Circulating inflammatory cytokines and risk of aortic stenosis: A Mendelian randomization analysis

Observational studies have consistently reported positive associations between inflammatory biomarkers and the risk of developing aortic stenosis (AS). However, it is crucial to acknowledge that conventional observational studies are prone to various forms of bias, including reverse causation and residual confounding. To delve deeper into unraveling the potential causal relationship between inflammatory biomarkers and aortic stenosis, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis.

In order to explore the causal effect of exposure to various circulating cytokines on the risk of developing AS, we carefully selected AS datasets as the exposures from the summary statistics of the genome-wide association study (GWAS) conducted by FinnGen. The dataset consisted of a sample size of 3283 for AS cases and 210,463 for controls. To estimate the MR analysis, we primarily adopted the inverse variance weighted (IVW) method. Additionally, we employed complementary methods, including Weighted Median, MR Egger, Weighted Mode, and Simple Mode, to analyze the causal associations comprehensively. In order to assess the presence of heterogeneity, we utilized Cochran's Q statistic and MR-Egger regression. To ensure the robustness and consistency of our findings, we conducted a leave-one-out analysis.

We observed a positive association between interleukin-18 (IL-18) levels and AS (odds ratio [OR] per standard deviation [SD] = 1.080; 95 % confidence interval [CI] 1.024 to 1.139), as well as between interferon-gamma levels (IFN-γ) and AS (OR per SD = 1.157; 95 % CI 1.028 to 1.302). Conversely, we found an inverse association between interleukin-13 (IL-13) levels and AS (OR per SD = 0.942; 95 % CI 0.890 to 0.997), as well as between interleukin-5 (IL-5) levels and AS (OR per SD = 0.892; 95 % CI 0.804 to 0.990).

Our research enhances the current understanding of the role of specific inflammatory biomarker pathways in aortic stenosis. Nevertheless, further validation is required to assess the viability of targeting these cytokines through pharmacological or lifestyle interventions as potential treatments for aortic stenosis.