IN SILICO DRUG REPOSITIONING OF TOPIRAMATE AS AN ANTIHYPERTENSIVE BY CONVERGING KIDNEY TRANSCRIPTOMIC, EPIGENOMIC AND GENOMIC DATA

Abstract

Objective: No new antihypertensive medication has been introduced to clinical practice since 2007. Mendel's second law states that genotype is allocated randomly at conception therefore, short nucleotide variants acting in cis can be utilised to deduce the pharmacological action on the same protein as in an RCT. Here, we investigate new therapeutic opportunities for hypertension through exploiting the druggable genome. Design and method: We conducted expression(e), splicing(s) and methylation(m) quantitative trait loci (QTL) analysis on 430 human kidneys from 5 studies [TRANScriptome of renaL humAn TissuE (TRANSLATE) study, Tissue Cancer Genome Atlas (TCGA), moleculAr analysis of human kiDney-Manchester renal tIssue pRojEct (ADMIRE) study, Molecular analysis of mechanisms regulating gene expression in post-ischemic injury to renal allograft (REPAIR) and Renal gEne expreSsion and PredispOsition to cardiovascular and kidNey Disease (RESPOND)]. Through their intersection with blood pressure variants from all previous genome wide association studies (GWAS) we identified genetic variants partnering with protein-coding kidney e-Genes, s-Genes and m-Genes. We then mapped the proteins encoded by these genes onto a set of licensed drugs or compounds with bioactivities against these targets in-silico. Results: Altogether, 479 informative genetic variants mapping onto 918 protein coding genes were identified. Of these, 201 (21.9%) genes were druggable. We found 209 unique associations with 44 (21.9%) protein coding genes. Of these, 23 associations acting on 7 drug targets were precisely concordant (captopril associated with ACE gene) and 16 associations (4 targets) had the indication association within the same disease area [for example, ambrisentan (an endothelin receptor antagonist) acting on a BP GWAS gene EDNRA]. 3 (1.3%) drugs were identified as repurposing opportunities for hypertension based on clinical evidence and directionality of effect on gene activity. Of those, topiramate [target for the alpha-subunit of Gamma-Aminobutyric Acid Type A receipt Alpha2 Subunit (GABRA2) gene], was deemed as clinically strongest drug repurposing opportunity for hypertension. The alpha subunit of this receptor is coded by GABRA2 gene, which is a hypertension risk gene identified in our study. Conclusions: Integration of pharmacological databases with -omic data of tissue of key relevance to hypertension may uncover novel drug repurposing opportunities.