Abstract

Retinopathy of prematurity (ROP) is a vaso-proliferative eye disease of prematurely born infants of low birth weight (<1500 g) and low gestational age (<32 weeks). More than 50% of premature infants weighing less than 1250g at birth show evidence of ROP, and about 10% of the infants develop severe ROP. It is characterized by abnormal retinal vascularization leading to blindness. An early detection of ROP and timely intervention is key to a successful management of disease and thereby preventing the vision loss caused by ROP. Our genomic study  on ROP revealed  a strong role for the genes involved in angiogenesis, growth and development of the fetal retina, trans-endothelial migration, oxidative stress, inflammation and neurodegenerative processes in ROP pathogenesis. We observed strong associations of ROP with the variants in CFH, CFB, CXCR4, FBLN5 andCETP genes along with increased levels of proteins in the extracellular matrix (ECM) and complement pathways in the vitreous of these babies We further demonstrated that  the activated microglial cells in the retina and vitreous under hypoxia expressed complement C3, VEGF and IL-1ß,thereby resulting in abnormal blood vessel proliferation in the ROP-affected eyes. Based on the findings of this study supplemented with increasing evidences on the role of inflammation in causing neovascularization, we speculated if MMPs could be detected in the tear samples of ROP babies so that it could be used as markers for ROP progression. The tear samples were an obvious choice for this study as it is fairly non-invasive, safe and convenient, although there were some restrictions of tear volume and sampling in these ROP babies.  It was interesting to note that the levels of MMPs in tears were significantly higher in severe ROP compared to no-ROP and mild ROP eyes that underscored its potential use as a biomarker for an early prediction of the condition. The subsequent validation of these initial findings in an extended cohort and the increasing levels of ROP with the increase in severity of disease further established the usefulness of MMPs in tears as potential biomarkers. Thus based on comprehensive genomics and proteomics, our study provided a proof of concept that tear MMP levels could serve as a potential predictor for ROP progression in preterm babies.