Skip to main content
Premium Trial:

Request an Annual Quote

Novel CNVs Uncovered Affecting Genes Involved in Drug Metabolism

NEW YORK (GenomeWeb) – Copy-number variants contribute to variability in genes linked to drug metabolism, a new study has found.

Genetic factors are estimated to contribute to between 20 percent and 30 percent of adverse drug reactions, and while SNVs have been linked to genetic variation in pharmacokinetics, the role of CNVs has been less clear.

An international team of researchers has now drawn on data from the 1000 Genomes Project and the Exome Aggregation Consortium to examine CNVs affecting more than 200 known pharmacogenes. As the researchers reported this week in Genetics in Medicine, they uncovered novel deletions and duplications in most of the genes they looked at. Many of these CNVs were specific to particular populations.

"We here show that novel CNVs significantly contribute to the functionality of relevant pharmacogenes, adding an additional layer of pharmacogenetic complexity with important implications for the prediction of drug response and toxicity," the Spanish National Cancer Research Center's Cristina Rodríguez-Antona and her colleagues wrote in their paper.

Using exome and whole-genome data from the ExAC and 1000 Genomes studies, the researchers conducted a bioinformatic analysis of 208 genes involved in drug pharmacokinetics, and found that 97 percent of those harbored novel CNVs. In total, they identified 5,589 novel CNVs and, of those, slightly less than half were deletions and slightly more than half were duplications.

The researchers also determined the minor allele frequencies of the CNVs in certain human populations from this data.

Most of deletions the researchers uncovered were population specific. The most common deletions they found affected CYP2C19 in Finns with a MAF of 1.1 percent, CYP2B6 in Africans with a MAF of 0.9 percent, and CYP4F2 in East Asians with a MAF of 0.4 percent.

The most frequent exonic duplications, meanwhile, affected CBR3 and CYP2B6 with MAFs of 0.7 percent in Finns and 0.4 percent in Africans, respectively.

Rodríguez-Antona and her colleagues confirmed a subset of the novel deletions they uncovered using Sanger sequencing and further performed CNV genotyping of three genes — CYP2C19, CYP4F2, and SLCO1B3 — in 1,080 people from Spain, 465 people from Finland, and 590 people from Japan.

From this, they found that the CYP2C19 exon 1-5 deletion had a MAF of 0.43 percent in the Finnish cohort. CYP2C19 is involved in the metabolism of a number of drugs and is included in the dosing guidelines of 21 US Food and Drug Administration drug labels, including labels for citalopram, clobazam, clopidogrel, escitalopram, and flibanserin, the researchers noted.

The full CYP4F2 gene deletion, meanwhile, had a MAF of 1.61 percent in the Japanese cohort — higher than the East Asian MAF of 0.36 percent, which the researchers said could reflect a population-specific distribution of the deletion. They added that they found one Japanese individual who was homozygous for the deletion.

Additionally, the SLCO1B3 exon 9-13 deletion had a MAF of 0.53 percent in the Spanish cohort. SLCO1B3 encodes OATP1B3, which the researchers said helps clear bilirubin and is involved in the transport of other drugs. The MAF of this deletion is some five times higher in Spanish individuals than in Finns, the researchers noted, which they attributed to population-specific differences.

This suggested to Rodríguez-Antona and her colleagues that folding in CNV data could help determine which pharmacotherapies might work best for certain patients. "In combination with the important role of rare SNVs, our results suggest that the quality of preemptive pharmacogenetic advice, which is typically based on the interrogation of few candidate variants, can be improved by comprehensive NGS-based genotype identification of relevant pharmacogenes," they wrote.