Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study

Abstract

Background: Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.

Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.

Results: Our results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).

Conclusions: Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Keywords: Mendelian randomization; bidirectional; meta-analysis; proliferative diabetic retinopathy; systemic inflammatory regulators.

Figure 1

Datasets, assumptions, and study design of the bidirectional Mendelian randomization study of the associations between 41 inflammatory factors and PDR. BMI, body mass index; DBP, diastolic blood pressure; FG, fasting glucose; FI, fasting insulin; IVs, instrumental variables; PDR, proliferative diabetic retinopathy; SBP, systolic blood pressure; SNPs, single-nucleotide polymorphisms; T1D, type 1 diabetes; T2D, type 2 diabetes.

Figure 2

Associations between genetically predicted systemic inflammatory regulators and proliferative diabetic retinopathy (with genome-wide significant SNPs). IL, interleukin; MCP1, monocyte chemotactic protein-1; MIP1b, macrophage inflammatory protein-1 beta; PDGFbb, platelet-derived growth factor BB; SCGFb, stem cell growth factor beta; SNPs, single-nucleotide polymorphisms; TRAIL, TNF-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.

Figure 3

Significant associations between genetically predicted systemic inflammatory regulators and proliferative diabetic retinopathy (with SNPs reaching P<5×10^-6). IL, interleukin; SCGFb, stem cell growth factor beta.

Figure 4

Scatter plot of SCGFb and IL-8 related SNPs with the risk of proliferative diabetic retinopathy. (A) Genetic association of SCGFb related SNPs and PDR from FinnGen. (B) Genetic association of IL-8 related SNPs and PDR from FinnGen. (C) Genetic association of SCGFb related SNPs and PDR from eight cohorts. (D) Genetic association of IL-8 related SNPs and PDR from eight cohorts. Black line indicates the estimate of effect using the inverse variance weighted method. Circles indicate marginal genetic associations with SCGFb or IL-8 and risk of outcome for each variant. Error bars indicate 95% confidence intervals. IL, interleukin; SCGFb, stem cell growth factor beta; SD, standard deviation.

Figure 5

Significant associations between genetically predicted proliferative diabetic retinopathy and systemic inflammatory regulators. GCSF, granulocyte colony-stimulating factor; GROa, growth-regulated oncogene-alpha; IL, interleukin; MCP3, monocyte chemotactic protein-3; SDF1a, stromal cell-derived factor 1.