Causal relationships between inflammatory cytokines and myopia: an analysis of genetic and observational studies

Objective: This study aims to explore the causal relationship between inflammatory markers and myopia through the use of bidirectional Mendelian Randomization (MR) and myopia animal models. Methods: We utilized data from a comprehensive and publicly accessible genome-wide association study (GWAS) for our analysis, which includes 460,536 European ancestry control subjects and 37,362 myopia patients. Utilising a two-sample Mendelian randomisation analysis framework, 27 inflammatory markers were investigated as exposure variables with myopia serving as the outcome variable. Nine MR analysis techniques were employed, with Inverse Variance Weighting (IVW) as the principal MR analysis method. Heterogeneity was assessed using Cochrane’s Q test. The identification of single-nucleotide polymorphisms (SNPs) and outliers linked to myopia was achieved via MR-PRESSO. The expression of interleukin-2 (IL-2) in the vitreous of guinea pigs subjected to experimentally induced form deprivation myopia (FDM) was examined. Results: Elevated concentrations of IL-2 and IL-2ra were found to be associated (IVW estimate odds ratio (OR): 1.003, 95% CI: 1.001-1.005, P =0.001) and strongly associated (IVW estimate OR: 1.002, 95% CI: 1.000-1.003, P =0.049) with an increased risk of myopia, respectively. Conversely, lower levels of CRP (IVW estimate OR: 0.996, 95% CI: 0.994-0.999, P =0.002) and tumour necrosis factor alpha (IVW estimate OR: 0.995, 95% CI: 0.994-0.996, P <0.001) were robustly linked to a heightened risk of myopia. IL-2 expression was notably upregulated in the vitreous of guinea pigs with experimentally induced FDM. Conclusions: Elevated levels of inflammatory factors, especially IL-2 and IL-2ra, have a potential causal relationship with myopia susceptibility, providing new insights into the pathogenesis of myopia.