Strengthening the Evidence for a Causal Link between Type 2 Diabetes Mellitus and Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Diabetes Mellitus, Type 2*/genetics ; Diabetes Mellitus, Type 2*/epidemiology ; Mendelian Randomization Analysis* ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/etiology ; Pancreatic Neoplasms*/epidemiology ; Genome-Wide Association Study*; Humans ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Odds Ratio ; Risk Factors

This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM's impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa.
Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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101017441 European Union's funded Project iHelp

Keywords: FinnGen; UK Biobank; pancreatic cancer; two-sample Mendelian randomization; type 2 diabetes mellitus

Date Created: 20240511 Date Completed: 20240511 Latest Revision: 20240513

20250114

PMC11082974

10.3390/ijms25094615

38731833