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摘要: 目的 寻找急性冠状动脉(冠脉)综合征相关的潜在生物标志物，为探讨其病理生理机制提供参考依据。方法 利用高效液相色谱-质谱联用技术对急性冠脉综合征患者和冠脉正常者血清样本进行非靶向代谢组学分析，筛选出两组间差异代谢物，采用受试者工作特征曲线评价差异代谢物的诊断价值，进行差异代谢物通路分析。结果 急性冠脉综合征人群与冠脉正常人群代谢谱存在显著差异，通过受试者工作特征曲线筛选出20个差异代谢物。差异代谢物通路分析发现，急性冠脉综合征患者受干扰的代谢途径包括非酒精性脂肪肝、烟酸和烟酰胺代谢、胰岛素信号通路、FoxO信号通路、2型糖尿病、糖尿病并发症中的AGE-RAGE信号通路、胆固醇代谢、心肌细胞的肾上腺素能信号传导、氧化磷酸化。结论 筛选得到急性冠脉综合征的潜在生物标志物20个，涉及非酒精性脂肪肝、烟酸和烟酰胺代谢等13条代谢途径。
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关键词:
- 急性冠状动脉综合征 /
- 非靶向代谢组学 /
- 高效液相色谱-质谱联用技术 /
- 生物标志物
Abstract: Objective To search for potential biomarkers related to ACS, and to provide reference basis for exploring its pathophysiological mechanism.Methods This study performed non-targeted serum metabolomics analysis in patients with acute coronary syndrome and normal coronary artery by high performance liquid chromatography-mass spectrometry. The differential metabolites between the two groups were screened, and the diagnostic value of differential metabolites was evaluated by receiver operating characteristic curve. Differential metabolite pathway analysis was carried out.Results There was significant difference in metabolic spectrum between acute coronary syndrome and normal coronary artery, and 20 differential metabolites were screened out by receiver operating characteristic curve. Differential metabolite pathway analysis showed that the disturbed metabolic pathways in patients with acute coronary syndrome included non-alcoholic fatty liver disease, nicotinate and nicotinamide metabolism, insulin signaling pathway, FoxO signaling pathway, type II diabetes mellitus, AGE-RAGE signaling pathway in diabetic complications, Cholesterol metabolism, adrenergic signaling in cardiomyocytes, oxidative phosphorylation.Conclusion The 20 potential biomarkers of ACS were screened, involving 13 metabolic pathways such as non-alcoholic fatty liver disease, nicotinate and nicotinamide metabolism. -
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图 1 典型样本基峰色谱图(正离子模式)
Figure 1. Typical sample base peak chromatogram(positive ion mode)
图 2 典型样本基峰色谱图(负离子模式)
Figure 2. Typical sample base peak chromatogram(negative ion mode)
图 3 实验样本与QC样本的PCA图(正离子模式)
Figure 3. PCA plots of experimental samples and QC samples(positive ion mode)
图 4 实验样本与QC样本的PCA图(负离子模式)
Figure 4. PCA diagram of experimental samples and QC samples(negative ion mode)
图 5 血清样本的OPLS-DA得分图(左边为正离子模式，右边为负离子模式)
Figure 5. OPLS-DA score of serum samples(positive ion mode on the left, negative ion mode on the right)
图 7 急性冠脉综合征患者血清生物标志物构建的代谢通路
Figure 7. Metabolic pathways constructed by serum biomarkers in patients with acute coronary syndrome
表 1 正负离子模式下模型参数R2X、R2Y、Q2值
Table 1. Model parameters R2X, R2Y, Q2 values in positive and negative ion mode
比对组 正离子模式 负离子模式 pre R2X(cum) R2Y(cum) Q2(cum) pre R2X(cum) R2Y(cum) Q2(cum) D vs C 3 0.343 0.999 0.512 3 0.352 0.998 0.562 注：pre：主成分数；R2X：模型对X变量数据集可解释度；R2Y：模型对Y变量数据集的可解释度；Q2：模型可预测度；D：实验组；C：对照组。 
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表 2 差异代谢物基本信息
Table 2. Basic information of differential metabolites
鉴定物质 中文名称 VIP P值 AUC 特异度 灵敏度 FC(D/C) log2(FC) Up/Down Methyl jasmonate 茉莉酸甲酯 2.613661375 0.0000212 1 1 1 1.1838 0.24347 ↑ 1-Pyrroline-4-hydroxy-2-carboxylate 1-吡咯啉基-4-羟基-2-甲酸乙酯 2.553357458 0.0000135 1 1 1 0.20546 -2.2831 ↓ Geranial 香叶醛 2.471406282 0.0000447 1 1 1 0.37048 -1.4325 ↓ Myristic acid 肉豆蔻酸 2.288558754 0.00035126 1 0.923 1 0.85213 -0.23085 ↓ Heptanoic acid 庚酸 1.973785906 0.005974332 1 0.923 1 1.1764 0.23443 ↑ Glutaric acid 戊二酸 1.888055466 0.00663257 1 0.923 1 3.8199 1.9335 ↑ Methyldopa 甲基多巴 1.782584297 0.015714848 1 0.923 1 7.1221 2.8323 ↑ Ergocalciferol 钙化醇 2.50780231 0.0000836 0.981 0.923 1 0.55905 -0.83895 ↓ Ursodeoxycholic acid 熊去氧胆酸 2.431963998 0.0000741 0.981 0.846 1 0.21266 -2.2334 ↓ 2-Methylbutanal 2-甲基丁醛 2.394841431 0.00011526 0.971 0.923 1 0.29557 -1.7584 ↓ L-Tryptophan L-色氨酸 1.814754381 0.01352811 0.962 0.923 1 1.5099 0.59448 ↑ Beta-Leucine β-亮氨酸 2.262807849 0.000876087 0.942 0.769 1 0.36188 -1.4664 ↓ Aminocaproic acid 氨基己酸 2.026705449 0.002831395 0.942 0.769 1 0.75535 -0.40478 ↓ Norepinephrine 去甲肾上腺素 2.022780712 0.002906188 0.942 0.923 1 1.1223 0.16648 ↑ Pelargonic acid 壬酸 2.006880444 0.003225859 0.923 0.846 1 1.1801 0.23894 ↑ 3, 3-Dimethoxybenzidine 3’3-二甲氧基联苯胺 1.722964627 0.015617621 0.923 0.846 1 0.81238 -0.29978 ↓ Suberic acid 辛二酸 1.680850163 0.018998759 0.923 0.923 1 3.7433 1.9043 ↑ 9, 10-DHOME 9, 10-二羟基-12(Z)- 十八碳烯酸 1.67909049 0.024683863 0.923 0.769 1 0.67184 -0.57382 ↓ L-2-Hydroxyglutaric acid L-2-羟基戊二酸 1.453893739 0.048090985 0.923 0.769 1 4.8314 2.2724 ↑ Glycocholic acid 甘氨胆酸 1.664600861 0.02620388 0.913 0.846 0.75 0.32061 -1.6411 ↓ 4-Quinolinecarboxylic acid 4-喹啉羧酸 1.660727769 0.020803943 0.894 0.846 0.75 4.0207 2.0074 ↑ Succinic acid 琥珀酸 1.538375284 0.034828958 0.885 0.769 1 2.4312 1.2817 ↑ 12-Hydroxydodecanoic acid 12-羟基十二酸 2.031058316 0.004294962 0.875 1 0.75 0.23991 -2.0595 ↓ DL-Glycerol 1-phosphate DL-甘油1-磷酸 1.909775673 0.008438434 0.875 0.923 0.75 0.58075 -0.78401 ↓ Uridine 尿苷 1.691841244 0.018065851 0.875 0.692 1 0.34062 -1.5538 ↓ Pyroglutamic acid 焦谷氨酸 1.607054931 0.026276433 0.865 0.769 1 0.54557 -0.87415 ↓ Sarcosine 肌氨酸 2.0448578 0.00250559 0.846 1 0.75 0.090852 -3.4603 ↓ Imidazole-4-acetaldehyde 咪唑-4-乙醛 2.009610412 0.003169029 0.846 1 0.75 0.22524 -2.1505 ↓ D-Glucose D-葡萄糖 1.776976883 0.016122915 0.846 0.846 0.75 0.33039 -1.5977 ↓ Creatine 肌酸 1.706128383 0.016907231 0.846 0.923 0.75 0.37158 -1.4283 ↓ Ribitol 戊五醇核糖醇 1.695095446 0.023085247 0.846 0.769 1 0.53381 -0.90561 ↓ Biotin 生物素 1.616842764 0.025203641 0.846 0.769 1 0.57732 -0.79255 ↓ Benzamide 苯甲酰胺 1.608918913 0.02606946 0.846 0.923 0.75 0.25422 -1.9759 ↓ Sphinganine 鞘氨醇 1.457431025 0.047469279 0.846 0.769 1 0.93425 -0.098117 ↓ Nicotinic acid 烟酸 1.447890041 0.049160166 0.846 0.692 1 5.8827 2.5565 ↑ Ketoleucine 酮亮氨酸 1.529183197 0.044152111 0.837 1 0.75 1.3366 0.41853 ↑ Adipate semialdehyde 己二酸半醛 1.729157647 0.015163222 0.827 1 0.75 0.17645 -2.5027 ↓ 1, 2-Epoxy-p-menth-8-ene 柠檬烯-1, 2-环氧化物 1.605616471 0.026437023 0.827 0.846 0.75 0.23377 -2.0968 ↓ 5-Hydroxypyrazinamide 5-羟基吡嗪酰胺 1.511633383 0.038680014 0.827 0.923 0.75 2.2601 1.1764 ↑ Pyrrolidonecarboxylic acid 吡咯烷酮羧酸 1.567836926 0.038289473 0.808 0.923 0.75 0.41675 -1.2627 ↓ Withaferin A 醉茄素A 1.70531079 0.016971919 0.788 0.846 0.75 0.46977 -1.09 ↓ Guanidinosuccinic acid 胍基琥珀酸 1.60642627 0.033046828 0.788 0.923 0.75 0.49889 -1.0032 ↓ Niacinamide 烟酰胺 1.548295864 0.04117419 0.779 0.769 1 1.2493 0.32114 ↑ Maslinic acid 马斯里酸 1.566941246 0.038418236 0.76 0.846 0.75 0.10312 -3.2776 ↓ Methionine sulfoximine 蛋氨酸磺酸盐 1.467500228 0.045732623 0.75 1 0.5 0.10929 -3.1937 ↓ Carnosine 肌肽 1.675920044 0.019429262 0.74 1 0.5 0.30913 -1.6937 ↓ 注：VIP：OPLS-DA第一主成分变量权重值；FC(fold change)：倍性变化；log2(FC)：倍性变化的log2值；Up：代谢物高表达(上调)；Down：代谢物低表达(下调)。
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表 3 通路影响因子表
Table 3. Pathway Influencing Factors Table
通路名称 -log(P) 代谢通路影响值 代谢物 代谢通路KEGG ID Non-alcoholic fatty liver disease 3.593 0.5 C00031 hsa04932 Nicotinate and nicotinamide metabolism 3.2309 0.25116 C00042；C00153；C00253 hsa00760 Insulin signaling pathway 2.9134 0.25 C00031 hsa04910 FoxO signaling pathway 2.6971 0.2 C00031 hsa04068 Type II diabetes mellitus 2.5215 0.16667 C00031 hsa04930 Prolactin signaling pathway 1.9488 0.15789 C00031 hsa04917 Insulin secretion 1.8685 0.15 C00031 hsa04911 Biotin metabolism 1.1258 0.14062 C00120 hsa00780 Vascular smooth muscle contraction 2.2472 0.125 C00547 hsa04270 AGE-RAGE signaling pathway in diabetic complications 2.1362 0.11111 C00031 hsa04933 Cholesterol metabolism 2.0375 0.1 C01921 hsa04979 Adrenergic signaling in cardiomyocytes 2.0375 0.1 C00547 hsa04261 Oxidative phosphorylation 1.6073 0.1 C00042 hsa00190 D-Glutamine and D-glutamate metabolism 1.7951 0.095238 C02237 hsa00471 Gap junction 1.9488 0.090909 C00547 hsa04540 Synaptic vesicle cycle 1.8685 0.083333 C00547 hsa04721 Insulin resistance 1.4104 0.083333 C00031 hsa04931 Central carbon metabolism in cancer 4.2753 0.075472 C00031；C00042；C00078 hsa05230 cAMP signaling pathway 3.0788 0.074074 C00042；C00547 hsa04024 Histidine metabolism 1.986 0.072 C00386；C05130 hsa00340 Sphingolipid signaling pathway 1.6652 0.068966 C00836 hsa04071 Carbohydrate digestion and absorption 1.1557 0.068966 C00031 hsa04973 Butanoate metabolism 0.8088 0.066176 C00042 hsa00650 Valine，leucine and isoleucine biosynthesis 1.2902 0.064516 C00233 hsa00290 African trypanosomiasis 1.6073 0.0625 C00078 hsa05143 Vitamin digestion and absorption 2.2954 0.061224 C00120；C00153 hsa04977 Valine，leucine and isoleucine degradation 0.8088 0.059289 C00233 hsa00280 GABAergic synapse 2.1362 0.058824 C00042 hsa04727 Pyrimidine metabolism 0.51133 0.057549 C00299 hsa00240 Mineral absorption 2.8109 0.057143 C00031；C00078 hsa04978 Pertussis 2.0375 0.055556 C00253 hsa05133 Galactose metabolism 0.7426 0.055556 C00031 hsa00052 Sphingolipid metabolism 1.2198 0.054795 C00836 hsa00600 Taste transduction 2.6366 0.052632 C00031；C00547 hsa04742 HIF-1 signaling pathway 1.6652 0.052632 C00031 hsa04066 Salivary secretion 1.5533 0.052632 C00547 hsa04970 注：-log(p)：对P值的自然对数取负值。
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