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

Esther Molina‐Montes; Claudia Coscia; Paulina Gómez-Rubio; Alba Méndez Fernández; Rianne Boenink; Marta Rava; Mirari Márquez; Xavier Molero; Matthias Löhr; Linda Sharp; Christoph Michalski; Antoni Farré; José Perea; Michael O’Rorke; William Greenhalf; Mar Iglesias; Adonina Tardón; Thomas M. Gress; Víctor Manuel Barberá; Tatjana Crnogorac‐Jurcevic; Luis Muñoz‐Bellvís; J. Enrique Domínguez‐Muñoz; Harald Renz; J. Balcells; Eithne Costello; Lucas Ilzarbe; Jörg Kleeff; Bo Kong; Josefina Móra; Damian O’Driscoll; Ignasi Poves; Aldo Scarpa; Jingru Yu; Manuel Hidalgo; Rita T. Lawlor; Weimin Ye; Alfredo Carrato; Francisco X. Real; Núria Malats

doi:10.1136/gutjnl-2019-319990

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

Esther Molina‐Montes(Spanish National Cancer Research Centre), Claudia Coscia(Spanish National Cancer Research Centre), Paulina Gómez-Rubio(Spanish National Cancer Research Centre), Alba Méndez Fernández(Spanish National Cancer Research Centre), Rianne Boenink(Spanish National Cancer Research Centre), Marta Rava(Spanish National Cancer Research Centre), Mirari Márquez(Spanish National Cancer Research Centre), Xavier Molero(Universitat Autònoma de Barcelona), Matthias Löhr(Karolinska University Hospital), Linda Sharp(University College Cork), Christoph Michalski(Technical University of Munich), Antoni Farré(Hospital de Sant Pau), José Perea(Research Institute Hospital 12 de Octubre), Michael O’Rorke(Queen's University Belfast), William Greenhalf(University of Liverpool), Mar Iglesias(Parc de Salut), Adonina Tardón(Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública), Thomas M. Gress(Universitätsklinikum Gießen und Marburg), Víctor Manuel Barberá(Hospital General Universitario de Elche), Tatjana Crnogorac‐Jurcevic(Queen Mary University of London), Luis Muñoz‐Bellvís(Complejo Hospitalario de Salamanca), J. Enrique Domínguez‐Muñoz(Universidade de Santiago de Compostela), Harald Renz(Philipps University of Marburg), J. Balcells(Universitat Autònoma de Barcelona), Eithne Costello(University of Liverpool), Lucas Ilzarbe(Parc de Salut), Jörg Kleeff(Technical University of Munich), Bo Kong(Technical University of Munich), Josefina Móra(Hospital de Sant Pau), Damian O’Driscoll(University College Cork), Ignasi Poves(Parc de Salut), Aldo Scarpa(University of Verona), Jingru Yu(Karolinska University Hospital), Manuel Hidalgo(Beth Israel Deaconess Medical Center), Rita T. Lawlor(University of Verona), Weimin Ye(Karolinska University Hospital), Alfredo Carrato(Instituto Cajal), Francisco X. Real(Spanish National Cancer Research Centre), Núria Malats(Spanish National Cancer Research Centre)

Gut

May 14, 2020

10.1136/gutjnl-2019-319990

Cited by 74Open Access

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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 (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). 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.

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