Abstract
The CYP2D6 gene encodes an enzyme important in the metabolism of many commonly used medications. Variation in CYP2D6 is associated with inter-individual differences in medication response, and genetic testing is used to optimize medication therapy. This report describes a retrospective study of CYP2D6 allele frequencies in a large population of 104,509 de-identified patient samples across all regions of the United States (US). Thirty-seven unique CYP2D6 alleles including structural variants were identified. A majority of these alleles had frequencies which matched published frequency data from smaller studies, while eight had no previously published frequencies. Importantly, CYP2D6 structural variants were observed in 13.1% of individuals and accounted for 7% of the total variants observed. The majority of structural variants detected (73%) were decreased-function or no-function alleles. As such, structural variants were found in approximately one-third (30%) of CYP2D6 poor metabolizers in this study. This is the first CYP2D6 study to evaluate, with a consistent methodology, both structural variants and single copy alleles in a large US population, and the results suggest that structural variants have a substantial impact on CYP2D6 function.
Highlights
The CYP2D6 enzyme is involved in the hepatic metabolism of many clinically used medications (Zhou et al, 2009)
Caucasians comprised the majority in all United States (US) geographic regions, with Hispanics more highly represented in Pacific, Mountain, and West South Central regions, and African Americans more highly represented in the East South Central and Middle Atlantic regions
We found that structural variants have both substantial frequencies and potential functional impact
Summary
The CYP2D6 enzyme is involved in the hepatic metabolism of many clinically used medications (Zhou et al, 2009). The CYP2D6 gene is highly polymorphic; over 100 allelic variants and subvariants have been designated to date by the Pharmacogene Variation Consortium (PharmVar) at www.PharmVar.org (Gaedigk et al, 2018). These include variations in single gene copies such as single nucleotide variants (SNVs) or insertions/deletions of a small number of nucleotides. The CYP2D6 gene is known to have structural variants, which include copy number variations (CNVs) such as the deletion of the entire CYP2D6 gene, gene duplications and multiplications, as well as duplications/multiplications of non-identical gene units ( called tandems), and rearrangements involving the CYP2D7 pseudogene (Figure 1). Guidelines for medication therapy adjustment based on CYP2D6 genotype have been published for codeine, tricyclic antidepressants (TCAs), ondansetron and selective serotonin reuptake inhibitors (SSRIs) (Hicks et al, 2013, 2015; Crews et al, 2014; Bell et al, 2017) and are under review for tamoxifen
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