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

Sep 21, 2026

Uploaded by Logic

Objective: This Mendelian randomization study evaluates the potential causal relationship between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using drug-targeting instruments. Methods: Instrumental variables within ±100 kb of the PCSK9 locus affecting LDL-C were used, with coronary heart disease as a positive control to validate causality and reverse MR to address reverse causation. Results: PCSK9 inhibition showed negative causality for breast and lung cancers, positive causality for gastric, hepatic, oral/pharyngeal cancers, and cervical intraepithelial neoplasia, with no heterogeneity/pleiotropy. Sensitivity and reverse MR supported these divergent findings; no causal links were found for multiple other cancers. Conclusions: Results indicate cancerspecific causal directions of PCSK9 inhibitors.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Introduction

Methods

Results

Sensitivity Analyses

Conclusions

Article The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting Wenxin Wang 1, Wei Li 2, Dan Zhang 1, Yongrun Mi 2, Jingyu Zhang 1 and Guoyang He 1, * Citation: Wang, W.; Li, W.; Zhang, D.; Mi, Y.; Zhang, J.; He, G. The Causal Relationship between PCSK9 Inhibitors and Malignant Tumors: A Mendelian Randomization Study Based on Drug Targeting. Genes 2024, 15, 132. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)genes15010132 Academic Editors: Albert Jeltsch and Peter Devilee Received: 24 November 2023 Revised: 10 January 2024 Accepted: 19 January 2024 Published: 21 January 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China; [wangwenxinisme@163.com](wangwenxinisme@163.com) (W.W.); [shuiyao112112@163.com](shuiyao112112@163.com) (D.Z.); [zjingyu233@outlook.com](zjingyu233@outlook.com) (J.Z.) 2 School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, China; [lwhn2008@163.com](lwhn2008@163.com) (W.L.); [miyongrun@outlook.com](miyongrun@outlook.com) (Y.M.) * Correspondence: [071014@xxmu.edu.cn](071014@xxmu.edu.cn) Abstract: Objective: This study explores the potential causal association between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within ±100 kb of the PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate the causal relationship between PCSK9 inhibitors and various cancers. We employed reverse MR to address thereverse causation concerns. Data from positive controls and tumors were sourced from OpenGWAS. Results: MR analysis suggested a negative causal relationship between PCSK9 inhibitors and both breast and lung cancers (95%CI Breast cancer 0.81~0.99, p = 2.25 × 10−2; 95%CILung cancer 0.65~0 .94, p = 2 .55 × 10−3) . In contrast, a positive causal link was observed with gastric, hepatic, and oral pharyngeal cancers and cervical intraepithelial neoplasia (95%CI Gastric cancer 1.14~1.75, p = 1.88 × 10−2; 95%CIHepatic cancer 1.46~2.53, p = 1.16 × 10−2; 95%CI Oral cavity and pharyngeal cancer 4.49~6 .33, p = 3 .36 × 10−4; 95%CI Carcinoma in situ of cervix uteri 4.56~7 . 12, p = 6 .91 × 10−3), without heterogeneity or pleiotropy (p > 0.05) . Sensitivity analyses confirmed these findings. The results of MR of drug targets suggested no causal relationship between PCSK9 inhibitors and bladder cancer, thyroid cancer, pancreatic cancer, colorectal cancer, malignant neoplasms of the kidney (except for renal pelvis tumors), malignant neoplasms of the brain, and malignant neoplasms of the esophagus (p > 0.05) . Reverse MR helped mitigate reverse causation effects. Conclusions: The study indicates a divergent causal relationship of PCSK9 inhibitors with certain cancers. While negatively associated with breast and lung cancers, a positive causal association was observed with gastric, hepatic, oral cavity, and pharyngeal cancers and cervical carcinoma in situ. No causal links were found with bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers. Keywords: PCSK9 inhibitor; drug target; Mendelian randomization; tumor 1. Introduction The World Health Organization reports that tumors remain the leading cause of global mortality [1] . Despite advancements in cancer research, significant treatment challenges persist [2] . Cholesterol, e

FAQs

How does the study assess causality between PCSK9 inhibitors and cancer risk?

It uses Mendelian randomization with instrumental variables tied to the PCSK9 gene locus that affect LDL-C. Coronary heart disease is included as a positive control, and reverse MR is applied to reduce reverse-causation concerns.

Which cancers showed a negative causal relationship with PCSK9 inhibitors?

The MR results suggest negative causal associations with breast cancer and lung cancer, with reported confidence intervals below 1 and statistically significant p values.

Were there causal links for all cancers examined?

No. The study reports no causal relationship (p > 0.05) for several cancers including bladder, thyroid, pancreatic, colorectal, malignant neoplasms of the kidney (except renal pelvis tumors), brain, and esophagus.

Sep 21, 2026

Uploaded by Logic