A two-sample Mendelian randomization analysis of the causal relationship between NMR-based lipid metabolites and pancreatic cancer risk
10.7659/j.issn.1005-6947.250294
- VernacularTitle:核磁共振脂质代谢物与胰腺癌风险因果关系的双样本孟德尔随机化分析
- Author:
Jing SUN
1
;
Jiaoyan LIU
;
Yongrong LIU
;
Hongwei ZHU
;
Kaiyan YANG
;
Wenxiu ZHANG
Author Information
1. 中南大学湘雅三医院 护理部,湖南 长沙 410013
- Publication Type:Journal Article
- Keywords:
Pancreatic Neoplasms;
Lipid Metabolites;
Causal Relationship;
Mendelian Randomization Analysis
- From:
Chinese Journal of General Surgery
2025;34(7):1440-1450
- CountryChina
- Language:Chinese
-
Abstract:
Background and Aims:Pancreatic cancer(PC)is a highly lethal gastrointestinal malignancy with poorly understood pathogenesis.Previous studies suggest that alterations in plasma metabolomics may be associated with PC development;however,traditional observational studies are prone to confounding and reverse causation,making it difficult to establish causal relationships.This study employed a two-sample Mendelian randomization(MR)approach to systematically evaluate the potential causal relationship between 325 nuclear magnetic resonance(NMR)metabolites and PC risk.Methods:Genome-wide association study(GWAS)data of 325 NMR metabolites from the UK Biobank were integrated with GWAS data of PC from FinnGen.Single nucleotide polymorphisms(SNPs)significantly associated with metabolites were selected as instrumental variables.The inverse variance weighted method served as the primary analysis,supplemented by MR-Egger regression,weighted median,weighted mode,Bayesian weighted Mendelian randomization(BWMR),and constrained maximum likelihood(cML)for validation.Multiple sensitivity analyses were performed to assess the robustness of the results.Results:Four metabolites were identified to have significant causal associations with PC risk.Higher phospholipid-to-total lipid ratios in intermediate-density lipoproteins(IDL)(GCST90445881)and small high density lipoproteins(HDL)(GCST90446027),as well as higher free cholesterol-to-total lipid ratios in extremely large very-low-density lipoproteins(VLDL)(GCST90446151),were inversely associated with PC risk.Conversely,an elevated triglyceride-to-total lipid ratio in chylomicrons and extremely large VLDL(GCST90446157)was positively associated with increased PC risk.The findings were consistently supported by multiple sensitivity analyses.Conclusion:This study provides genetic evidence linking lipid metabolism alterations to PC risk.Elevated phospholipid and free cholesterol ratios appear protective,whereas increased triglyceride levels act as risk factors.These metabolite profiles may serve as promising biomarkers for early diagnosis and intervention in PC,offering novel insights for risk assessment and potential metabolic-targeted therapies.
