Identification of genetic factors underlying severe retinopathy of prematurity in preterm infants.

Objective: Retinopathy of prematurity (ROP) is a pathological condition characterized by abnormal proliferation of retinal vessels and it represents the primary cause of visual impairment in preterm infants. There is increasing backing for the involvement of genetic factors in the onset of ROP.

Methods: A prospective cohort study assessed the allele frequency and genotype distribution of gene polymorphisms in angiogenesis, inflammation and oxygen-sensing pathways in preterm infants with severe ROP. The role of genetic polymorphism in ROP development was investigated using next-generation sequencing (NGS) combined with candidate genes and data mining methods.

Results: A total of 47 confirmed severe ROP cases and gestational age, birthweight and days of oxygen therapy plus 35 similar control infants were enrolled in this study. In the initial hypothesis-generating survey, we selected a p value of 0.01 to minimize false positives while retaining true positives. Using this criterion, we identified 19 single-nucleotide polymorphisms across 11 genes that were associated with the occurrence of ROP (ZNF717, IHH, SEC22B, IGSF3, HYDIN), GGT1, FRG1, CDC27, LRRC37A3, CTAGE4 and ADAMTS7; all p<0.001). Compared with the control group, 62 single-nucleotide polymorphisms in 19 candidate genes (VEGF, EPO, EPAS-1, HIF1A, RUNX1, ESR1, CFH, PDGFB, JAK, STAT, IGF-1, IGFBP2, GPX4, TLR4, ROS1, CYP, TP53BP1, NOS3, TNF) representing angiogenic, inflammation, oxygen-sensing pathways and proliferative retinopathic diseases were found to be associated with the development of severe ROP (all p<0.01).

Conclusions: Using NGS gene analysis suggests that genetic risk factors may play an important role in susceptibility to the development of ROP.