Abstract
BACKGROUND: Coronary heart disease (CHD) represents a substantial global burden in terms of morbidity and mortality. Understanding the causal relationships between serum metabolites and CHD can provide a crucial understanding of disease mechanisms and potential therapeutic targets. METHODS: We conducted a Mendelian randomization (MR) approach to explore the potential causal associations between serum metabolites and CHD risk. The primary analysis employed the inverse variance weighted (IVW) method, supplemented by additional analyses, including MR-Egger, weighted median, weighted mode, and sample mode. To bolster the robustness and reliability of our findings, we performed sensitivity analyses, which included evaluating, horizontal pleiotropy and leave-one-out analysis. Additionally, pathway enrichment analysis was conducted. RESULTS: We identified 15 known and 11 unknown metabolites with potential associations to CHD. Among the known, six displayed protective effects, while nine were identified as risk factors. Notably, many of these metabolites are closely related to mitochondrial function, which was further supported by pathways and enrichment analysis. Using multiple statistical models to ensure robust results, we unveiled a significant association between hexadecanedioate, a palmitoyl lipid metabolized in mitochondria, and a ∼18% reduced risk of CHD (OR = 0.82, 95%CI: 0.72-0.93). CONCLUSION: MR analysis revealed 6 protective molecules, 9 hazardous metabolites associated with CHD. Many of these known metabolites are closely link to mitochondrial function, suggesting a critical role of mitochondria in CHD development. In particular, hexadecanedioate, an essential component for mitochondrial energy production, was inversely associated with CHD risk. This suggests that mitochondrial function, and specifically the role of hexadecanedioate, may be pivotal in the development and progression of CHD.