The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug...

Area of Science:

• Genetics and Epidemiology
• Oncology
• Pharmacology

Background:

• Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are a class of drugs targeting low-density lipoprotein cholesterol (LDL-C).
• The potential impact of PCSK9 inhibition on tumor development remains an area of active investigation.
• Mendelian randomization (MR) offers a robust approach to infer causal relationships using genetic variants as instrumental variables.

Purpose of the Study:

• To investigate the potential causal associations between PCSK9 inhibition and the development of various cancers.
• To utilize a drug-target Mendelian randomization approach to assess these relationships.
• To explore both protective and risk-increasing effects of PCSK9 inhibitors on different cancer types.

Main Methods:

• Mendelian randomization (MR) analysis using genetic variants near the PCSK9 gene locus associated with LDL-C levels.
• Coronary heart disease (CHD) was used as a positive control to validate the MR approach.
• Reverse MR and sensitivity analyses were performed to address potential biases like pleiotropy and reverse causation.

Main Results:

• A significant negative causal association was found between PCSK9 inhibition and breast cancer (OR 0.81-0.99) and lung cancer (OR 0.65-0.94).
• Conversely, a positive causal association was observed for gastric cancer (OR 1.14-1.75), hepatic cancer (OR 1.46-2.53), oral cavity and pharyngeal cancer (OR 4.49-6.33), and cervical intraepithelial neoplasia (OR 4.56-7.12).
• No significant causal relationships were detected for bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers.

Conclusions:

• PCSK9 inhibitors exhibit a divergent causal relationship with cancer development.
• These drugs may offer a protective effect against breast and lung cancers.
• However, they appear to increase the risk for gastric, hepatic, oral cavity/pharyngeal cancers, and cervical intraepithelial neoplasia.