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

Author:

Molina-Montes Esther,Coscia Claudia,Gómez-Rubio Paulina,Fernández Alba,Boenink Rianne,Rava Marta,Márquez Mirari,Molero Xavier,Löhr Matthias,Sharp LindaORCID,Michalski Christoph W,Farré Antoni,Perea JoséORCID,O’Rorke Michael,Greenhalf William,Iglesias Mar,Tardón Adonina,Gress Thomas M,Barberá Victor M,Crnogorac-Jurcevic Tatjana,Muñoz-Bellvís Luis,Dominguez-Muñoz J Enrique,Renz Harald,Balcells Joaquim,Costello EithneORCID,Ilzarbe Lucas,Kleeff Jörg,Kong Bo,Mora Josefina,O’Driscoll Damian,Poves Ignasi,Scarpa AldoORCID,Yu Jingru,Hidalgo ManuelORCID,Lawlor Rita T,Ye Weimin,Carrato Alfredo,Real Francisco X,Malats NúriaORCID

Abstract

ObjectivesTo 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).DesignInformation 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.ResultsT2DM 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).ConclusionFindings 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.

Funder

Instituto de Salud Carlos III

Associazione Italiana Ricerca sul Cancro

Cancer Focus Northern Ireland and Department for Employment and Learning

Red Temática de Investigación Cooperativa en Cáncer

European Cooperation in Science and Technology

Sixth Framework Programme

ALF

FP7 Health

Publisher

BMJ

Subject

Gastroenterology

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