Unveiling the Immune Mechanisms of Hypertension With Single‐Cell Transcriptome‐Wide Mendelian Randomization

Immune dysregulation is closely implicated in hypertension pathogenesis, yet specific therapeutic targets are lacking. We integrated expression quantitative trait loci (eQTLs) for genes expressed in 14 immune cell subsets (OneK1K) with two-sample Mendelian randomization (MR) and colocalization to provide evidence for cell type-specific causal effects of eGenes (genes with eQTLs) on hypertension and related complications (FinnGen and UK Biobank). Single cell-level expression of causal eGenes was compared between individuals with and without hypertension. A tiered framework was built to prioritize crucial eGenes for therapeutic translation. The druggability of the prioritized eGenes was surveyed, with potential on-target side effects evaluated using phenome-wide MR. Immune cell-specific expression of 172 eGenes was causally associated with hypertension, with prioritization of 17 eGenes performed by colocalization. eGenes in naïve and central memory CD4+ T cell (CD4 NC), effector memory CD8+ T cell (CD8 ET), and natural killer cell (NK) were most significantly associated with hypertension. Among these, FNBP4 and PRELID1 in multiple cell subsets moonlight as causal drivers of hypertensive heart disease. Higher expression levels of DDX5 in CD4 NC and CD8 NC, VIM in CD8 ET, and CTSW in NK were observed in hypertensive patients than normotensive controls. Most eGenes categorized as Tier 1 and 2 targets were druggable, and genetically mimicked therapeutics targeted at Tier 1 targets were predicted to generate limited on-target side effects. Our findings provided robust genetic insights into the immunological etiology of hypertension, opening up new avenues for the development of immune-mediated anti-hypertensive therapies.