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. 2024 Nov;15(11):1626-1636.
doi: 10.1111/jdi.14273. Epub 2024 Aug 12.

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

Yimeng Ruan  1 , Ping Zhang  2 , Xiangzhe Li  1 , Xinru Jia  1 , Dongwei Yao  1
Affiliations

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

Yimeng Ruan et al. J Diabetes Investig. 2024 Nov.

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.

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Conflict of interest statement

Conflict of interest: N/A.

Approval of the research protocol: N/A.

Informed Consent: N/A.

Approval date of Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

Figures

Figure 1
Figure 1
Schematic representation of Mendelian randomization analysis.
Figure 2
Figure 2
Forest plot for the Mendelian randomization results of cystatin C on DR/PDR/SNPBDR; PDR, proliferative diabetic retinopathy; SNPBDR, severe non‐proliferative background diabetic retinopathy.
Figure 3
Figure 3
Scatter plot of the causality of cystatin C with DR/PDR/SNPBDR. The slopes of the lines represent the causal effect of each method, respectively; PDR, proliferative diabetic retinopathy; SNPBDR, severe non‐proliferative background diabetic retinopathy.
Figure 4
Figure 4
Leave‐one‐out sensitivity analysis of cystatin C on (a) DR; (b) PDR; (c) SNPBDR; PDR, proliferative diabetic retinopathy; SNPBDR, severe non‐proliferative background diabetic retinopathy.
Figure 5
Figure 5
Forest plot for the multivariable Mendelian randomization results adjusting for confounding factors.
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