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: The authors 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. Utilizing a two-sample Mendelian randomization 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, =0.001] and strongly associated (IVW estimate OR: 1.002, 95% CI: 1.000-1.003, =0.049) with an increased risk of myopia, respectively. Conversely, lower levels of C-reactive protein (CRP) (IVW estimate OR: 0.996, 95% CI: 0.994-0.999, =0.002) and tumour necrosis factor alpha (IVW estimate OR: 0.995, 95% CI: 0.994-0.996, <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.