Assessment of the Genetic Relationship Between Circulating Cytokines and Calcific Aortic Valvular Stenosis Using a Bidirectional Mendelian Randomization Analysis

Available studies have found associations between several cytokines and calcific aortic valvular stenosis (CAVS). To better comprehend the causal link between circulating cytokines and CAVS, we performed a bidirectional Mendelian randomization (MR) study. Genetic variants associated with 41 cytokines were obtained from public genome-wide association study (GWAS), and summary statistics for GWAS of CAVS were obtained from the FinnGen consortium. Forward MR analysis was conducted to determine the impacts of 41 cytokines on CAVS risk and reverse MR analysis was used to determine whether genetic susceptibility to CAVS altered the levels of these cytokines. Inverse-variance weighting (IVW) was implemented as the primary method, and several different sensitivity analyses were used to verify the reliability of the findings. Our results found no significant association between 41 cytokines and CAVS risk. However, increased levels of interleukin-18 (IL-18) (odds ratio [OR] = 1.080, 95% CI: 1.024-1.139) and interferon-gamma (IFN-γ) (OR = 1.157, 95% CI: 1.028-1.302) had suggestive connections with an elevated risk of CAVS, and increased levels of IL-13 (OR = 0.942, 95% CI: 0.890-0.997) and IL-5 (OR = 0.892, 95% CI: 0.804-0.990) had suggestive associations with a reduced risk of CAVS. A reverse MR analysis found that CAVS had a suggestive relationship with a reduced level of platelet-derived growth factor BB (PDGF-BB) (OR = 0.920, 95% CI: 0.853-0.993) and IL-4 (OR = 0.925, 95% CI: 0.856-1.000). Our findings suggest the causal effects of IL-18, IFN-γ, IL-13, and IL-5 on CAVS risk, and genetic predisposition of CAVS may reduce the levels of PDGF-BB and IL-4.