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Inderjeet Kaur, Sonika Rathi, Ganeswara R. Musada, Subhadra Jalali, Ramesha Kekunnaya, Padmaja K. Rani, Subhabrata Chakrabarti; Molecular Genetic and Functional Analysis in a Large Cohort Indicate Novel Genes in Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3996.
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© ARVO (1962-2015); The Authors (2016-present)
Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disorder and the leading cause of blindness in premature children worldwide. Although there are evidences for the genetic susceptibility of ROP, the underlying molecular mechanisms are unclear. Herein, we undertook a comprehensive analysis of candidate genes involved in the development of early retinal vasculature and regulation of angiogenesis, in ROP-affected babies to identify genetic variants conferring disease susceptibility. Additionally, functional analysis were undertaken to substantiate the genetic data.
Initially, intragenic variants (n=384) spanning 27 candidate genes were screened in a cohort of 400 premature babies that included clinically well characterized cases of ROP (n=200) and unaffected controls without ROP (n=200). Screening was accomplished by customized genotyping followed by validation through resequencing. Allele and genotype frequencies, linkage disequilibrium and haplotype analysis were done to delineate the ROP-associated variants. Furthermore, the vitreous humor levels of 27 growth factors and genes involved in angiogenesis were assessed in patients with advanced stages of ROP (n=30) and congenital cataract (n=30) by multiplex bead array method to assess the concordance between the protein expression and genetic association data.
There were no deviations from Hardy Weinberg equilibrium for these 384 single nucleotide polymorphisms (SNPs) among the normal controls (p>0.05). There was a significant difference in the alleles and corresponding haplotype frequencies of few intragenic SNPs in TSPAN12, CFH, C2/BF, IHH, and MMP9, between cases and controls that withstood Bonferroni correction for multiple testing (p=1.3x10-4). Variations in the other genes (OPTC, EPAS1,PRELP, AGTR1 GP1BA, VEGFA etc.) did not exhibit any association to ROP. The associated SNPs in CFH and C2/ BF genes conferred a significant risk and protection to ROP, respectively, as observed in AMD. The levels of 8/27 proteins were significantly increased in the vitreous humor of ROP patients compared to the controls.
The present study highlights the potential involvement of novel genes in ROP based on their allelic (and haplotype) associations and expression levels in the vitreous humor that underscore their potential role in disease susceptibility.
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