Causal association between cystatin C and diabetic retinopathy: A two‐sample Mendelian randomization study

Abstract

ABSTRACT Objective To explore the causal relationship between cystatin C levels and different stages of diabetic retinopathy through Mendelian randomization (MR). Methods The MRC Integrative Epidemiology Unit provided the Genome‐wide association studies (GWAS) data related to cystatin C (exposure). GWAS data for outcomes [DR, proliferative diabetic retinopathy (PDR), severe non‐proliferative background diabetic retinopathy (SNPBDR)] were sourced from the FinnGen. Adopted Inverse Variance Weighting (IVW), MR‐Egger regression MR‐PRESSO, Weighted Median, Constrained Maximum Likelihood and Model Averaging (cML‐MA), Weighted model, Radial MR, and MR‐Lasso to estimate the causal relationship between cystatin C and diabetic retinopathy. We conducted multivariable MR analysis to evaluate the independent causal effects of cystatin C levels on diabetic retinopathy. Results Based on the IVW method, we observed a causal relationship between cystatin C and diabetic retinopathy [odds ratio (OR)random effect = 1.137, 95% confidence interval (CI): 1.035–1.250]/PDR (ORrandom effect = 1.123, 95%CI: 1.004–1.255)/SNPBDR (ORfixed effect = 2.002, 95%CI: 1.343–2.986). Consistent findings were obtained through the cML‐MA method. Cochran's Q test suggested the presence of heterogeneity between the cystatin C level and instrumental variables in relation to diabetic retinopathy and proliferative diabetic retinopathy, respectively. After adjusting for outliers using MR‐PRESSO and Radial MR, it was observed that the statistical significance of the association between cystatin C level and diabetic retinopathy persists. Reverse MR analysis indicated that genetically related SNPBDR may influence the cystatin C level. In multivariable MR analysis, there were indications suggesting a causal relationship of cystatin C with the risk of DR/PDR/SNPBDR adjusting for confounders. Conclusions This study utilizes Mendelian randomization analyses to establish a causal relationship between cystatin C and diabetic retinopathy, and reveals the impact of cystatin C on the risk of diabetic retinopathy, thus providing new evidence for clinical intervention of diabetic retinopathy.

Keywords

• Cystatin C
• Diabetic retinopathy
• Mendelian randomization