Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses

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dc.contributor.authorMolina-Montes, Estheren
dc.contributor.authorCoscia, Claudiaen
dc.contributor.authorGómez-Rubio, Paulinaen
dc.contributor.authorFernández, Albaen
dc.contributor.authorBoenink, Rianneen
dc.contributor.authorRava, Martaen
dc.contributor.authorMárquez, Mirarien
dc.contributor.authorMolero, Xavieren
dc.contributor.authorLöhr, Matthiasen
dc.contributor.authorSharp, Lindaen
dc.contributor.authorMichalski, Christoph W.en
dc.contributor.authorFarré, Antonien
dc.contributor.authorPerea, Joséen
dc.contributor.authorO’Rorke, Michaelen
dc.contributor.authorGreenhalf, Williamen
dc.contributor.authorIglesias, Maren
dc.contributor.authorTardón, Adoninaen
dc.contributor.authorGress, Thomas M.en
dc.contributor.authorBarberá, Victor M.en
dc.contributor.authorCrnogorac-Jurcevic, Tatjanaen
dc.contributor.authorMuñoz-Bellvís, Luisen
dc.contributor.authorDominguez-Muñoz, J. Enriqueen
dc.contributor.authorRenz, Haralden
dc.contributor.authorBalcells, Joaquimen
dc.contributor.authorCostello, Eithneen
dc.contributor.authorIlzarbe, Lucasen
dc.contributor.authorKleeff, Jörgen
dc.contributor.authorKong, Boen
dc.contributor.authorMora, Josefinaen
dc.contributor.authorO’Driscoll, Damianen
dc.contributor.authorPoves, Ignasien
dc.contributor.authorScarpa, Aldoen
dc.contributor.authorYu, Jingruen
dc.contributor.authorHidalgo, Manuelen
dc.contributor.authorLawlor, Rita T.en
dc.contributor.authorYe, Weiminen
dc.contributor.authorCarrato, Alfredoen
dc.contributor.authorReal, Francisco X.en
dc.contributor.authorMalats, Núriaen
dc.contributor.funderInstituto de Salud Carlos IIIen
dc.contributor.funderRed Temática de Investigación Cooperativa en Cáncer, Spainen
dc.contributor.funderSixth Framework Programmeen
dc.contributor.funderSeventh Framework Programmeen
dc.contributor.funderAssociazione Italiana per la Ricerca sul Cancroen
dc.contributor.funderCancer Focus Northern Irelanden
dc.contributor.funderVetenskapsrådeten
dc.date.accessioned2023-07-06T12:45:56Z
dc.date.available2023-07-06T12:45:56Z
dc.date.issued2020-05-14en
dc.description.abstractObjectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.en
dc.description.sponsorshipInstituto de Salud Carlos III, Spain (PI11/01542, PI0902102, PI12/01635, PI12/00815, PI15/01573); Red Temática de Investigación Cooperativa en Cáncer, Spain (RD12/0036/0034, RD12/0036/0050, RD12/0036/0073); WCR (15-0391); Sixth Framework Programme (COST Action BM1204: EUPancreas. EU-6FP Integrated Project (018771-MOLDIAG-PACA); Associazione Italiana Ricerca sul Cancro (12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and Vetenskapsrådet (SLL20130022)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMolina-Montes, E., Coscia, C., Gómez-Rubio, P., Fernández, A., Boenink, R., Rava, M., Márquez, M., Molero, X., Löhr, M., Sharp, L. and Michalski, C. W., Farré, A., Perea, J., O’Rorke, M., Greenhalf, W., Iglesias, M., Tardón, A., Gress, T. M., Barberá, V. M., Crnogorac-Jurcevic, V. M., Muñoz-Bellvís, L., Dominguez-Muñoz, J. Enrique, Renz, H., Balcells, J., Costello, E., Ilzarbe, L., Kleeff, J., Kong, B., Mora, J., O’Driscoll, D., Poves, I., Scarpa, A., Yu, J., Hidalgo, M., Lawlor, R. T., Ye, W., Carrato, A., Real, F. X. and Malats, N. (2020) 'Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses', Gut, 70(2), pp.319-329. doi: 10.1136/gutjnl-2019-319990en
dc.identifier.doi10.1136/gutjnl-2019-319990en
dc.identifier.eissn1468-3288en
dc.identifier.endpage329en
dc.identifier.issn0017-5749en
dc.identifier.issued2en
dc.identifier.journaltitleGuten
dc.identifier.startpage319en
dc.identifier.urihttps://hdl.handle.net/10468/14703
dc.identifier.volume70en
dc.language.isoenen
dc.publisherBMJ Publishing Group Ltden
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/259737/EU/Development of novel diagnostic and therapeutic approaches to improve patient outcome in lung and pancreatic tumours/CANCERALIAen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::HEALTH/256974/EU/Targeting the tumour microenvironment to improve pancreatic cancer prognosis/EPC-TM-NETen
dc.rights© 2020, the Authors. No commercial re-use. Published by BMJ. This article has been accepted for publication in Gut following peer review, and the Version of Record can be accessed online at: http://dx.doi.org/10.1136/gutjnl-2019-319990en
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectPancreatic cancer risken
dc.subjectDiabetes mellitus type 2en
dc.subjectObesityen
dc.subjectCase-controlen
dc.subjectCausal inferenceen
dc.subjectMendelian randomization analysisen
dc.titleDeciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analysesen
dc.typeArticle (peer-reviewed)en
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