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

Qiqin Shi; Qiangsheng Wang; Zhenqian Wang; Jiawen Lu; Ruobing Wang

doi:10.3389/fimmu.2023.1088778

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

Front Immunol. 2023 Feb 10:14:1088778. doi: 10.3389/fimmu.2023.1088778. eCollection 2023.

Authors

Qiqin Shi¹, Qiangsheng Wang², Zhenqian Wang³, Jiawen Lu³, Ruobing Wang⁴

Affiliations

¹ Department of Ophthalmology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, China.
² Department of Haematology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, China.
³ School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China.
⁴ Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus*
Diabetic Retinopathy* / genetics
Genome-Wide Association Study
Humans
Interleukin-12
Interleukin-8 / genetics
Mendelian Randomization Analysis

Substances

Interleukin-8
Interleukin-12

Grants and funding

This work was supported by the National Natural Science Foundation of China (81770932 and 82171061), Natural Science Foundation of Shanghai (22ZR1438400) and Ningbo Science and Technology Bureau (No. 2022J053).