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.
AIMS: Allelic variants of cytochrome P450CYP2D6 (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.
Authors: A Gaedigk; L Ndjountché; K Divakaran; L Dianne Bradford; I Zineh; T F Oberlander; D C Brousseau; D G McCarver; J A Johnson; S W Alander; K Wayne Riggs; J Steven Leeder Journal: Clin Pharmacol Ther Date: 2007-02 Impact factor: 6.875
Authors: Jessica Tay-Sontheimer; Laura M Shireman; Richard P Beyer; Taurence Senn; Daniela Witten; Robin E Pearce; Andrea Gaedigk; Cletus L Gana Fomban; Justin D Lutz; Nina Isoherranen; Kenneth E Thummel; Oliver Fiehn; J Steven Leeder; Yvonne S Lin Journal: Pharmacogenomics Date: 2014-12 Impact factor: 2.533
Authors: Charity Nofziger; Amy J Turner; Katrin Sangkuhl; Michelle Whirl-Carrillo; José A G Agúndez; John L Black; Henry M Dunnenberger; Gualberto Ruano; Martin A Kennedy; Michael S Phillips; Houda Hachad; Teri E Klein; Andrea Gaedigk Journal: Clin Pharmacol Ther Date: 2019-12-09 Impact factor: 6.875
Authors: Alison Fohner; LeeAnna I Muzquiz; Melissa A Austin; Andrea Gaedigk; Adam Gordon; Timothy Thornton; Mark J Rieder; Mark A Pershouse; Elizabeth A Putnam; Kevin Howlett; Patrick Beatty; Kenneth E Thummel; Erica L Woodahl Journal: Pharmacogenet Genomics Date: 2013-08 Impact factor: 2.089