Deciphering genetic associations with blood pressure in peripheral blood mononuclear cells through single-cell transcriptomic profiling.

Functional genes within genomic loci associated with blood pressure (BP) identified by genome-wide association studies (GWASs) are cell type-specific. This study aims to identify such genes in immune cells by employing single-cell transcriptomic analysis in peripheral blood mononuclear cells (PBMCs). By integration of single-cell transcriptomic sequencing data with GWAS (1 million individuals) findings using the summary data-based Mendelian randomization (SMR) method, we identified candidate BP-associated genes across diverse immune cell subsets. We performed single-cell RNA sequencing on PBMCs (111,694 cells) from 10 individuals (three hypertensive, three pre-hypertensive and four normotensive), identifying gene expression in distinct cell types associated with hypertension. Finally, publicly available data from eight individuals were utilized for validation (28,919 cells). Single-cell expression quantitative trait locus analysis revealed that the BP-associated SNPs were associated with expression levels of 353 genes across 14 distinct immune cell types. The single-cell SMR analysis identified 566 significant associations between expression levels of 159 genes and BP. The analysis of data from hypertensive and normotensive individuals unveils 99 differential expression genes across various immune cell types, with ERAP2 exhibiting significant dysregulation in CD8+ T cells and natural killer cells. These findings were corroborated through validation analyses. Our study contributes to a comprehensive understanding of the intricate relationships between genetic variation, immune cell-specific gene expression, and BP. We demonstrate a compelling association between ERAP2 expression levels in CD8+ T cells and natural killer cells and BP.