Evaluation of the genetic architecture of human blood metabolites on sudden cardiac arrest: A Mendelian randomization analysis

Abstract

Background Previous studies supported metabolic disturbances in sudden cardiac arrest (SCA) patients. Still, the evidence about the causal role of metabolites in SCA is lacking. We investigated the causality between the two, aiming at providing novel targets for SCA prevention. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis based on genome-wide association study (GWAS). The summary dataset for 1,091 metabolites and 309 metabolite ratios was obtained from a GWAS including 8,299 participants. The summary datasets for SCA were obtained from the FinnGen consortium (ncases =2,308 and ncontrols =191,924) and the meta-analysis (ncases =3,939 and ncontrols =25,989), respectively. Sensitivity analyses were performed for the assessment of horizontal pleiotropy and heterogeneity. In order to fully verify the causality, we also used Steiger test, linkage disequilibrium score regression (LDSC), and multivariable MR (MVMR). Results Through inverse variance weighted (IVW) and sensitivity analysis filtration, five metabolites and one metabolite ratio with causal effects on SCA were identified from the FinnGen consortium, except for one of the metabolites categorized as unknown. After excluding biased SNPs, the causality still remained significant for [N2,N5-diacetylornithine (odds ratio (OR) = 1.12, 95% confidence interval (CI) = 1.02–1.22, P = 0.019), ascorbic acid 3-sulfate (OR = 1.16, 95% CI = 1.04–1.30, P = 0.009), uridine to pseudouridine ratio (OR = 1.21, 95% CI = 0.598–0.930, P = 0.009)]. These metabolites still remained significant associations with SCA when combined with the SCA GWAS of meta-analysis. Conclusions This MR study presented a unique perspective that might support the causal relationships between human blood metabolites and SCA, offering valuable opportunities to enhance screening, prevention, and therapeutic strategies for SCA. (253)