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

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Molina-Montes, Esther, Coscia, Claudia, Gomez-Rubio, Paulina, Fernandez, Alba, Boenink, Rianne, Rava, Marta, Marquez, Mirari, Molero, Xavier, Lohr, Matthias, Sharp, Linda et al (show 29 more authors) , Michalski, Christoph W, Farre, Antoni, Perea, Jose, O'Rorke, Michael, Greenhalf, William, Iglesias, Mar, Tardon, Adonina, Gress, Thomas M, Barbera, Victor M, Crnogorac-Jurcevic, Tatjana, Munoz-Bellvis, Luis, Enrique Dominguez-Munoz, J, Renz, Harald, Balcells, Joaquim, Costello, Eithne, Ilzarbe, Lucas, Kleeff, Jorg, Kong, Bo, Mora, Josefina, O'Driscoll, Damian, Poves, Ignasi, Scarpa, Aldo, Yu, Jingru, Hidalgo, Manuel, Lawlor, Rita T, Ye, Weimin, Carrato, Alfredo, Real, Francisco X and Malats, Nuria (2021) 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.

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Abstract

<h4>Objectives</h4>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).<h4>Design</h4>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.<h4>Results</h4>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 (OR_LSDM=1.08, 95% CI: 0.86 to 1.29, OR_NODM=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).<h4>Conclusion</h4>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.

Item Type:	Article
Uncontrolled Keywords:	PanGenEU Study Investigators, Humans, Pancreatic Neoplasms, Diabetes Mellitus, Type 2, Obesity, C-Peptide, Body Mass Index, Risk Factors, Case-Control Studies, Smoking, Causality, Sex Factors, Polymorphism, Single Nucleotide, Aged, Middle Aged, Educational Status, Female, Male, Mediation Analysis, Glycated Hemoglobin
Depositing User:	Symplectic Admin
Date Deposited:	26 Jun 2020 08:11
Last Modified:	09 Feb 2023 13:55
DOI:	10.1136/gutjnl-2019-319990
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3091012