Novel and Known Genetic Players in Hypertension: From Gene Expression to Striking Insights

Abstract

Cardiovascular diseases (CVDs) are the most common non-communicable diseases, responsible for 17.9 million deaths each year. Hypertension is a major risk factor for CVDs. Gene expression data obtained from RNA sequencing can help identify novel genes associated with hypertension and provide deeper insights into the functional roles of the [~]2,000 known hypertension GWAS loci. In this study, we utilized RNA-seq data from 1,796 individuals from the KORA FF4 cohort. Differential gene expression analyses were done for hypertension and its phenotypes, i.e., systolic blood pressure, diastolic blood pressure and pulse pressure, followed by gene set enrichment analyses. The significant genes were then further tested in a sensitivity analysis using participants without any reported cardiometabolic disorders or medication use. To investigate the connection between genetic variants, environment and gene expression, we integrated RNA-seq data, genotyping array data and methylation data to perform eQTL and CpG methylation-gene expression analyses. Mendelian randomization analyses were performed to answer the question of causality between the gene expression of these genes and blood pressure phenotypes. Our findings highlight novel and known genetic contributors to hypertension, establish potential downstream consequences of hypertension-related genetic variants and CpG sites, and reveal that blood pressure is mostly a cause for change in gene expression. We propose 7 novel genes that can be further targeted as candidate genes for functional follow-ups to get insight into potential new pathways for hypertension, i.e., MIR23AHG (also known as LOC284454), PGPEP1, RNASEK-C17orf49, PDCD4-AS1, SNRPA1, AGO4 and CCT6P1. In light of Mendelian randomization analyses and what genes are druggable in our analyses, we recommend LMNA, already known to be involved in cardiovascular diseases, as a drug target for managing the adverse effects of hypertension. Our results provide a foundation for future functional studies and drug development efforts.