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

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Molina Montes, Esther
• dc.contributor.author Iglesias Coma, Mar
• dc.contributor.author Ilzarbe Sánchez, Lucas
• dc.contributor.author Poves Prim, José Ignacio
• dc.contributor.author Real, Francisco X.
• dc.contributor.author PanGenEU Study Investigators
• dc.date.accessioned 2022-03-22T06:56:21Z
• dc.date.available 2022-03-22T06:56:21Z
• dc.date.issued 2021
• dc.description.abstract Objectives: 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.
• dc.description.sponsorship The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto 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); European Cooperation in Science and Technology - COST Action BM1204: EUPancreas. EU-6FP Integrated Project (018771-MOLDIAG-PACA), EU-FP7-HEALTH (259737- CANCERALIA, 256974-EPC-TM-Net); Associazione Italiana Ricerca sul Cancro (12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (Agreement between the Swedish state and some county councils on cooperation on basic education of doctors, medical research, and the development of health care,SLL20130022), Sweden.
• dc.format.mimetype application/pdf
• dc.identifier.citation Molina-Montes E, Coscia C, Gómez-Rubio P, Fernández A, Boenink R, Rava M et al. Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses. Gut. 2021;70(2):319-29. DOI: 10.1136/gutjnl-2019-319990
• dc.identifier.doi http://dx.doi.org/10.1136/gutjnl-2019-319990
• dc.identifier.issn 0017-5749
• dc.identifier.uri http://hdl.handle.net/10230/52748
• dc.language.iso eng
• dc.publisher BMJ Publishing Group
• dc.relation.ispartof Gut. 2021;70(2):319-29
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/259737
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/256974
• dc.rights © BMJ Publishing Group http://dx.doi.org/10.1136/gutjnl-2019-319990
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Cancer epidemiology
• dc.subject.keyword Diabetes mellitus
• dc.subject.keyword Obesity
• dc.subject.keyword Pancreatic cancer
• dc.title Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion