Ma Keru, Wang Hao, Du Yubo, Chen Tianyu, Yang Dongxu, Li Yue, Li Dalin
Department of Breast Surgery Harbin Medical University Cancer Hospital Harbin China.
Department of Medical Oncology Harbin Medical University Cancer Hospital Harbin China.
Food Sci Nutr. 2025 May 19;13(5):e70293. doi: 10.1002/fsn3.70293. eCollection 2025 May.
The relationship between lipid-lowering drugs and the risk of digestive system cancers remains unclear. This study aims to assess the risk association between lipid-lowering drugs and digestive system cancers through mendelian randomization (MR) analysis. We utilized genetic instruments to substitute for the exposure to lipid-lowering drugs, including expression quantitative trait loci (eQTL) for HMGCR, PCSK9, and NPC1L1, as well as genetic variants associated with low-density lipoprotein (LDL) from the Global Lipids Genetics Consortium's genome-wide association study (GWAS) data for target genes. We used MR and SMR methods to assess the risk estimates of lipid-lowering drug target genes on digestive system tumors. The MR analysis indicated a negative association between HMGCR-mediated LDL and hepatocellular carcinoma (OR = 0.06, 95% CI: 0.00-0.81, = 0.03), and a positive association between NPC1L1-mediated LDL and gastric cancer risk (OR = 15.45, 95% CI: 5.96-40.56, < 0.01). In the SMR analysis, it was observed that HMGCR expression decreased the risk of hepatocellular carcinoma (OR = 0.11, 95% CI: 0.02-0.68, = 0.02), while NPC1L1 expression increased the risk of gastric cancer (OR = 1.33, 95% CI: 1.08-1.64, < 0.01). Our study results suggested a potential risk association between HMGCR inhibitors and NPC1L1 with hepatocellular carcinoma and gastric cancer.
降脂药物与消化系统癌症风险之间的关系仍不明确。本研究旨在通过孟德尔随机化（MR）分析评估降脂药物与消化系统癌症之间的风险关联。我们利用基因工具替代降脂药物暴露，包括HMGCR、PCSK9和NPC1L1的表达定量性状位点（eQTL），以及来自全球脂质遗传学联盟全基因组关联研究（GWAS）数据中与目标基因低密度脂蛋白（LDL）相关的基因变异。我们使用MR和SMR方法评估降脂药物靶基因对消化系统肿瘤的风险估计。MR分析表明，HMGCR介导的LDL与肝细胞癌呈负相关（OR = 0.06，95%CI：0.00 - 0.81，P = 0.03），NPC1L1介导的LDL与胃癌风险呈正相关（OR = 15.45，95%CI：5.96 - 40.56，P < 0.01）。在SMR分析中，观察到HMGCR表达降低了肝细胞癌的风险（OR = 0.11，95%CI：0.02 - 0.68，P = 0.02），而NPC1L1表达增加了胃癌的风险（OR = 1.33，95%CI：1.08 - 1.64，P < 0.01）。我们的研究结果表明，HMGCR抑制剂和NPC1L1与肝细胞癌和胃癌之间存在潜在的风险关联。
