RT Journal Article SR Electronic T1 Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2019-319990 DO 10.1136/gutjnl-2019-319990 A1 Esther Molina-Montes A1 Claudia Coscia A1 Paulina Gómez-Rubio A1 Alba Fernández A1 Rianne Boenink A1 Marta Rava A1 Mirari Márquez A1 Xavier Molero A1 Matthias Löhr A1 Linda Sharp A1 Christoph W Michalski A1 Antoni Farré A1 José Perea A1 Michael O’Rorke A1 William Greenhalf A1 Mar Iglesias A1 Adonina Tardón A1 Thomas M Gress A1 Victor M Barberá A1 Tatjana Crnogorac-Jurcevic A1 Luis Muñoz-Bellvís A1 J Enrique Dominguez-Muñoz A1 Harald Renz A1 Joaquim Balcells A1 Eithne Costello A1 Lucas Ilzarbe A1 Jörg Kleeff A1 Bo Kong A1 Josefina Mora A1 Damian O’Driscoll A1 Ignasi Poves A1 Aldo Scarpa A1 Jingru Yu A1 Manuel Hidalgo A1 Rita T Lawlor A1 Weimin Ye A1 Alfredo Carrato A1 Francisco X Real A1 Núria Malats A1 , YR 2020 UL http://gut.bmj.com/content/early/2020/05/06/gutjnl-2019-319990.abstract AB 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.