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

María Santos, Mikko Niemi, Masahiro Hiratsuka, Masaki Kumondai, Magnus Ingelman-Sundberg, Volker M. Lauschke, Cristina Rodríguez-Antona

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)622-629
Number of pages8
JournalGenetics in Medicine
Issue number6
Publication statusPublished - 2018 Jun 1


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