Genome-wide identification of structural variants in genes encoding drug targets: possible implications for...

The objective of the present study was to identify structural variants of drug target-encoding genes on a genome-wide scale. We also aimed at identifying drugs that are potentially amenable for individualization of treatments based on knowledge about structural variation in the genes encoding their targets.

Information about human drug targets of all therapeutic drugs and nutraceuticals approved by the Food and Drug Administration and with an Anatomical Therapeutic Chemical (ATC) code, namely, 876, was obtained from the DrugBank and applied to interrogate the Database of Genomic Variants.

We identified 1721 structural variants, which affected 495 of 1005 different genes encoding drug targets. About 70% of the Food and Drug Administration-approved drugs had targets subjected to structural variation, in particular copy number variation. The distribution of drugs with targets encoded by copy number variable genes differed between ATC groups with pronounced over-representation in ATC group N, that is, nervous system drugs (P=3.75e-5). Several narrow therapeutic index drugs with targets subjected to genomic structural variation were identified. Information about the frequencies of the structural variants and drug consumption allowed us to identify potential candidates for implementation in pharmacogenetic testing and individualized drug treatments.

Structural variants in pharmacodynamic genes may play a larger role in determining individual variation in drug responses than currently believed. Inclusion of such genes in pharmacogenetic testing holds promising prospects as they may have large effect sizes.