Abstract
Purpose :
Discovery of biomarkers that could predict the risk of developing diabetic retinopathy is an unmet need. Due to ethical and practical issues, it is very difficult to obtain eye tissues from patients for biomarker testing. However, serum is an excellent non-invasive source for biomarkers because it contains several signaling molecules and secreted proteins from pathological sites. In an effort to discover new biomarkers and to understand the mechanism of disease, we examined the levels of 61 proteins in the serum from patients with and without proliferative diabetic retinopathy (PDR).
Methods :
Using a comprehensive literature search we compiled a list of 61 proteins from pathways known to be involved in the pathogenesis of diabetic retinopathy. Luminex multiplex immunoassays were used to measure levels of these proteins in 527 type 1 diabetes (T1D) patients from the Phenome and Genome of Diabetes Autoimmunity (PAGODA) study (n=450 with no complications; n=77 with PDR). Statistical analysis was performed to discover the proteins associated with PDR. Ingenuity pathway analysis (IPA) was conducted to decipher the cascade of upstream transcriptional regulators of the differentially expressed proteins.
Results :
We found significant changes in the levels of 26 serum proteins (16 upregulated and 10 downregulated) associated with PDR. Three proteins involved in the TNF-signaling pathway, sTNFR1 (1.8-fold), sTNFR2 (1.98-fold) and OPG (1.41-fold) were significantly increased in PDR. Among the proteins implicated in IGF signaling, four proteins significantly upregulated in PDR were IGFBP2 (3.55-fold), IGFBP1 (1.78-fold), IGFBP6 (1.74-fold), and IGFBP7 (1.28-fold). Interestingly, IGFBP3 was significantly downregulated in PDR (0.8-fold). MMP-1 (1.63-fold) and MMP-2 (1.19-fold) were also slightly increased in PDR. IPA analysis revealed several upstream factors including IL1B, IL6, TNF, IL1 and NFkB regulating the expression of these 26 proteins.
Conclusions :
The significant differences in the serum levels of proteins between the two groups highlight their potential as PDR biomarkers. A noteworthy finding was that a majority of these proteins belonged to IGF and TNF signaling, thereby emphasizing the need to target these pathways to develop novel treatments for PDR.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.