Zhou Qingyi, Yang Lichun, Zhu Peiyu, Wang Yutong, Zhang Zilu, Chu Liang
Second Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Bengbu Medical University, Bengbu, China.
Metabolomics. 2025 Aug 12;21(5):110. doi: 10.1007/s11306-025-02305-4.
Emerging evidence shows significant differences in plasma metabolites between colorectal cancer (CRC) patients and healthy controls. However, previous observational studies have been limited by small sample sizes and single sample sources, leading to an incomplete understanding of these metabolites' causal roles in CRC. This study systematically evaluated the causal relationships between 325 nuclear magnetic resonance (NMR) biomarkers and CRC risk using Mendelian randomization (MR), supplemented by colocalization analysis and an independent validation dataset to confirm key biomarkers.
A genome-wide association study (GWAS) was conducted in a cohort of 250,341 participants from the UK Biobank. MR analysis identified NMR biomarkers with significant causal relationships with CRC. Colocalization analysis was then performed, revealing five biomarkers with high colocalization probabilities (PPH4 > 0.8). These findings were validated in an independent Finnish dataset to confirm the consistency of causal relationships and colocalization signals.
MR analysis identified 28 NMR biomarkers with significant causal associations with CRC risk (P_fdr < 0.05). Colocalization analysis highlighted five biomarkers with strong colocalization signals (PPH4 > 0.8), including Omega-6 fatty acids, Omega-6 to total fatty acids ratio, Omega-3 fatty acids, Linoleic acid to total fatty acids percentage, and Degree of unsaturation. Notably, in the Finnish validation dataset, Linoleic acid to total fatty acids percentage demonstrated a significant causal association with CRC (OR 0.77, 95% CI 0.67-0.87, P = 7.5 × 10, P_fdr = 3.8 × 10) while maintaining a high colocalization probability (PPH4 > 0.8), reinforcing its role as a key causal biomarker.
This study provides the first comprehensive assessment of NMR biomarkers in relation to rectal cancer risk, identifying linoleic acid to total fatty acids percentage as a key causal biomarker. Additionally, omega-6 to omega-3 ratio, omega-6 to polyunsaturated fatty acids percentage, omega-3 to polyunsaturated fatty acids percentage, and degree of unsaturation were also identified, sharing genetic loci with CRC.
新出现的证据表明，结直肠癌（CRC）患者与健康对照者的血浆代谢物存在显著差异。然而，以往的观察性研究受到样本量小和样本来源单一的限制，导致对这些代谢物在结直肠癌中的因果作用了解不完整。本研究使用孟德尔随机化（MR）系统评估了325种核磁共振（NMR）生物标志物与CRC风险之间的因果关系，并辅以共定位分析和独立验证数据集以确认关键生物标志物。
在来自英国生物银行的250341名参与者队列中进行了全基因组关联研究（GWAS）。MR分析确定了与CRC有显著因果关系的NMR生物标志物。然后进行共定位分析，揭示了五个共定位概率高（PPH4＞0.8）的生物标志物。这些发现在一个独立的芬兰数据集中得到验证，以确认因果关系和共定位信号的一致性。
MR分析确定了28种与CRC风险有显著因果关联的NMR生物标志物（P_fdr＜0.05）。共定位分析突出了五个具有强共定位信号（PPH4＞0.8）的生物标志物，包括欧米伽-6脂肪酸、欧米伽-6与总脂肪酸比率、欧米伽-3脂肪酸、亚油酸与总脂肪酸百分比以及不饱和度。值得注意的是，在芬兰验证数据集中，亚油酸与总脂肪酸百分比显示出与CRC有显著因果关联（OR 0.77，95%CI 0.67-0.87，P = 7.5×10，P_fdr = 3.8×10），同时保持高共定位概率（PPH4＞0.8），强化了其作为关键因果生物标志物的作用。
本研究首次全面评估了与直肠癌风险相关的NMR生物标志物，确定亚油酸与总脂肪酸百分比为关键因果生物标志物。此外，还确定了欧米伽-6与欧米伽-3比率、欧米伽-6与多不饱和脂肪酸百分比、欧米伽-3与多不饱和脂肪酸百分比以及不饱和度，它们与CRC共享基因位点。
