A common variant near TGFBR3 is associated with primary open angle glaucoma

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution.We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

A common variant near TGFBR3 is associated with primary open angle glaucoma

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

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Abstract Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array ), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, OR G-allele = 1.13, P meta = 1.60 × 10 −8 ). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

Relatively anterior lens position in primary angle-closure glaucoma eyes with long axial length

Purpose: To evaluate the refractive status and ocular biometric parameters in primary angle-closure glaucoma (PACG) eyes with different axial lengths (ALs). Methods: In total, 742 Chinese PACG subjects with complete ophthalmic examinations were enrolled. The refractive status was categorized as myopia (spherical equivalent [SE] ≤−0.5 D), emmetropia (−0.5 D < SE < +0.5 D), and hyperopia (SE ≥+0.5 D), whereas the AL was divided into short (AL <22.5 mm), regular (22.5 ≤ AL <23.5 mm), and long (AL ≥23.5 mm). The refractive status and ocular biometric parameters were compared among different AL groups. Results: The mean AL of the PACG eyes was 22.53 ± 0.84 mm (range: 19.68–25.57 mm). The refractive status was significantly different among different AL groups (P < 0.001). Also, 92.6% of hyperopic PACG eyes showed AL <23.5 mm, and 19.0% of myopic PACG eyes showed AL ≥23.5 mm. The SE showed significant differences among different AL groups only in the hyperopic subjects (P = 0.012). The AL was significantly longer in myopic eyes (P < 0.001). The PACG eyes with longer AL exhibited lower keratometry, longer central anterior chamber depth and corneal diameter, and lens position and relative lens position closer to the anterior (P < 0.001). Conclusion: Axial hyperopia was common in PACG eyes, and axial myopia was not uncommon. Relatively anterior lens position could explain the occurrence of PACG in the eyes with long AL

Mutations of RagA GTPase in mTORC1 Pathway Are Associated with Autosomal Dominant Cataracts.

Cataracts are a significant public health problem with no proven methods for prevention. Discovery of novel disease mechanisms to delineate new therapeutic targets is of importance in cataract prevention and therapy. Herein, we report that mutations in the RagA GTPase (RRAGA), a key regulator of the mechanistic rapamycin complex 1 (mTORC1), are associated with autosomal dominant cataracts. We performed whole exome sequencing in a family with autosomal dominant juvenile-onset cataracts, and identified a novel p.Leu60Arg mutation in RRAGA that co-segregated with the disease, after filtering against the dbSNP database, and at least 123,000 control chromosomes from public and in-house exome databases. In a follow-up direct screening of RRAGA in another 22 families and 142 unrelated patients with congenital or juvenile-onset cataracts, RRAGA was found to be mutated in two unrelated patients (p.Leu60Arg and c.-16G>A respectively). Functional studies in human lens epithelial cells revealed that the RRAGA mutations exerted deleterious effects on mTORC1 signaling, including increased relocation of RRAGA to the lysosomes, up-regulated mTORC1 phosphorylation, down-regulated autophagy, altered cell growth or compromised promoter activity. These data indicate that the RRAGA mutations, associated with autosomal dominant cataracts, play a role in the disease by acting through disruption of mTORC1 signaling

The c.-16G>A mutation in the 5’-UTR of <i>RRAGA</i> is associated with reduced promoter activity.

<p>(<b>A</b>) The 5’-UTR and start codon of <i>RRAGA</i>. The start codon (ATG) is shown in green. The <i>RRAGA</i> 5’-UTR is predicted to be associated with promoter activity (Ensembl feature: ENSR00001469646) in the Ensembl database, and is enriched with CpG dinucleotides (highlighted in blue). The c.-16G>A mutation indicated by a red triangle, overlaps with a CpG dinucleotide and a predicted binding site for transcription factor E2F1, which regulates mTORC1 signaling [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006090#pgen.1006090.ref017" target="_blank">17</a>]. The mutant A allele was predicted by PROMO [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006090#pgen.1006090.ref016" target="_blank">16</a>] to abolish the binding site. (<b>B</b>) The c.-16G>A mutant is associated with reduced luciferase reporter expression compared with the wild-type (WT) in B-3 cells. B-3 cells were transfected with pGL3-enhancer vectors with no RRAGA 5’-UTR (VT), or with the wild-type RRAGA 5’-UTR (WT), or 5’-UTR c.-16G>A mutant. The expression level of luciferase reporter was determined using immunoblotting. (<b>C</b>) Quantification of the immunoblotting results of luciferase expression. Data are presented as the mean plus S.E.M. <i>P</i> values were determined by Student's t test. *, <i>P</i> < 0.05.</p