The Impact of the CYP2D6 "Enhancer" Single Nucleotide Polymorphism on CYP2D6 Activity

rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant "enhancer" single nucleotide polymorphism (SNP), our goal was to further assess the impact of r...

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Veröffentlicht in:Clinical pharmacology and therapeutics Jg. 111; H. 3; S. 646
Hauptverfasser: Dinh, Jean C, Boone, Erin C, Staggs, Vincent S, Pearce, Robin E, Wang, Wendy Y, Gaedigk, Roger, Leeder, James Steven, Gaedigk, Andrea
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2022
Schlagworte:
Adolescent
Alleles
Atomoxetine Hydrochloride - therapeutic use
Child
Cytochrome P-450 CYP2D6 - genetics
Dextromethorphan - therapeutic use
Genotype
Haplotypes - genetics
Humans
Pharmacogenomic Testing - methods
Phenotype
Polymorphism, Single Nucleotide - genetics
ISSN:1532-6535, 1532-6535
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Zusammenfassung:rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant "enhancer" single nucleotide polymorphism (SNP), our goal was to further assess the impact of rs5758550 on CYP2D6 activity toward two probe substrates, atomoxetine (ATX) and dextromethorphan (DM), using in vivo urinary metabolite (DM; n = 188) and pharmacokinetic (ATX; n = 70) and in vitro metabolite formation (ATX and DM; n = 166) data. All subjects and tissues were extensively genotyped, the "enhancer" SNP phased with established CYP2D6 haplotypes either computationally or experimentally, and the impact on CYP2D6 activity investigated using several linear models of varying complexity to determine the proportion of variability in CYP2D6 activity captured by each model. For all datasets and models, the "enhancer" SNP had no or only a modest impact on CYP2D6 activity prediction. An increased effect, when present, was more pronounced for ATX than DM suggesting potential substate-dependency. In addition, CYP2D6*2 alleles with the "enhancer" SNP were associated with modestly higher metabolite formation rates in vitro, but not in vivo; no effect was detected for CYP2D6*1 alleles with "enhancer" SNP. In summary, it remains inconclusive whether the small effects detected in this investigation are indeed caused by the "enhancer" SNP or are rather due to its incomplete linkage with other variants within the gene. Taken together, there does not appear to be sufficient evidence to warrant the "enhancer" SNP be included in clinical CYP2D6 pharmacogenetic testing.
Bibliographie:ObjectType-Article-1
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ISSN:1532-6535
1532-6535
DOI:10.1002/cpt.2469