not Available
  • CYP2D7/2D6 hybrid gene structure
Effect InferredPoor drug metabolizer, increased side effects.Details