Assessment of causality between circulating inflammatory proteins and subtypes of diabetic retinopathy

To explore the causal links among circulating inflammatory proteins (CIPs) and the varying severities of diabetic retinopathy (DR).

This research utilized a two sample Mendelian randomization (MR) approach to explore the causal relationships between 91 CIPs and various severities of DR: background DR (BDR) or non-proliferative DR (NPDR), and proliferative DR (PDR). Single-nucleotide polymorphisms (SNPs) related to the 91 CIPs as exposure factors were identified. These SNPs were selected from an extensive genome-wide association study (GWAS) analyzing large genomic datasets. Genetic variation data of various DR phenotypes provided by the FinnGen collaboration were utilized as outcomes. Inverse-variance weighting (IVW) was used as the main MR analysis. Robustness of study results was evaluated through a series of sensitivity analyses, employing the MR-pleiotropy-test and mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) to confirm the absence of pleiotropy.

In a bidirectional MR analysis, we uncovered a complex relationship between CIPs and DR. Elevated levels of tumor necrosis factor ligand superfamily member 14 (TNFSF14), latency associated peptide transforming growth factors beta-1 (LAP-TGF-beta1), interleukin-10 (IL-10), and vascular endothelial growth factor A (VEGF-A) were associated with a reduced risk of NPDR. Conversely, elevated levels of fibroblast growth factor 23 (FGF-23) were associated with an increased risk of NPDR. Concentrations of adenosine deaminase (ADA), matrix metalloproteinase-10 (MMP-10), eotaxin, and IL-10 showed elevated levels and were linked to a reduced risk of NPDR. On the other hand, the levels of oncostatin-M, beta-nerve growth factor (β-NGF), and interleukin-7 (IL-7) were elevated and associated with an increased risk of SNPDR. Elevated levels of ADA, MMP-10, and macrophage colony-stimulating factor 1 (CSF1) were linked to a lower likelihood of PDR. Conversely, elevated levels of Caspase 8 and glial cell line-derived neurotrophic factor (GDNF) were associated with an increased risk of PDR. In reverse MR analysis, DR affected the expression of these factors.

Our research demonstrates evidence supporting a potential causal link between key inflammatory factors and the risk and prognosis of various DR phenotypes. These findings emphasize the regulation of inflammatory factors responses as a strategic approach for preventing and managing DR. Altogether, our results validate the pathogenic role of inflammatory factors dysregulation in DR and support the rationale for exploring immunotherapeutic targets further.