Identification of Novel Therapeutic Targets for Hypertension

Abstract

Background: Persistently high blood pressure remains the leading risk factor for mortality worldwide. This study aims to identify potential drug targets for hypertension.

Methods: Mendelian randomization was used to identify therapeutic targets for hypertension. Genome-wide association study summary statistics were obtained from the UK Biobank and FinnGen study. Cis-expression quantitative trait loci from the eQTLGen Consortium served as genetic instruments. Colocalization analysis evaluated the likelihood of shared causal variants between single-nucleotide polymorphisms influencing hypertension and gene expression. Survival analysis of UK Biobank data assessed hypertension and mortality risks across participants with different gene alleles.

Results: Mendelian randomization analysis identified 190 drug targets in the discovery cohort and 65 in the replication cohort after multiple testing correction. Colocalization analysis identified 14 hypertension-related drug targets, including ACE, AIMP1, CDC25A, EHMT2, FES, GPX1, GRK4, HSD3B7, NEK4, PTPN12, SIK2, SLC22A4, SLC2A4, and TNFSF12. Survival analysis revealed individuals with the A allele at rs4308 in the ACE gene had a higher incidence of hypertension, while those with the T allele at rs11242109 in the SLC22A4 gene showed a lower hypertension-specific mortality rate.

Conclusions: Drug target Mendelian randomization studies offer new directions for hypertension treatment, providing insights into its mechanisms and robust targets for developing antihypertensive drugs.

Keywords: Mendelian randomization analysis; alleles; genome-wide association study; hypertension; risk factors.