Wang Weitao, Qiao Jingwen, Su Zhaoyin, Wei Hui, Wu Jincan, Liu Yatao, Lin Rubing, Michael Nerich
The First Clinical College of Medicine, Lanzhou University, Lanzhou, China.
Graduate Department of Shanxi Medical University, Taiyuan, Shanxi, China.
Front Cardiovasc Med. 2024 Jul 25;11:1410006. doi: 10.3389/fcvm.2024.1410006. eCollection 2024.
Hypercholesterolemia, a critical contributor to cardiovascular disease, is not fully understood in terms of its relationship with serum metabolites and their role in disease pathogenesis.
This 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.
Out 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.
This 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.
高胆固醇血症是心血管疾病的一个关键促成因素，但其与血清代谢物的关系及其在疾病发病机制中的作用尚未完全明确。
本研究利用全基因组关联研究（GWAS）数据来探索血清代谢物与高胆固醇血症之间的关系，通过孟德尔随机化（MR）和KEGG通路富集分析确定显著的代谢物。代谢物数据来源于欧洲人群，分析重点是被诊断为高胆固醇血症的个体。
在分析的486种代谢物中，有10种与高胆固醇血症显示出显著关联，分为增加风险的代谢物和具有保护作用的代谢物。具体而言，硫酸2-甲氧基对乙酰氨基酚和1-油酰甘油（1-单油酸甘油酯）被确定为增加风险的代谢物，其比值比（OR）分别为1.545（95%置信区间：1.230-1.939；P_FDR = 3E-04）和1.462（95%置信区间：1.036-2.063；P_FDR = 0.037）。在具有保护作用的方面，3-(半胱氨酸-S-基)对乙酰氨基酚、硫酸氢醌和硫酸2-羟基对乙酰氨基酚的OR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八个关键通路，包括“缬氨酸、亮氨酸和异亮氨酸的生物合成”、“苯丙氨酸代谢”和“丙酮酸代谢”，强调了它们在高胆固醇血症发病机制中的重要作用。
本研究强调了特定血清代谢物与高胆固醇血症之间潜在的因果联系，为该疾病的代谢基础提供了新的观点。所确定的代谢物和通路为治疗干预提供了有希望的靶点，值得进一步研究。
