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 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.

Automated summary

Research on the impact of the enhancer SNP rs5758550 on CYP2D6 activity suggests minimal effects on activity prediction, with potential substrate-dependency for certain probe substrates. Although in vitro studies found a modestly higher metabolite formation rate for CYP2D6*2 alleles with the enhancer SNP, the lack of significant effect in vivo raises questions on whether the observed effects are truly caused by the enhancer SNP. Further investigation is needed to determine the exact role of this SNP in CYP2D6 pharmacogenetic testing.