Lipids, lipid-lowering drug target genes and pancreatic cancer: a Mendelian randomization study

Background Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking. This Mendelian Randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk. Methods We used genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes to conduct MR analyses with PC risk. MR estimation utilized genome-wide association study (GWAS) data from two substantial sample sets, which were meta-analyzed to evaluate their influence on PC risk. To confirm the reliability of lipid modification drug targets, a Summary Data-based Mendelian Randomization (SMR) analysis was conducted. Additionally, a two-step MR (TSMR) analysis was implemented to investigate potential mediating roles. Result In the Discovery Dataset, HMGCR inhibition was statistically associated with a lower risk of PC (OR = 0.46, [95% CI, 0.22–0.97]; p  = 0.0404), and did not show statistical significance in the Replication Dataset, but the result of the meta-analysis reached statistical significance (OR = 0.50, [95% CI, 0.25-1.00]; p  = 0.0453). The SMR analysis enhanced the robustness of the results (OR = 0.51, [95% CI, 0.28–0.96]; p  = 0.0369). Furthermore, mediation analysis revealed that lowering BMI levels mediated the protective effect of HMGCR inhibitors on PC (mediation effect: OR = 0.91, [95% CI,0.84–0.97], mediation proportion:11.69%, [95% CI, 10.04%-13.61%]). Conclusions This study found that HMGCR inhibitors were significantly associated with the risk of PC, suggesting that HMGCR has the potential to be a candidate drug target for the treatment or prevention of PC.