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AimsTo determine the association of single nucleotide polymorphisms (SNPs) downstream from the TMCO1gene with primary open-angle glaucoma (POAG) in African Americans (AA).MethodsAA subjects were recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study from the Scheie Eye Institute and its satellite sites in Philadelphia. A region containing an AluJbrepeat and seven SNPs, including rs4656461 near the TMCO1gene, were PCR-Sanger sequenced from POAAGG cases (n=1537) and controls (n=1570). Association between POAG and SNPs near TMCO1was investigated by logistic regression analysis. Phenotypic trait associations with these SNPs were assessed by analysis of variance. Electrophoretic mobility shift assay (EMSA) was performed to assess the affinity of human T-box 5 (TBX5) protein for a predicted binding motif in the TMCO1region. Dual Luciferase assays were performed by transfecting recombinant plasmids containing the region surrounding the above SNPs in HEK293T and trabecular meshwork cells.ResultsThe SNP rs4657473 (C>T) was associated with POAG; the TT genotype was protective (OR 0.20, 95% CI 0.09 to 0.42; p<0.001). No significant associations were found between the TMCO1variants and phenotypic traits. EMSA confirmed the affinity of TBX5 for a predicted binding motif containing TMCO1SNP rs4657475. Luciferase assays demonstrated a regulatory function for the genomic region around SNP rs4656561, located within AluJbrepeat.ConclusionOur results demonstrate that a SNP downstream of TMCO1, rs4657473, is associated with POAG in an AA population. Our studies suggest a regulatory role for the previously POAG-associated locus near the TMCO1gene that may affect gene expression.

AimRetinopathy of prematurity (ROP) is a vasoproliferative eye disease in preterm infants. Based on its phenotypic similarities with familial exudative vitreo retinopathy (FEVR), the present study was conducted to screen the Norrin signalling pathway genes (already been implicated in FEVR) for understanding their involvement among Indian patients with ROP.MethodsThe study cohort consisted of patients with ROP (n=246) and controls (n=300) that included full term (n=110) and preterm babies devoid of ROP (n=190). Screening of the NDP, FZD4, TSPAN12genes were accomplished by resequencing the entire coding and untranslated regions (UTR). The genotype data of the patients with ROP were analysed in the background of their clinical manifestations and further analysed in conjunction with other available data on these genes worldwide.ResultsTwo novel variants in intron 1 (IVS1 +16A>G) and 3′UTR (c.5 22T>C) along with a previously reported change in the 5′UTR (c.395_409del14bp) were observed in the NDPgene in three patients with ROP. Screening of the FZD4revealed four heterozygous variants, p.(Pro33Ser), p.(Pro168Ser), p.(Ile192Ile) and p.(Ile360Val), a compound heterozygous (p.(Pro33Ser)/p.(Pro168Ser)) and a 3′UTR (c*G>T) variants in the study cohort. Variants p.(Pro33Ser) and p.(Pro168Ser) were found to be significantly associated with ROP. A heterozygous variant p.(Leu119Arg) in TSPAN12gene was observed in a patient with threshold ROP. However, a formal genotype–phenotype correlation could not be established due to the low frequencies of the variant alleles in these genes.ConclusionsThis is a first study that revealed association of few variants in Norrin signalling genes among Indian patients with ROP that warrants further detailed investigation worldwide.