Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs.

ABSTRACT

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii). We then assessed these two factors with 31 genes encoding ion channels or GPCRs that are targeted by the United States Food and Drug Administration (FDA)-approved drugs. Out of the 118 ion channel genes studied, 80 met either factor (i) or (ii), resulting in a 68% match. In contrast, a 78% match was found for the 143 GPCR genes. We also found that the GPCR genes (n = 20) targeted by FDA-approved drugs have a relatively lower mutability than those genes encoding ion channels (n = 11), where targeted genes encoding GPCRs were shorter in length. The result of this study suggests that the use of matching rate analysis on factor-druggable genome is feasible to systematically compare the relative mutability of GPCRs and ion channels. The analysis on chromosomes by two factors identified a unique characteristic of GPCRs, which have a significant relationship between their nucleotide sizes and proximity to telomeres, unlike most genetic loci susceptible to human diseases.