PMID- 32409590
OWN - NLM
STAT- MEDLINE
DCOM- 20210907
LR  - 20221207
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Linking)
VI  - 70
IP  - 2
DP  - 2021 Feb
TI  - Deciphering the complex interplay between pancreatic cancer, diabetes mellitus 
      subtypes and obesity/BMI through causal inference and mediation analyses.
PG  - 319-329
LID - 10.1136/gutjnl-2019-319990 [doi]
AB  - 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.
CI  - (c) Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and 
      permissions. Published by BMJ.
FAU - Molina-Montes, Esther
AU  - Molina-Montes E
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
AD  - CIBERONC, Madrid, Spain.
FAU - Coscia, Claudia
AU  - Coscia C
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
AD  - CIBERONC, Madrid, Spain.
FAU - Gomez-Rubio, Paulina
AU  - Gomez-Rubio P
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
AD  - CIBERONC, Madrid, Spain.
FAU - Fernandez, Alba
AU  - Fernandez A
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
FAU - Boenink, Rianne
AU  - Boenink R
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
FAU - Rava, Marta
AU  - Rava M
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
FAU - Marquez, Mirari
AU  - Marquez M
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain.
AD  - CIBERONC, Madrid, Spain.
FAU - Molero, Xavier
AU  - Molero X
AD  - Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Barcelona, 
      Spain.
AD  - Universitat Autonoma de Barcelona, CIBEREHD, Barcelona, Spain.
FAU - Lohr, Matthias
AU  - Lohr M
AD  - Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, Sweden.
FAU - Sharp, Linda
AU  - Sharp L
AUID- ORCID: 0000-0001-9515-1722
AD  - National Cancer Registry Ireland, Cork, Ireland.
AD  - HRB Clinical Research Facility, University College Cork, Cork, Ireland.
FAU - Michalski, Christoph W
AU  - Michalski CW
AD  - Department of Surgery, Technical University of Munich, Munich, Germany.
AD  - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat 
      Halle-Wittenberg, Halle, Germany.
FAU - Farre, Antoni
AU  - Farre A
AD  - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa 
      Creu i Sant Pau, Barcelona, Spain.
FAU - Perea, Jose
AU  - Perea J
AUID- ORCID: 0000-0001-5522-8844
AD  - Department of Surgery, Hospital 12 de Octubre, Madrid, Spain.
AD  - Department of Surgery, Health Research Institute, Fundacion Jimenez Diaz, Madrid, 
      Spain.
FAU - O'Rorke, Michael
AU  - O'Rorke M
AD  - Centre for Public Health, Queen's University Belfast, Belfast, UK.
AD  - College of Public Health, University of Iowa, Iowa City, Iowa, USA.
FAU - Greenhalf, William
AU  - Greenhalf W
AD  - Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer 
      Research-UK Centre, University of Liverpool, Liverpool, UK.
FAU - Iglesias, Mar
AU  - Iglesias M
AD  - CIBERONC, Madrid, Spain.
AD  - Hospital del Mar-Parc de Salut Mar, Barcelona, Spain.
FAU - Tardon, Adonina
AU  - Tardon A
AD  - Department of Medicine, Instituto Universitario de Oncologia del Principado de 
      Asturias, Oviedo, Spain.
AD  - CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain.
FAU - Gress, Thomas M
AU  - Gress TM
AD  - Department of Gastroenterology, University Hospital of Giessen and Marburg, 
      Marburg, Germany.
FAU - Barbera, Victor M
AU  - Barbera VM
AD  - Molecular Genetics Laboratory, University General Hospital of Elche, Elche, 
      Spain.
FAU - Crnogorac-Jurcevic, Tatjana
AU  - Crnogorac-Jurcevic T
AD  - Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of 
      London, London, UK.
FAU - Munoz-Bellvis, Luis
AU  - Munoz-Bellvis L
AD  - Department of Surgery, Hospital Universitario de Salamanca, Salamanca, Spain.
FAU - Dominguez-Munoz, J Enrique
AU  - Dominguez-Munoz JE
AD  - Department of Gastroenterology, University Hospital of Santiago de Compostela, 
      Santiago de Compostela, Spain.
FAU - Renz, Harald
AU  - Renz H
AD  - Institute of Laboratory Medicine and Pathobiochemistry, Phillips University of 
      Marburg, Marburg, Germany.
FAU - Balcells, Joaquim
AU  - Balcells J
AD  - Universitat Autonoma de Barcelona, CIBEREHD, Barcelona, Spain.
AD  - Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de 
      Recerca (VHIR), Barcelona, Spain.
FAU - Costello, Eithne
AU  - Costello E
AUID- ORCID: 0000-0002-0104-8992
AD  - Department of Molecular and Clinical Cancer Medicine, Liverpool Cancer 
      Research-UK Centre, University of Liverpool, Liverpool, UK.
FAU - Ilzarbe, Lucas
AU  - Ilzarbe L
AD  - Department of Gastroenterology, Hospital del Mar - Parc de Salut Mar, Barcelona, 
      Spain.
FAU - Kleeff, Jorg
AU  - Kleeff J
AD  - Department of Surgery, Technical University of Munich, Munich, Germany.
AD  - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-Universitat 
      Halle-Wittenberg, Halle, Germany.
FAU - Kong, Bo
AU  - Kong B
AD  - Department of Surgery, Technical University of Munich, Munich, Germany.
FAU - Mora, Josefina
AU  - Mora J
AD  - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa 
      Creu i Sant Pau, Barcelona, Spain.
FAU - O'Driscoll, Damian
AU  - O'Driscoll D
AD  - National Cancer Registry Ireland, Cork, Ireland.
AD  - HRB Clinical Research Facility, University College Cork, Cork, Ireland.
FAU - Poves, Ignasi
AU  - Poves I
AD  - Hospital del Mar - Parc de Salut Mar, Barcelona, Spain.
FAU - Scarpa, Aldo
AU  - Scarpa A
AUID- ORCID: 0000-0003-1678-739X
AD  - ARC-Net Research Centre and Department of Diagnostics and Public Health-Section 
      of Pathology, University of Verona, Verona, Italy.
FAU - Yu, Jingru
AU  - Yu J
AD  - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and 
      University Hospital, Stockholm, Sweden.
FAU - Hidalgo, Manuel
AU  - Hidalgo M
AUID- ORCID: 0000-0003-4977-4544
AD  - Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 
      USA.
AD  - Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
FAU - Lawlor, Rita T
AU  - Lawlor RT
AD  - ARC-Net Research Centre and Department of Diagnostics and Public Health-Section 
      of Pathology, University of Verona, Verona, Italy.
FAU - Ye, Weimin
AU  - Ye W
AD  - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and 
      University Hospital, Stockholm, Sweden.
FAU - Carrato, Alfredo
AU  - Carrato A
AD  - CIBERONC, Madrid, Spain.
AD  - Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain.
FAU - Real, Francisco X
AU  - Real FX
AD  - CIBERONC, Madrid, Spain.
AD  - Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, 
      Spain.
FAU - Malats, Nuria
AU  - Malats N
AUID- ORCID: 0000-0003-2538-3784
AD  - Genetic and Molecular Epidemiology Group, Spanish National Cancer Research 
      Center, Madrid, Spain nuria@cnio.es.
AD  - CIBERONC, Madrid, Spain.
CN  - PanGenEU Study Investigators
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200514
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (C-Peptide)
RN  - 0 (Glycated Hemoglobin A)
SB  - IM
MH  - Aged
MH  - Body Mass Index
MH  - C-Peptide/blood
MH  - Case-Control Studies
MH  - Causality
MH  - Diabetes Mellitus, Type 2/*complications/etiology/genetics
MH  - Educational Status
MH  - Female
MH  - Glycated Hemoglobin/analysis
MH  - Humans
MH  - Male
MH  - Mediation Analysis
MH  - Middle Aged
MH  - Obesity/*complications/genetics
MH  - Pancreatic Neoplasms/complications/*etiology/genetics
MH  - Polymorphism, Single Nucleotide/genetics
MH  - Risk Factors
MH  - Sex Factors
MH  - Smoking/adverse effects
OTO - NOTNLM
OT  - cancer epidemiology
OT  - diabetes mellitus
OT  - obesity
OT  - pancreatic cancer
COIS- Competing interests: None declared.
EDAT- 2020/05/16 06:00
MHDA- 2021/09/08 06:00
CRDT- 2020/05/16 06:00
PHST- 2019/10/03 00:00 [received]
PHST- 2020/04/07 00:00 [revised]
PHST- 2020/04/12 00:00 [accepted]
PHST- 2020/05/16 06:00 [pubmed]
PHST- 2021/09/08 06:00 [medline]
PHST- 2020/05/16 06:00 [entrez]
AID - gutjnl-2019-319990 [pii]
AID - 10.1136/gutjnl-2019-319990 [doi]
PST - ppublish
SO  - Gut. 2021 Feb;70(2):319-329. doi: 10.1136/gutjnl-2019-319990. Epub 2020 May 14.