Evaluating Causal Relationship Between Metabolites and Six Cardiovascular Diseases Based on GWAS Summary Statistics

Abstract

Cardiovascular diseases (CVDs) remain the main cause of morbidity and mortality worldwide. The pathological mechanism and underlying biological processes of these diseases with metabolites remain unclear. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of metabolites on these diseases by making full use of the latest GWAS summary statistics for 486 metabolites and six major CVDs. Extensive sensitivity analyses were implemented to validate our MR results. We also conducted linkage disequilibrium score regression (LDSC) and colocalization analysis to investigate whether MR findings were driven by genetic similarity or hybridization between LD and disease-associated gene loci. We identified a total of 310 suggestive associations across all metabolites and CVDs, and finally obtained four significant associations, including bradykinin, des-arg(9) (odds ratio [OR] = 1.160, 95% confidence intervals [CIs]: 1.080–1.246, false discovery rate [FDR] = 0.022) on ischemic stroke, N-acetylglycine (OR = 0.946, 95%CIs: 0.920–0.973, FDR = 0.023), X-09026 (OR = 0.845, 95%CIs: 0.779–0.916, FDR = 0.021) and X-14473 (OR = 0.938, 95%CIs = 0.907–0.971, FDR = 0.040) on hypertension. Sensitivity analyses showed that these causal associations were robust, the LDSC and colocalization analyses demonstrated that the identified associations were unlikely confused by LD. Moreover, we identified 15 important metabolic pathways might be involved in the pathogenesis of CVDs. Overall, our work identifies several metabolites that have a causal relationship with CVDs, and improves our understanding of the pathogenesis and treatment strategies for these diseases.

Association between human blood metabolome and the risk of hypertension

“…To enhance the rigor of our selection process for instrumental variables (IVs), we employed more stringent criteria compared to a previous study [19]. However, for metabolites with multiple IVs (more than two), several sensitivity analyses were performed to validate the robustness of our findings.…”

“…In the previous Mendelian randomization (MR) analysis from Qiao et al [19], three metabolites, namely N-acetylglycine (OR = 0.95, 95%CI: 0.92-0.97, FDR = 0.023), X-09026 (OR = 0.85, 95%CI: 0.78-0.92, FDR = 0.02), and X-14473 (OR = 0.94, 95%CI: 0.91-0.97, FDR = 0.04), were found to be significantly associated Fig. 3 Bidirectional Mendelian randomization analysis supports causal associations for blood metabolites on hypertension and vice versa.…”

Association between human blood metabolome and the risk of coronary heart disease: Mendelian randomization study

“…The scatter plots and funnel plots further substantiate the reliability of these results. Employing the latest GWAS summary data, this study eclipses previous research in terms of scale of exposure data (8299 compared to 7828) and a wider range of metabolites 27 , ensuring a more thorough and rigorous analysis. While the selection criteria were exacting, more lenient conditions were adopted for identifying factors influencing CHD (genome-wide significance level of p<1× 10^-5, r2<0.001 within 10000kb).…”

Systematic metabolomic studies identified adult adiposity biomarkers with acetylglycine associated with fat loss in vivo

“…Further investigations into the long-term effect are needed to clarify these contradictory results. In addition to obesity-related traits, a study on the causal effect of metabolites on cardiovascular diseases found that acetylglycine is associated with a lower risk of diastolic blood pressure and is considered a potential cause (Qiao et al, 2021). The glycine N-acyltransferase (GLYAT) enzyme, linked with phenylalanine metabolism (Supplementary Figure S4), forms N-acylglycines (Westhuizen et al, 2000) and catalyzes glycine conjugation of acyl-Coa-species, producing intermediate products such as acetylglycine in amino acid and fatty acid metabolism (Badenhorst et al, 2013).…”