Journal
GUT
Volume 69, Issue 11, Pages 2008-2015Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2019-319811
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Funding
- Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services
- US Army Medical Research Acquisition Activity through the Peer Review Cancer Research Program Discovery Award [W81XWH-12-1-0369]
- NATIONAL CANCER INSTITUTE [ZIACP010195] Funding Source: NIH RePORTER
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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-E xactive 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<9.04x10(-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 alpha-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, gamma-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.
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