Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study

Shuwan Zhang; Wenchuan Zhang; Hanxue Sun; Rui Xue; Qingjie Lv

doi:10.1016/j.heliyon.2023.e20474

Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study

Heliyon. 2023 Sep 27;9(10):e20474. doi: 10.1016/j.heliyon.2023.e20474. eCollection 2023 Oct.

Authors

Shuwan Zhang^{1

2}, Wenchuan Zhang^{1

3}, Hanxue Sun¹, Rui Xue⁴, Qingjie Lv^{1

2}

Affiliations

¹ Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China.
² Key Laboratory of Intelligent and Precision Pathology Diagnosis in Oncology, China Medical University, Shenyang 110004, Liaoning Province, China.
³ Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
⁴ School of Medicine, Chongqing University, Chongqing 400044, China.

Abstract

Background: Interleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous.

Methods: An inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study.

Results: The selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results.

Conclusion: Therefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

Keywords: Anticancer therapy; Drug target validation; Interleukin-6 signaling downregulation; Inverse variance-weighted test; Mendelian randomization.