Abstract 14286: New Drug Repurposing Opportunities for Hypertension Uncovered by the Convergence of Genomics With Kidney Transcriptomics and Epigenomics

Introduction:Hypertension is a major cause of premature mortality. Currently, there are only 6 main pharmacological classes used in the management of hypertension and no new antihypertensive medication has been introduced to clinical practice since 2007. Therefore, we investigated new therapeutic opportunities for hypertension through exploiting the druggable genome.Methods:We conducted expression(e), splicing(s) and methylation(m) quantitative trait loci (QTL) analysis on 430 human kidneys. 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:We identified 479 informative genetic variants mapped onto 918 protein coding genes. In total, 201 (21.9%) of the 918 identified genes were drugged or druggable. We uncovered 209 drugs targeting 44 (21.9%) of the protein coding genes. We rediscovered key classes of drugs with known anti-hypertensive effect (e.g. ACE-inhibitors and nitrates). 45 (21.5%) drugs were identified as repurposing opportunities for hypertension based on clinical evidence and directionality of effect on gene activity. Of those, topiramate, approved for treatment of tonic-clonic seizures, emerged as the clinically strongest drug repurposing opportunity for hypertension. Topiramate enhances the inhibitory effect of the GABA-A receptor [encoded by Gamma- Aminobutyric acid Type A receptor Alpha2 subunit (GABRA2) gene] and previous small RCTs have shown that topiramate results in a reduction in blood pressure, corroborating our findings.Conclusion:In conclusion, integration of pharmacological databases with -omic data of tissue of key relevance to hypertension may uncover novel drug repurposing opportunities.