Table1_Serum metabolites and hypercholesterolemia: insights from a two-sample Mendelian randomization study.xlsx

BackgroundHypercholesterolemia, a critical contributor to cardiovascular disease, is not fully understood in terms of its relationship with serum metabolites and their role in disease pathogenesis.
MethodsThis study leveraged GWAS data to explore the relationship between serum metabolites and hypercholesterolemia, pinpointing significant metabolites via Mendelian Randomization (MR) and KEGG pathway enrichment analysis. Data on metabolites were sourced from a European population, with analysis focusing on individuals diagnosed with hypercholesterolemia.
ResultsOut of 486 metabolites analyzed, ten showed significant associations with hypercholesterolemia, categorized into those enhancing risk and those with protective effects. Specifically, 2-methoxyacetaminophen sulfate and 1-oleoylglycerol (1-monoolein) were identified as risk-enhancing, with odds ratios (OR) of 1.545 (95% CI: 1.230–1.939; P_FDR = 3E−04) and 1.462 (95% CI: 1.036–2.063; P_FDR = 0.037), respectively. On the protective side, 3-(cystein-S-yl)acetaminophen, hydroquinone sulfate, and 2-hydroxyacetaminophen sulfate demonstrated ORs of 0.793 (95% CI: 0.735–0.856; P_FDR = 6.18E−09), 0.641 (95% CI: 0.423–0.971; P_FDR = 0.042), and 0.607 (95% CI: 0.541–0.681; P_FDR = 5.39E−17), respectively. In addition, KEGG pathway enrichment analysis further revealed eight critical pathways, comprising “biosynthesis of valine, leucine, and isoleucine”, “phenylalanine metabolism”, and “pyruvate metabolism”, emphasizing their significant role in the pathogenesis of hypercholesterolemia.
ConclusionThis study underscores the potential causal links between particular serum metabolites and hypercholesterolemia, offering innovative viewpoints on the metabolic basis of the disease. The identified metabolites and pathways offer promising targets for therapeutic intervention and warrant further investigation.

背景：高胆固醇血症是心血管疾病的关键致病因素，但其与血清代谢物的关联以及代谢物在疾病发病机制中的作用尚未完全阐明。
方法：本研究利用全基因组关联研究（Genome-Wide Association Study, GWAS）数据探究血清代谢物与高胆固醇血症的关联，并通过孟德尔随机化（Mendelian Randomization, MR）及京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析，精准定位具有显著关联的代谢物。代谢物数据源自欧洲人群，分析对象为确诊高胆固醇血症的个体。
结果：在分析的486种代谢物中，有10种与高胆固醇血症存在显著关联，可分为风险增强型和保护型两类。具体而言，硫酸化2-甲氧基对乙酰氨基酚和1-油酰甘油（又称1-单油精）被鉴定为风险增强型代谢物，其比值比（odds ratio, OR）分别为1.545（95%置信区间：1.230–1.939；错误发现率P_FDR = 3E−04）和1.462（95%置信区间：1.036–2.063；P_FDR = 0.037）。在保护型代谢物中，3-（半胱氨酸-S-基）对乙酰氨基酚、硫酸化对苯二酚以及硫酸化2-羟基对乙酰氨基酚的OR值分别为0.793（95%置信区间：0.735–0.856；P_FDR = 6.18E−09）、0.641（95%置信区间：0.423–0.971；P_FDR = 0.042）和0.607（95%置信区间：0.541–0.681；P_FDR = 5.39E−17）。此外，KEGG通路富集分析进一步揭示了8条关键通路，包括“缬氨酸、亮氨酸与异亮氨酸生物合成”、“苯丙氨酸代谢”以及“丙酮酸代谢”，凸显了这些通路在高胆固醇血症发病机制中的重要作用。
结论：本研究明确了特定血清代谢物与高胆固醇血症之间潜在的因果关联，为该疾病的代谢基础提供了创新性视角。所鉴定的代谢物及通路有望成为治疗干预的潜在靶点，值得开展进一步研究。