Dataset Information

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

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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC10556766 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Zhang Shuwan S Zhang Wenchuan W Sun Hanxue H Xue Rui R Lv Qingjie Q

Heliyon 20230927 10

<h4>Background</h4>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.<h4>Methods</h4>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 sing ...[more]

PMID: 37810867

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Project description:Background: Interleukin-6 receptor (IL-6R) blockade has been approved for inflammation-associated diseases and whether it is effective in treating non-alcoholic fatty liver disease (NAFLD) is still unknown. Methods: A target-based Mendelian randomization was performed to appraise whether inhibiting the IL-6 signaling pathway via IL-6R blockade can reduce the risk of NAFLD. The previously established genetic proxy SNP rs2228145 was mainly used to appraise the therapeutic effects and the genetic-predicted circulating IL-6 level was treated as the exposure with ∼30,000 samples. The genetic association between SNP rs2228145 (A > C) and NAFLD was obtained from non-FinnGen GWAS (1,483 cases and 17,781controls) and FinnGen GWAS (894 cases and 217,898 controls). The causal effects were estimated using a Wald ratio method and were combined using a fixed-effects meta-analysis. Furthermore, the SNP rs12048091 was employed as another proxy in the sensitivity analysis. Results: The positive control analysis suggested the SNP rs2228145 can mimic the effects of IL-6R blockade where inhibiting IL-6 signaling can reduce the risk of rheumatoid arthritis [OR = 0.68 (0.58, 0.80)] and coronary heart disease [OR = 0.75 (0.68, 0.84)]. This Mendelian randomization analysis suggested that IL-6R blockade can adversely increase the risk of NAFLD in the non-FinnGen GWAS [OR = 1.99 (1.27, 3.13)] while not significant in the FinnGen consortium. The fixed-effects meta-analysis indicated inhibiting the IL-6 signaling pathway can reduce the risk of NAFLD [OR = 1.80 (1.26, 2.57)]. When including SNP rs12048091 as the genetic instrument, the meta-analysis using two genetic variants also indicated a similar effect on NAFLD [OR = 1.83 (1.32, 2.53)]. There was no heterogeneity in the whole analysis. Conclusion: Our Mendelian randomization suggested inhibiting the IL-6 signaling pathway via IL-6R blockade might increase the risk of NAFLD, suggesting IL-6R should play a protective role in NAFLD.

Project description:BackgroundAsthma poses a significant global health challenge, characterized by high rates of morbidity and mortality. Despite available treatments, many severe asthma patients remain poorly managed, highlighting the need for novel therapeutic strategies. This study aims to identify potential drug targets for asthma by examining the influence of circulating plasma proteins on asthma risk.MethodsThis study employs summary-data-based Mendelian randomization (MR) and two-sample MR methods to investigate the association between 2940 plasma proteins from the UK Biobank study and asthma. The analysis includes discovery (FinnGen cohort) and replication (GERA cohort) phases, with Bayesian colocalization used to validate the relationships between proteins and asthma. Furthermore, protein-protein interaction and druggability assessments were conducted on high-evidence strength protein biomarkers, and candidate drug prediction and molecular docking were performed for proteins without targeted drugs. Given the complexity of asthma pathogenesis, the study also explores the relationships between plasma proteins and asthma-related endpoints (e.g., obesity-related asthma, infection-related asthma, childhood asthma) to identify potential therapeutic targets for different subtypes.ResultsIn the discovery cohort, 75 plasma proteins were associated with asthma, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8. Additionally, 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, and SCLY) were validated through co-localization analysis and validation cohort. The assessment of drug targetability revealed potential drug targets for IL4R, CASP8, and SCLY, while candidate drugs were predicted for LTB and MAX proteins. MAX exhibited strong binding affinity with multiple small molecules indicating a highly stable interaction and significant druggability potential. Analysis of the 75 proteins with 9 asthma-related endpoints highlighted promising targets such as DOK2, ITGAM, CA1, BTN2A1, and GZMB.ConclusionThese findings elucidate the link between asthma, its related endpoints, and plasma proteins, advancing our understanding of molecular pathogenesis and treatment strategies. The discovery of potential therapeutic targets offers new insights into asthma drug target research.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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