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

• Published in: International journal of molecular sciences Vol. 25; no. 9; p. 4615
• Main Authors: Ke, Te-Min, Lophatananon, Artitaya, Muir, Kenneth R
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.05.2024
• Subjects: Analysis; Biobanks; Cancer; Datasets; Diabetes; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; FinnGen; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Health aspects; Humans; Mendelian Randomization Analysis; Methods; Mortality; Observational studies; Odds Ratio; Oncology, Experimental; Pancreatic cancer; Pancreatic Neoplasms - epidemiology; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - genetics; Polymorphism, Single Nucleotide; Prevention; Risk Factors; two-sample Mendelian randomization; Type 2 diabetes; type 2 diabetes mellitus; UK Biobank; United Kingdom > UK; type 2 diabetes mellitus; pancreatic cancer; UK Biobank; two-sample Mendelian randomization; FinnGen
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25094615

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.