Metabolic Nutrition Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
Gut. 2020 Nov;69(11):2008-2015. doi: 10.1136/gutjnl-2019-319811. Epub 2020 Feb 14.
To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study.
We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis.
Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter.
Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.
在一项前瞻性队列研究中，评估预诊断代谢物与胰腺导管腺癌（PDAC）发病的相关性。
我们对 554 种已知的预诊断血清代谢物（最长可达 24 年）进行了非靶向分析，以确定它们与男性吸烟者的巢式病例对照研究（372 个匹配的病例对照集）和包括女性和非吸烟者的独立巢式病例对照研究（107 个匹配集）中 PDAC 发病的相关性。代谢物使用 Orbitrap Elite 或 Q-Exactive 高分辨率/精确质量质谱仪进行测量。对照与病例按年龄、性别、种族、采血日期和随访时间进行匹配。我们使用条件逻辑回归，根据年龄进行调整，以计算每个队列中 1 个 SD 对数代谢物水平增加的 OR 和 95%CI，并使用固定效应荟萃分析对两个 OR 进行合并。
在错误发现率<0.05 的情况下，有 31 种代谢物与 PDAC 显著相关，其中 12 种代谢物低于 Bonferroni 校正阈值（p<9.04×10）。在两个队列中都观察到了类似的相关性。二肽甘氨酰缬氨酸、天冬氨酰苯丙氨酸、吡咯酮二肽甘氨酸、苯丙氨酰苯丙氨酸、苯丙氨酰亮氨酸和色氨酰谷氨酸以及天冬氨酸和谷氨酸呈正相关，而二肽酪氨酸谷氨酰胺和α-谷氨酰酪氨酸、纤维蛋白原裂解肽 DSGEGDFXAEGGGVR 和与谷胱甘肽有关的氨基酸半胱氨酸-谷胱甘肽二硫化物则在 Bonferroni 校正后与 PDAC 呈负相关。前 5 种代谢物表现出与时间相关的显著相关性（p<0.023），在参与者采血后 10-15 年观察到最强的相关性，随后相关性减弱。
我们的结果表明，与亚临床疾病、γ-谷氨酰循环代谢和肥胖/胰岛素抵抗相关的预诊断代谢物与 PDAC 相关。
