@article {Molina-Montes319, author = {Esther Molina-Montes and Claudia Coscia and Paulina G{\'o}mez-Rubio and Alba Fern{\'a}ndez and Rianne Boenink and Marta Rava and Mirari M{\'a}rquez and Xavier Molero and Matthias L{\"o}hr and Linda Sharp and Christoph W Michalski and Antoni Farr{\'e} and Jos{\'e} Perea and Michael O{\textquoteright}Rorke and William Greenhalf and Mar Iglesias and Adonina Tard{\'o}n and Thomas M Gress and Victor M Barber{\'a} and Tatjana Crnogorac-Jurcevic and Luis Mu{\~n}oz-Bellv{\'\i}s and J Enrique Dominguez-Mu{\~n}oz and Harald Renz and Joaquim Balcells and Eithne Costello and Lucas Ilzarbe and J{\"o}rg Kleeff and Bo Kong and Josefina Mora and Damian O{\textquoteright}Driscoll and Ignasi Poves and Aldo Scarpa and Jingru Yu and Manuel Hidalgo and Rita T Lawlor and Weimin Ye and Alfredo Carrato and Francisco X Real and N{\'u}ria Malats}, editor = {,}, title = {Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses}, volume = {70}, number = {2}, pages = {319--329}, year = {2021}, doi = {10.1136/gutjnl-2019-319990}, publisher = {BMJ Publishing Group}, 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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/70/2/319}, eprint = {https://gut.bmj.com/content/70/2/319.full.pdf}, journal = {Gut} }