Blood cell traits and risk of glaucoma: A two-sample mendelian randomization study

Importance: Glaucoma is the second leading cause of blindness in the world. The causal direction and magnitude of the association between blood cell traits and glaucoma is uncertain because of the susceptibility of observational studies to confounding and reverse causation. Objective: To explore whether there is a causal relationship of blood cell traits including white blood cell (WBC) count (WBCC) and its subtypes [basophil cell count (BASO), monocyte cell count (MONO), lymphocyte cell count (LYMPH), eosinophil cell count (EOS), neutrophil cell count (NEUT)], red blood cell (RBC) count (RBCC), red blood distribution width (RDW), platelet count (PLT), and plateletcrit (PCT) on glaucoma risk. Methods: A two-sample Mendelian randomization (MR) analysis was conducted. Genome-wide significant single nucleotide polymorphisms (SNPs) from published genome-wide association studies (GWAS) on human blood cell traits were utilized as exposure instruments and the dataset for outcome was from the GWAS summary data of glaucoma. In the univariable MR analysis, we examined the association between genetic evidence of blood cell traits and glaucoma. To further investigate the potential causal mechanisms underlying the observed association, we performed multivariable MR analysis with three models, taking into account the mediator effect of inflammation and oxidative stress. According to Bonferroni-corrected for the 10 exposures in 3 methods, the MR study yielded a statistically significant p-value of 0.0017. Results: Genetically BASO, PCT, LYMPH, and PLT were potentially positively associated with glaucoma in the European ancestry [BASO: Odds ratio (OR) = 1.00122, 95% confidence interval (CI), 1.00003-1.00242, p = 0.045; PCT: OR = 1.00078, 95% CI, 1.00012-1.00143, p = 0.019; LYMPH: OR = 1.00076, 95% CI, 1.00002-1.00151, p = 0.045; PLT: OR = 1.00065, 95% CI, 1.00006-1.00123, p = 0.030], There was insufficient evidence to support a causal association of MONO, NEUT, EOS, WBCC, RBCC and RDW (MONO: OR = 1.00050, p = 0.098; NEUT: OR = 1.00028, p = 0.524; EOS: OR = 1.00020, p = 0.562; WBCC: OR = 1.00008, p = 0.830; RBCC: OR = 0.99996, p = 0.920; RDW: OR = 0.99987, p = 0.734) with glaucoma. The multivariable MR with model 1, 2, and 3 demonstrated that BASO, PCT, LYMPH, and PLT were still potentially genetically associated with the risk of glaucoma. Conclusion: Our study reveals a genetic predisposition to higher LYMPH, BASO, PLT, and PCT are associated with a higher risk of glaucoma, whereas WBCC, MONO, EOS, NEUT, RBCC, and RDW are not associated with the occurrence of glaucoma. This finding also supports previous observational studies associating immune components with glaucoma, thus provide guidance on the predication and prevention for glaucoma.