Causal association between inflammatory markers and malignant neoplasms of bone and articular cartilage using Mendelian randomization

Background
The pathogenesis of malignant neoplasms of bone and articular cartilage is not fully understood, as the inflammatory immune microenvironment may play a crucial role in tumor development and progression. This study aimed to investigate the causal associations between specific inflammatory immune markers and the risk of bone and articular cartilage malignancies.

Methods
On the basis of genome-wide association study (GWAS) data from inflammatory factors and blood metabolites, single nucleotide polymorphisms (SNPs) with F statistics greater than 10 were selected as valid instrumental variables. Mendelian randomization (MR) methodology was employed to assess causal relationships between inflammatory markers and bone tumor risk, with sensitivity analyses conducted via MR‒Egger, heterogeneity tests, leave-one-out analysis, and MR-PRESSO. Additionally, qRT-PCR was used to validate the expression of key markers in cell lines.

Results
Mendelian randomization analysis revealed that elevated CXCL6 levels were positively correlated with tumor occurrence risk (OR = 1.5, 95% CI: 1.1–2.0), while MIP (OR = 0.5, 95% CI: 0.3–0.7), CCL4 (OR = 0.6, 95% CI: 0.4–0.8), and LIF-R (OR = 0.5, 95% CI: 0.3–0.8) were significantly associated with reduced tumor risk. Sensitivity analyses confirmed robust results with no significant horizontal pleiotropy. Meta-analysis showed CCL4 expression was reduced in most studies, while CXCL6 was significantly upregulated in tumor tissues. qRT-PCR validation demonstrated that all four inflammatory markers were significantly higher in tumor cell lines compared to normal cells (P < 0.01).ConclusionThis study, which uses Mendelian randomization, suggests potential causal associations between inflammatory immune markers and the risk of malignant neoplasms of bone and articular cartilage.