Objective To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. Design 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. Results Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10–5). 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. Conclusion Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.

中文翻译：

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一项大型前瞻性流行病学研究中代谢物与胰腺癌风险之间的关联

目的 在一项前瞻性队列研究中评估诊断前代谢物是否与胰腺导管腺癌 (PDAC) 发生相关。设计 我们对诊断前血清（长达 24 年）中测量的 554 种已知代谢物进行了非靶向分析，以确定它们与男性吸烟者嵌套病例对照研究（372 个匹配病例对照集）和独立嵌套病例中 PDAC 事件的关联- 包括女性和非吸烟者的对照研究（107 个匹配组）。使用 Orbitrap Elite 或 Q-Exactive 高分辨率/准确质谱仪测量代谢物。对照按年龄、性别、种族、抽血日期和随访时间与病例相匹配。我们使用针对年龄调整的条件逻辑回归来计算每个队列中对数代谢物水平分别增加 1 SD 的 OR 和 95% CI，并使用固定效应荟萃分析将这两个 OR 结合起来。结果 31 种代谢物与 PDAC 显着相关，错误发现率 <0.05，其中 12 种代谢物低于 Bonferroni 校正阈值 (p<9.04×10–5)。在两个队列中都观察到了类似的关联。二肽甘氨酰缬氨酸、天冬氨酰苯丙氨酸、焦谷氨酰甘氨酸、苯丙氨酰苯丙氨酸、苯丙氨酰苯丙氨酸和色氨酸谷氨酸以及氨基酸天冬氨酸和谷氨酸呈阳性，而二肽酪氨酰谷氨酰胺和α-谷氨酰酪氨酸则呈阳性。Bonferroni 校正后，纤维蛋白原裂解肽 DSGEGDFXAEGGGVR 和谷胱甘肽相关氨基酸半胱氨酸-谷胱甘肽二硫化物与 PDAC 呈负相关。五种顶级代谢物显示出显着的时变关联 (p<0.023)，其中最强关联在参与者采血后 10-15 年观察到，此后减弱。结论 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。