Journal article
Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses
Gut, Vol.70(2), pp.319-329
05/14/2020
DOI: 10.1136/gutjnl-2019-319990
PMID: 32409590
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.
Details
- Title: Subtitle
- Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses
- Creators
- Esther Molina-Montes - CIBERONC, Madrid, SpainClaudia Coscia - CIBERONC, Madrid, SpainPaulina Gómez-Rubio - CIBERONC, Madrid, SpainAlba Fernández - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, SpainRianne Boenink - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, SpainMarta Rava - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, SpainMirari Márquez - CIBERONC, Madrid, SpainXavier Molero - Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, SpainMatthias Löhr - Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, SwedenLinda Sharp - HRB Clinical Research Facility, University College Cork, Cork, IrelandChristoph W Michalski - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat Halle-Wittenberg, Halle, GermanyAntoni Farré - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainJosé Perea - Department of Surgery, Health Research Institute, Fundación Jiménez Díaz, Madrid, SpainMichael A O'Rorke - EpidemiologyWilliam Greenhalf - Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UKMar Iglesias - Hospital del Mar—Parc de Salut Mar, Barcelona, SpainAdonina Tardón - CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, SpainThomas M Gress - Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, GermanyVictor M Barberá - Molecular Genetics Laboratory, University General Hospital of Elche, Elche, SpainLuis Muñoz-Bellvís - Department of Surgery, Hospital Universitario de Salamanca, Salamanca, SpainJ Enrique Dominguez-Muñoz - Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, SpainHarald Renz - Institute of Laboratory Medicine and Pathobiochemistry, Phillips University of Marburg, Marburg, GermanyJoaquim Balcells - Exocrine Pancreas Research Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Barcelona, SpainEithne Costello - Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer Research-UK Centre, University of Liverpool, Liverpool, UKLucas Ilzarbe - Department of Gastroenterology, Hospital del Mar - Parc de Salut Mar, Barcelona, SpainJörg Kleeff - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat Halle-Wittenberg, Halle, GermanyBo Kong - Department of Surgery, Technical University of Munich, Munich, GermanyJosefina Mora - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainDamian O’Driscoll - HRB Clinical Research Facility, University College Cork, Cork, IrelandIgnasi Poves - Hospital del Mar - Parc de Salut Mar, Barcelona, SpainAldo Scarpa - ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University of Verona, Verona, ItalyJingru Yu - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Stockholm, SwedenManuel Hidalgo - Hospital Universitario Madrid Sanchinarro, Madrid, SpainRita T Lawlor - ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University of Verona, Verona, ItalyWeimin Ye - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Stockholm, SwedenAlfredo Carrato - Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, SpainFrancisco X Real - Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, SpainNúria Malats - CIBERONC, Madrid, SpainPanGenEU Study Investigators
- Resource Type
- Journal article
- Publication Details
- Gut, Vol.70(2), pp.319-329
- DOI
- 10.1136/gutjnl-2019-319990
- PMID
- 32409590
- NLM abbreviation
- Gut
- ISSN
- 0017-5749
- eISSN
- 1468-3288
- Grant note
- DOI: 10.13039/501100004587, name: Instituto de Salud Carlos III, award: PI0902102, PI11/01542, PI12/00815, PI12/01635, PI15/01573; DOI: 10.13039/501100005010, name: Associazione Italiana Ricerca sul Cancro, award: 12182; name: Cancer Focus Northern Ireland and Department for Employment and Learning; name: Red Temática de Investigación Cooperativa en Cáncer, award: RD12/0036/0034, RD12/0036/0050, RD12/0036/0073; DOI: 10.13039/501100000921, name: European Cooperation in Science and Technology, award: BM1204; DOI: 10.13039/100011103, name: Sixth Framework Programme, award: 018771-MOLDIAG-PACA; name: ALF, award: SLL20130022; DOI: 10.13039/100011272, name: FP7 Health, award: 256974-EPC-TM-Net, 259737-CANCERALIA
- Language
- English
- Date published
- 05/14/2020
- Academic Unit
- Epidemiology; Pathology
- Record Identifier
- 9984214814402771
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