Blood metabolites mediate effects of breakfast skipping on heart failure via Mendelian randomization analysis

Numerous observational studies have suggested a potential causal relationship between skipping breakfast and cardiovascular diseases, including heart failure (HF). However, these studies are susceptible to inherent confounders and the challenge of reverse causation, and the underlying metabolic factors are not yet clear. Therefore, our aim is to assess the causal impact of breakfast skipping on HF and the role of potential mediating metabolic products from a genetic perspective, by conducting Mendelian Randomization (MR) studies and mediation analysis. We leveraged summary data from the most extensive genome-wide association studies to date on breakfast skipping (with 193,860 participants), blood metabolites (with 118,461 participants), and HF (involving 47,309 cases and 930,014 controls). To explore the causal relationship between breakfast skipping and HF, as well as the role of 249 potential blood metabolite mediators, we conducted bidirectional MR and mediation MR analyses. We primarily employed the Inverse Variance Weighted (IVW) method, complemented by various other techniques to ensure the comprehensiveness and reliability of our analysis. Our research confirms a causal association between breakfast skipping and an increased risk of HF (odds ratio [OR]: 1.378, 95% confidence interval [CI]: 1.047-1.813; p = 0.022). Furthermore, our research findings demonstrate that breakfast skipping is positively correlated with 6 blood metabolites and negatively correlated with 2 others. Notably, our mediation MR analysis further reveals that three blood metabolites act as mediators in the relationship between breakfast skipping and the risk of HF. Specifically, the mediating effects are attributed to the ratio of docosahexaenoic acid (DHA) to total fatty acids (proportion mediated = 9.41%, 95% CI: 2.10-28.61%), glucose (proportion mediated = 6.17%, 95% CI: 0.97-28.53%), and glycoprotein acetyls (GlycA) (proportion mediated = 5.68%, 95% CI: 0.94-21.62%). The combined mediating effects of these three factors total 20.53% (95%CI: 8.59-91.06%). Our research confirms the causal relationship between genetically instrumented breakfast skipping and HF, underscoring the potential mediating roles played by three key blood metabolites: ratio of DHA to total fatty acids, glucose and GlycA. This discovery offers valuable perspectives for clinical strategies targeting HF.