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. 2021 Feb;70(2):319-329.
doi: 10.1136/gutjnl-2019-319990. Epub 2020 May 14.

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

Esther Molina-Montes  1   2 , Claudia Coscia  1   2 , Paulina Gómez-Rubio  1   2 , Alba Fernández  1 , Rianne Boenink  1 , Marta Rava  1 , Mirari Márquez  1   2 , Xavier Molero  3   4 , Matthias Löhr  5 , Linda Sharp  6   7 , Christoph W Michalski  8   9 , Antoni Farré  10 , José Perea  11   12 , Michael O'Rorke  13   14 , William Greenhalf  15 , Mar Iglesias  2   16 , Adonina Tardón  17   18 , Thomas M Gress  19 , Victor M Barberá  20 , Tatjana Crnogorac-Jurcevic  21 , Luis Muñoz-Bellvís  22 , J Enrique Dominguez-Muñoz  23 , Harald Renz  24 , Joaquim Balcells  4   25 , Eithne Costello  15 , Lucas Ilzarbe  26 , Jörg Kleeff  8   9 , Bo Kong  8 , Josefina Mora  10 , Damian O'Driscoll  6   7 , Ignasi Poves  27 , Aldo Scarpa  28 , Jingru Yu  29 , Manuel Hidalgo  30   31 , Rita T Lawlor  28 , Weimin Ye  29 , Alfredo Carrato  2   32 , Francisco X Real  2   33 , Núria Malats  34   2 ; PanGenEU Study Investigators
Affiliations

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

Esther Molina-Montes et al. Gut. 2021 Feb.

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.

Keywords: cancer epidemiology; diabetes mellitus; obesity; pancreatic cancer.

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Conflict of interest statement

Competing interests: None declared.

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