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Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.
- Source :
-
Gut [Gut] 2021 Feb; Vol. 70 (2), pp. 319-329. Date of Electronic Publication: 2020 May 14. - Publication Year :
- 2021
-
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).<br />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.<br />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 <subscript>LSDM</subscript> =1.08, 95% CI: 0.86 to 1.29, OR <subscript>NODM</subscript> =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).<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Subjects :
- Aged
Body Mass Index
C-Peptide blood
Case-Control Studies
Causality
Diabetes Mellitus, Type 2 etiology
Diabetes Mellitus, Type 2 genetics
Educational Status
Female
Glycated Hemoglobin analysis
Humans
Male
Mediation Analysis
Middle Aged
Obesity genetics
Pancreatic Neoplasms complications
Pancreatic Neoplasms genetics
Polymorphism, Single Nucleotide genetics
Risk Factors
Sex Factors
Smoking adverse effects
Diabetes Mellitus, Type 2 complications
Obesity complications
Pancreatic Neoplasms etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 70
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 32409590
- Full Text :
- https://doi.org/10.1136/gutjnl-2019-319990