Novel copy-number variations in pharmacogenes contribute to interindividual differences in drug pharmacokinetics

Abstract

PurposeVariability in pharmacokinetics and drug response is shaped by single-nucleotide variants (SNVs) as well as copy-number variants (CNVs) in genes with importance for drug absorption, distribution, metabolism, and excretion (ADME). While SNVs have been extensively studied, a systematic assessment of the CNV landscape in ADME genes is lacking.MethodsWe integrated data from 2,504 whole genomes from the 1000 Genomes Project and 59,898 exomes from the Exome Aggregation Consortium to identify CNVs in 208 relevant pharmacogenes.ResultsWe describe novel exonic deletions and duplications in 201 (97%) of the pharmacogenes analyzed. The deletions are population-specific and frequencies range from singletons up to 1%, accounting for >5% of all loss-of-function alleles in up to 42% of the genes studied. We experimentally confirmed novel deletions in CYP2C19, CYP4F2, and SLCO1B3 by Sanger sequencing and validated their allelic frequencies in selected populations.ConclusionCNVs are an additional source of pharmacogenetic variability with important implications for drug response and personalized therapy. This, together with the important contribution of rare alleles to the variability of pharmacogenes, emphasizes the necessity of comprehensive next-generation sequencing-based genotype identification for an accurate prediction of the genetic variability of drug pharmacokinetics.

Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles

“…The full gene and partial‐gene CYP2C19 deletions have been designated by the PharmVar Consortium as CYP2C19 *36 and CYP2C19 *37, respectively (http://www.pharmvar.org). Of note, the CYP2C19* 37 partial deletion allele is consistent with the CYP2C19 partial‐gene deletions recently identified in the Exome Aggregation Consortium (ExAC) database (Ruderfer et al, ; Santos et al, ). Dissemination of these newly defined CYP2C19 alleles through the widely utilized PharmVar database will likely increase awareness of these low frequency structural variants across the pharmacogenomics community.…”

“…Pharmacogenomic structural variation has been previously characterized at several clinically relevant regions (Santos et al, ), including CYP450 genes ( CYP2A6 , CYP2B6 , CYP2C cluster, and CYP2D6 ), glutathione S‐transferases ( GSTT1 and GSTM1 ), and sulfotransferases ( SULT1A1 and SULT2A1; Gaedigk et al, , ; Martis et al, ; Schulze et al, ; Vijzelaar et al, ). Notably, individuals with greater than two functional CYP2D6 copies (e.g.…”

“…Interestingly, CYP2C19 deletions have previously been reported in a Northern Finnish case‐control study, which identified an association between CYP2C19 deletion and triple‐negative breast cancer (ER/PR/HER2 negative), implicating CYP2C19 in estrogen catabolism (Tervasmaki, Winqvist, Jukkola‐Vuorinen, & Pylkas, ). Our combined analysis of clinical CMA data from two academic medical centers and publicly available databases indicate that the carrier frequency of a CYP2C structural variant is ~1 in 1,000, with ~1 in 2,000 being a CYP2C19 deletion carrier; however, these aberrations may have higher allele frequencies in specific subpopulations (Santos et al, ; Tervasmaki et al, ).…”

“…However, pharmacogenomic CNV alleles can play important roles in enzyme activity and drug response variability (He, Hoskins, & McLeod, ), which have been characterized among some cytochrome P450 ( CYP2B6 and CYP2D6 ), glutathione S‐transferase ( GSTT1 and GSTM1 ), and sulfotransferase ( SULT1A1 and SULT2A1 ) genes (Gaedigk, Gaedigk, & Leeder, , ; Gjerde et al, ; Martis et al, ; Schulze et al, ; Vijzelaar et al, ). Notably, interrogation of publicly available sequencing data has recently indicated that some populations harbor CNV alleles at the CYP2C gene region (Santos et al, ). The potential clinical significance of low frequency structural variation at the CYP2C gene region in the general population prompted our interrogation of chromosomal microarray (CMA) data from multiple database sources for pharmacogenomic CNV discovery.…”

Genetic insight into cytochrome P450 in Chinese from the Chinese Millionome Database

“…These absences could be caused by the low depth of sequencing and short read methodology. However, CNVs and SVs are important indicators of pharmacogenetic variability and have clinical implications for drug response and personalized medication . Together with the underestimated contribution of rare alleles to the variability of CYP genes, the results of this study emphasize the necessity of comprehensive NGS‐based genotyping identification to accurately predict the genetic variability of drug metabolism and disposition.…”