Analysis of pathological changes in collagen genes in children with retinopathy of premature

BACKGROUND: Collagen is the most ubiquitous protein in the human body; it is involved in maintaining the structure of various tissues, including the eye. Mutations or changes in the expression of genes encoding collagen or the related genes may hinder normal development of tissues and cause structural and functional abnormalities in the retinal extracellular matrix that are typical of retinopathy of prematurity and other proliferative retinal diseases. AIM: To examine changes in the expression of collagen-encoding genes and genes involved in their interactome and to analyze the effect of the identified molecular disorders on the disease severity. METHODS: It was an observational, multicenter, prospective, parallel-group study. Inclusion criteria: children born before week 32 of gestation or with a birth weigh of 1800 g. Additional inclusion criteria for the study group and control group: a confirmed diagnosis of active stage 3 to 4b retinopathy of prematurity or its absence, respectively. Venous blood samples were obtained from all patients. Genomic DNA was isolated and whole genome sequencing was performed. Changes in the expression of collagen genes and the related genes, as well as their effect on the disease severity, were analyzed. RESULTS: The study group comprised 35 children diagnosed with active stage 3 to 4b retinopathy of prematurity. The control group included 30 preterm children without signs of retinopathy. A total of 115 genes were analyzed, and for 50 of them a statistically significant change in expression was found in the study group vs the control group. Particularly, mutations in COL1A1 and COL2A1 are associated with severe retinopathy of prematurity (p 0.01). The most frequent variant of single-nucleotide polymorphism of the COL1A1 gene was rs1800012, demonstrating correlation with the severity of retinopathy of prematurity (p 0.005). Logistic regression identified an association between the genetic variants and the clinical outcomes of the disease. Mutations in COL1A1 and COL2A1 are associated with a high risk of retinal detachment and poor prognosis for vision, with an odds ratio of 4.5 (95% confidence interval: 2.1 to 9.4), p 0.01. Besides, patients with multiple polymorphisms in these genes are more likely to develop active disease progression accompanied with high treatment failure rates and the need for surgery. CONCLUSION: The results show that changes in collagen genes and the genes involved in their interactome do not just promote retinopathy of prematurity, but may also have potential value as predictive biomarkers of its severity and outcomes.