Exploring the Causal Effects of Circulating ST2 and Galectin-3 on Heart Failure Risk: A Mendelian Randomization Study

Abstract

BackgroundHeart failure (HF), primarily caused by conditions such as coronary heart disease or cardiomyopathy, is a global health problem with poor prognosis and heavy burden on healthcare systems. As biomarkers of myocardial injury and fibrosis, suppression of tumorigenicity 2 (ST2) and galectin-3 were recommended for prognosis stratification in HF guidelines. However, the causality between these two mediators and HF remains obscure. This study aimed to explore the causal relationship of genetically determined ST2 and galectin-3 with the risk of HF.MethodsWe used the two-sample Mendelian randomization (MR) method, incorporating available genome-wide association summary statistics, to investigate the causal association of ST2 and galectin-3 with HF risk. We applied inverse-variance weighted analysis as the main method of analysis.ResultsIn our final MR analysis, 4 single-nucleotide polymorphisms (SNPs) of ST2 and galectin-3, respectively, were identified as valid instrumental variables. Fixed-effect inverse variance weighted (IVW) analysis indicated that genetically predicted ST2 and galectin-3 were not causally associated with HF risk 3. [odds ratio (OR) = 0.9999, 95% confidence interval [CI] = 0.9994–1.0004, p = 0.73; OR = 1.0002, 95% CI = 0.9994–1.0010, p = 0.60, respectively]. These findings were robust in sensitivity analyses, including MR-Egger regression and leave-one-out analysis.ConclusionThis MR study provided no evidence for the causal effects of ST2 and galectin-3 on HF risk.

Genetically determined serum bilirubin level and the risk of heart failure: A mendelian randomization study

“…With the aid of large-scale GWAS datasets, two-sample MR analysis has been widely used to examine the etiological roles of risk factors that reported in conventional observational studies in the development of various cardiovascular diseases (Lamina and Kronenberg, 2021). Similar to our study, previous MR analysis reported non-significant causal associations between cystatin C, galectin-3 and C-reactive protein with HF (van der Laan et al, 2016;Li et al, 2021;Wang et al, 2022), suggesting that these factors may function as bystanders instead of contributors to HF. While most of the previous MR analyses were conducted in European population, our study conducted a separate analysis by utilizing datasets in East Asian to limit the confounding effect of genetic background, which may improve the generalizability of our results.…”

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