Background: Mendelian randomization(MR) is a method that uses instrumental variables (IVs) to examine exposure factors and simulates the influence of exposure factors on diseases by using the causal relationship effect between genotype and disease. Objective: To explore the causal relationships between homocysteine(Hcy) level and the risk of diabetic retinopathy(DR) and three DR phenotypes, background DR(BDR), severe non-proliferative DR(SNPDR), and proliferative DR(PDR). Methods: As instrumental variables for the MR analysis, we utilized 18 single nucleotide polymorphisms (SNPs) that were significantly associated with circulating serum Hcy levels at genomewide significance (p<5×10–8). GWAS data pertaining to various stages of DR was obtained from the FinnGen database(www.finngen.fi/fi). Eight MR approaches, including inverse variance weighted(IVW), MR-Egger, Weighted Median, IVW(fixed effects), Maximum likelihood, Penalised weighted median, Simple mode and Weighted mode, were analysed using the Two Sample MR packages in R version 4.2.2. Results: All analysis indicated no causal association between Hcy and DR, BDR, SNPDR, and PDR using the IVW approach(p value>0.05). Sensitivity analysis indicated the robustness of the main findings, with no outliers, heterogeneity, horizontal pleiotropy, or significant influence of individual SNPs. Conclusion: This study does not support a causal relationship between Hcy and various stages of DR.
Keywords: Mendelian randomization; homocysteine; diabetic retinopathy; Causal inference