Shared Genetics of Hypertension and Preeclampsia Converges on Immune Regulation

BackgroundHypertension and preeclampsia are clinically distinct, yet biologically related conditions characterized by vascular dysfunction and elevated cardiovascular risk. Although genome-wide association studies (GWAS) have identified loci associated with blood pressure traits and preeclampsia, the functional mechanisms linking shared variants to gene regulation and clinical phenotypes remain unclear. MethodsWe integrated GWAS summary statistics for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and preeclampsia to identify shared variants (p [≤] 1x10-). Cis-expression quantitative trait loci (eQTL) analyses were performed in whole blood using RNA-seq data from 180 African American women. Significant associations (FDR [≤] 0.05) were evaluated for replication across vascular, metabolic, and endocrine tissues in the Genotype-Tissue Expression (GTEx) project. Associations between gene expression and blood pressure traits were also assessed. ResultsWe identified 4,792 shared GWAS variants, of which 4,663 were tested in eQTL analyses, yielding 1,837 significant variant-gene associations across 78 genes. Replication in GTEx confirmed 645 associations involving 24 genes, many showing cross-tissue regulatory effects. Three genes (C4B, HLA-C, and HLA-DQB1) demonstrated convergent evidence across GWAS, gene regulation, and expression-trait analyses. C4B expression was positively associated with hypertension and SBP, while HLA-C showed consistent negative associations with hypertension, SBP, and DBP. HLA-DQB1 expression was specifically associated with DBP, suggesting trait-specific effects. ConclusionsThese findings highlight immune-related pathways as key mediators linking hypertension and preeclampsia. Integrating genetic, transcriptomic, and phenotypic data provides a framework for identifying functionally relevant loci and advancing mechanistic insights into cardiometabolic and pregnancy-related disorders. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/26352450v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1332b09org.highwire.dtl.DTLVardef@4e7c49org.highwire.dtl.DTLVardef@c1b980org.highwire.dtl.DTLVardef@799767_HPS_FORMAT_FIGEXP M_FIG C_FIG Shared genetic variants across hypertension, blood pressure traits, and preeclampsia converge on immune regulatory genes linking gene regulation to clinical phenotypes. GWAS summary statistics for hypertension, SBP, DBP, and preeclampsia were intersected to identify 4,792 shared variants, of which 4,663 were tested in cis-eQTL analyses in whole blood from 180 African American women (left). Shared variants regulate immune-related genes through cis-eQTL effects, yielding 1,837 associations involving 78 genes (FDR [≤] 0.05). Three convergent genes emerged: C4B (upregulated), HLA-C (downregulated), and HLA-DQB1 (upregulated), with 645 associations involving 24 genes replicated across eight tissues in GTEx (center). Expression-trait analyses confirmed that C4B expression was positively associated with hypertension and SBP, HLA-C expression was negatively associated with hypertension, SBP, and DBP, and HLA-DQB1 expression was specifically associated with DBP. These genes implicate complement activation, antigen presentation, and adaptive immunity as shared mechanisms contributing to vascular dysfunction in both hypertension and preeclampsia. eQTL indicates expression quantitative trait locus; FDR, false discovery rate; GTEx, Genotype-Tissue Expression project; SBP, systolic blood pressure; DBP, diastolic blood pressure; APC, antigen-presenting cell; TCR, T-cell receptor; MHC, major histocompatibility complex.