Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS.

Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results.

UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk.

Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

Epidemiological studies have suggested a potential connection between psoriasis and an increased risk of aortic valve stenosis (AS), though the impact of psoriasis on AS progression remains uncertain. The study aims to investigate the causal relationship between psoriasis and AS using Mendelian randomization (MR) analysis, as well as to uncover potential mechanisms underlying this association.

A two-sample MR analysis was conducted using publicly available summary statistics from genome-wide association studies (GWAS) of psoriasis and AS. Cis-eQTL and significant genes were identified for each causal single-nucleotide polymorphisms (SNPs), followed by pathway enrichment and protein-protein interaction (PPI) analysis for functional evaluation. Hub genes were pinpointed by Cytospace. The transcriptional profile of AS population was acquired, and interconnected genes networks were clustered using Molecular Complex Detection (MCODE).

Our results demonstrate a significant causal relationship between psoriasis and AS, with a genetic predisposition to psoriasis associated with a higher AS risk (odds ratio: 1.46). Pathway and PPI analyses unveiled 15 hub genes, including HLA-C, HLA-B, ISG15, IFIT3, and MX2, along with immune-related pathways linking psoriasis and AS. Moreover, the transcriptional profiling of the AS database highlighted the significant involvement of adaptive immune cells in AS development. Notably, among the 15 hub genes, ISG15, MX2, OAS3, OASL, IFI6, and EPSTI1 exhibited higher expression in the AS population.

Our study provides compelling evidence supporting a causal relationship between psoriasis and AS. Furthermore, the identified hub genes and immune-related pathways may play an important role in the development of both diseases.