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Background <p>Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking.</p> Aim <p>This Mendelian randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk.</p> Method <p>Genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes were used to perform MR analyses of PC risk. MR estimation was based on genome-wide association study data from two large sample sets, and the MR results were meta-analyzed to assess their impact on PC risk. To ensure the reliability of lipid-modifying drug targets, we conducted a Summary Data-based Mendelian Randomization (SMR) analysis. Additionally, a two-step MR analysis was employed to explore potential mediating effects.</p> Results <p>In two independent datasets, HMG-CoA reductase (HMGCR) inhibition was statistically associated with a lower risk of PC (OR 0.50, [95% CI 0.25–1.00]; <i>p</i> = 0.0453). The results were further supported by SMR analysis, which showed a similar association (OR 0.51, [95% CI 0.28–0.96]; <i>p</i> = 0.0369). Mediation analysis revealed that 11.69% of the protective effect of HMGCR inhibitors on PC is mediated through lower BMI levels. No significant effect of lipid traits and the other eight lipid-lowering drug targets on PC risk was found.</p> Conclusion <p>This study suggests that HMGCR may be a potential drug target for the treatment or prevention of PC, providing important insights into the use of lipid-targeted drugs in PC therapy.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月17日

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  • Yuxuan Zhan,
  • Kai Zhang,
  • Yiqun Fan,
  • Siyi Lin,
  • Jian Wu,
  • Hongxia Xu

摘要

Background

Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking.

Aim

This Mendelian randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk.

Method

Genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes were used to perform MR analyses of PC risk. MR estimation was based on genome-wide association study data from two large sample sets, and the MR results were meta-analyzed to assess their impact on PC risk. To ensure the reliability of lipid-modifying drug targets, we conducted a Summary Data-based Mendelian Randomization (SMR) analysis. Additionally, a two-step MR analysis was employed to explore potential mediating effects.

Results

In two independent datasets, HMG-CoA reductase (HMGCR) inhibition was statistically associated with a lower risk of PC (OR 0.50, [95% CI 0.25–1.00]; p = 0.0453). The results were further supported by SMR analysis, which showed a similar association (OR 0.51, [95% CI 0.28–0.96]; p = 0.0369). Mediation analysis revealed that 11.69% of the protective effect of HMGCR inhibitors on PC is mediated through lower BMI levels. No significant effect of lipid traits and the other eight lipid-lowering drug targets on PC risk was found.

Conclusion

This study suggests that HMGCR may be a potential drug target for the treatment or prevention of PC, providing important insights into the use of lipid-targeted drugs in PC therapy.