Investigating the Association between Low-Density Lipoprotein Cholesterol and Pancreatic Cancer Risk: A Mendelian Randomization Study

Abstract Objective Mendelian randomization is a method that utilizes genetic variants that are randomly assigned at conception to investigate causal relationships between an exposure (such as low-density lipoprotein cholesterol) and an outcome (such as pancreatic cancer). This study employs a Mendelian randomization approach to investigate the potential relationship between low-density lipoprotein cholesterol (LDL-C) levels and the risk of developing pancreatic cancer. Methods The study data were derived from a genome-wide association study (GWAS) meta-analysis dataset, which included 115,078 samples for LDL-C and 218,187 samples for pancreatic cancer. This study utilized several Mendelian randomization (MR) methods, including the inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger approaches, to examine the potential causal relationship between LDL-C and the risk of developing pancreatic cancer. The odds ratio was used as the measure of association between LDL-C and pancreatic cancer in the MR analyses. MR-PRESSO and leave-one-out sensitivity analyses were conducted to detect horizontal pleiotropy and assess the robustness of the results. Results To investigate the causal relationship between LDL-C and pancreatic cancer risk, this study utilized 46 single nucleotide polymorphisms (SNPs) associated with LDL-C as instrumental variables, which were extracted from GWAS (R 2 < 0.001, P < 5x10 − 8 ). The F-statistics of all included SNPs were above 10, indicating the absence of weak instrument bias and confirming the reliability of the results. The IVW analysis revealed an odds ratio (OR) of 0.66 [95% confidence interval (CI): 0.44–0.98; P < 0.05], indicating a potential protective effect of LDL-C against pancreatic cancer. Weighted mode and weighted median analyses also demonstrated similar causal relationships with ORs of 0.49 [95% CI: 0.27–0.91, P < 0.05] and 0.47 [95% CI: 0.26–0.82, P < 0.05], respectively. However, the simple mode regression analysis and MR-Egger intercept test did not yield similar results with P > 0.05, suggesting no statistical significance. The funnel plot and MR-Egger intercept did not indicate horizontal pleiotropy or heterogeneity (P = 0.31), further supporting the reliability of the study's findings. Conclusion The results of this Mendelian randomization study suggest that high levels of LDL-C may have a protective effect against the development of pancreatic cancer. These findings highlight the potential importance of LDL-C levels in pancreatic cancer prevention and may inform future studies and interventions aimed at reducing pancreatic cancer incidence.