TCERG1L hypermethylation is a risk factor of diabetic retinopathy in Chinese children with type 1 diabetes.

AIM: To identify the differential methylation sites (DMS) and their according genes associated with diabetic retinopathy (DR) development in type 1 diabetes (T1DM) children. METHODS: This study consists of two surveys. A total of 40 T1DM children was included in the first survey. Because no participant has DR, retina thinning was used as a surrogate indicator for DR. The lowest 25% participants with the thinnest macular retinal thickness were included into the case group, and the others were controls. The DNA methylation status was assessed by the Illumina methylation 850K array BeadChip assay, and compared between the case and control groups. Four DMS with a potential role in diabetes were identified. The second survey included 27 T1DM children, among which four had DR. The methylation patterns of the four DMS identified by 850K were compared between participants with and without DR by pyrosequencing. RESULTS: In the first survey, the 850K array revealed 751 sites significantly and differentially methylated in the case group comparing with the controls (|Δß|>0.1 and Adj.P<0.05), and 328 of these were identified with a significance of Adj.P<0.01. Among these, 319 CpG sites were hypermethylated and 432 were hypomethylated in the case group relative to the controls. Pyrosequencing revealed that the transcription elongation regulator 1 like (TCERG1L, cg07684215) gene was hypermethylated in the four T1DM children with DR (P=0.018), which was consistent with the result from the first survey. The methylation status of the other three DMS (cg26389052, cg25192647, and cg05413694) showed no difference (all P>0.05) between participants with and without DR. CONCLUSION: The hypermethylation of the TCERG1L gene is a risk factor for DR development in Chinese children with T1DM.

Development of the retina and its relation with myopic shift varies from childhood to adolescence.

AIMS: To elucidate the influence of age and myopic shift on retinal development. METHODS: This 1-year longitudinal study included 769 participants aged 6-17 years. Cycloplegic refraction, axial length and swept-source optical coherence tomography were examined at baseline and follow-up. The thickness changes in the retina, ganglion cell complex (GCC) and outer retinal layers (ORL) in the macular region were calculated, and their relation with age and myopic shift was analysed with multiple linear regression analysis. RESULTS: The thickness of the central foveal retinal layers was increased in children (<10 years) but unchanged or decreased in adolescents (>13 years). The thickness changes in the retina, GCC and ORL decreased with age (r=-0.24,-0.23, -0.15, respectively, all p<0.01). Multiple regression analysis showed that the changes in central foveal retinal thickness (RT) and GCC thickness were independently associated with age and baseline spherical equivalent (SE), while the changes in ORL thickness were associated with age and SE changes. In children 8-9 years, a greater increase was observed in central foveal ORL thickness in those with no myopic shift (p<0.01). The thickness of the most parafoveal and perifoveal retinal layers was less increased or more decreased in children <9 years with myopic shift (p<0.05). CONCLUSIONS: Retinal development and its relation with myopic shift varies from childhood to adolescence. Myopia-related retinal thinning may result from less increase in the RT in childhood rather than a decrease in RT in adolescents. Children under 9 years old could be at a critical age for future myopia-related retinal thinning.

Long-Term Effects of a Photodisruptive Laser-Induced Traumatic Neuropathy Model.

Purpose: To create a mouse traumatic optic neuropathy (TON) model that is reproducible, reliable, and easy to manipulate with high specificity to retinal ganglion cell (RGC) layer and no mortality. The model will be useful for understanding the pathophysiology of retinal ganglion cell death and for testing neuroprotective therapeutics. Methods: An Nd:YAG laser was used to generate focal photodisruptive retinal damage. Noninvasive in vivo ophthalmologic imaging technologies such as optical coherence tomography (OCT) and confocal laser scanning ophthalmoscopy (CSLO) were used to longitudinally track the retinal nerve fiber layer (RNFL) thickness and RGC number change, respectively. Immunostaining and pattern electroretinography (PERG) were also used to evaluate structure and functional change after laser injury. Results: Our ND:YAG laser generates a concussive photodisruptive laser shockwave force which induces focal RGC death in the targeted area. We observed a correlative decrease in RGCs number, RNFL, and PERG function of RGC in the laser zone. The pattern of RNFL thinning and RGC soma loss correlates with the pattern and amount of fluorescence loss on OCT and CSLO images, respectively. The ND:YAG laser does not cause any damage to other layers in the retina nor any side effects including changes in intraocular pressure, corneal edema, and calcification or mortality (which has been observed in other TON models). Conclusions: We have created a new and novel RGC TON death model that confers no mortality and produces a quantifiable decrease in RGC number and function. The laser targeted regions of the retina correlate with both in vivo imaging by OCT and CSLO and histologically with regions of RGC loss without ophthalmic side effects. Translational Relevance: This laser-based TON injury model is simple to implement, is reproducible, and is useful for determining the molecular and cellular pathophysiology of TON and RGC death and for testing neuroprotective therapeutics.

Multi-scale GCN-assisted two-stage network for joint segmentation of retinal layers and discs in peripapillary OCT images.

An accurate and automated tissue segmentation algorithm for retinal optical coherence tomography (OCT) images is crucial for the diagnosis of glaucoma. However, due to the presence of the optic disc, the anatomical structure of the peripapillary region of the retina is complicated and is challenging for segmentation. To address this issue, we develop a novel graph convolutional network (GCN)-assisted two-stage framework to simultaneously label the nine retinal layers and the optic disc. Specifically, a multi-scale global reasoning module is inserted between the encoder and decoder of a U-shape neural network to exploit anatomical prior knowledge and perform spatial reasoning. We conduct experiments on human peripapillary retinal OCT images. We also provide public access to the collected dataset, which might contribute to the research in the field of biomedical image processing. The Dice score of the proposed segmentation network is 0.820 ± 0.001 and the pixel accuracy is 0.830 ± 0.002, both of which outperform those from other state-of-the-art techniques.

Analysis of association between common variants of uncoupling proteins genes and diabetic retinopathy in a Chinese population.

BACKGROUND: The aim of this study was to explore the association between diabetic retinopathy (DR) and the variants of uncoupling proteins (UCPs) genes in a Chinese population of type 2 diabetes, in total and in patients of different glycemic status separately. METHODS: This case-control study included a total of 3107 participants from two datasets, among which 662 were DR patients (21.31%). Eighteen tag single nucleotide polymorphisms (SNPs) of UCP1, UCP2, and UCP3 were selected as genetic markers. TaqMan probes, Sequenom MassARRAY MALDI-TOF mass spectrometry platform and Affymetrix Genome-Wide Human SNP Array were used for genotyping. Online SHEsis software was used for association analysis. Bonferroni correction was used for multiple comparisons correction. RESULTS: Three SNPs of UCP1: rs7688743 (A allele, OR = 1.192, p = 0.013), rs3811787 (T allele, OR = 0.863, p = 0.023), and rs10011540 (G allele, OR = 1.368, p = 0.004) showed association with DR after the adjustment of glucose, but only rs10011540 was marginally significantly associated with DR when Bonferroni correction was strictly applied (padj = 0.048). In patients with uncontrolled glucose, rs7688743 (A allele, p = 0.012, OR = 1.309), rs10011540 (G allele, p = 0.033, OR = 1.432), and rs3811787 (T allele, p = 0.022, OR = 0.811) were associated with DR, while in participants with well controlled glucose, the rs2734827 of UCP3 was associated with DR (A allele, p = 0.017, OR = 0.532). Rs3811787 of UCP1 showed a protective effect to sight threatening DR (T allele, p = 0.007, OR = 0.490), and the association existed after the adjustment for environmental factors and the correction. In patients with uncontrolled glucose, the rs3811787 of UCP1 (T allele, p = 0.017, OR = 0.467) and the rs591758 of UCP3 (C allele, p = 0.026, OR = 0.103) were associated with STDR. While in those with well controlled glucose, only the rs7688743 of UCP1 showed a protective effect (A allele, p = 0.024, OR = 0.049). None of the associations remain significant when Bonferroni correction was strictly applied (all p < 0.05). CONCLUSIONS: The rs10011540 and rs3811787 of the UCP1 gene was marginally significantly associated with DR in Chinese type 2 diabetes patients. There might be different mechanisms of DR development in patients with different glycemic status.

LONGITUDINAL CHANGES IN CHOROIDAL AND RETINAL THICKNESSES IN CHILDREN WITH MYOPIC SHIFT.

PURPOSE: To elucidate the development of the choroid and retina in children, and to explore changes in these during myopic shift. METHODS: A total of 118 children aged 7 to 12 years participated in this 1-year longitudinal study. Children underwent several examinations at baseline and follow-up, including cycloplegic refraction, axial length measurement, and swept-source optical coherence tomography. Thickness changes in the choroid and retina were compared among children with or without myopic shift. RESULTS: Eighty-eight children (74.6%) developed a myopic shift after 1 year, and their central foveal choroid was significantly attenuated (P < 0.01). No significant change was observed in choroids of children without myopic shift (P = 0.83). Choroidal thickness decreased in all subfields during myopic shift, whereas the thickness of the retinal layers increased or were unchanged in most subfields. Axial length increase and central foveal choroidal thinning were associated with myopic shift (R = 0.157, P < 0.01), but axial length increase was not significantly related to choroidal thinning (P > 0.05). CONCLUSION: Choroidal thinning occurs early in myopic progression. Axial length increase and choroidal thinning are independently associated with myopic shift.

PPARG Polymorphisms Are Associated with Unexplained Mild Vision Loss in Patients with Type 2 Diabetes Mellitus.

OBJECTIVES: To investigate whether the presence of peroxisome proliferator-activated receptor gamma (PPARG) gene polymorphisms is associated with unexplained mild visual impairment (UMVI) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 135 T2DM residents with UMVI and 133 with normal vision (NV; best-corrected visual acuity ≥ 20/25 in both eyes) were enrolled. UMVI was defined as best-corrected visual acuity (BCVA) < 20/25 and ≥ 20/63 in both eyes, with no visual impairment-causing diseases found. Four PPARG gene single-nucleotide polymorphisms (SNPs) (rs3856806, rs1801282, rs709158, and rs10865710) were assessed with the HAPLOVIEW 4.0 software to examine the statistical association of PPARG polymorphisms and UMVI in patients with T2DM. RESULTS: Four SNPs qualified the Hardy-Weinberg equilibrium (p > 0.05). The frequency of genotype GC at SNP rs10865710 was significantly higher in the UMVI group than in the NV group (p < 0.001; GG + GC versus CC) (OR = 8.94, 95% CI: 4.90-16.31), whereas genotype CC decreased the risk (OR = 0.07, 95% CI: 0.03-0.14). Genotype TT at SNP rs3856806 was strongly associated with UMVI (p < 0.0001, TT + TC versus CC) (OR = 4.74, 95% CI: 2.68-8.54), whereas genotype CC appeared to be protective for UMVI (OR = 0.55, 95% CI: 0.37-0.82). CONCLUSIONS: Susceptibilities of PPARG variants may lead to differences in PPARG transcription, result in early function loss of retinal photoreceptor cells, and eventually cause UMVI.

CHOROIDAL THICKNESS IN HEALTHY CHINESE CHILDREN AGED 6 to 12: The Shanghai Children Eye Study.

PURPOSE: To explore the characteristics of choroidal thickness (ChT) in Chinese children. METHODS: A total of 144 healthy children, aged 6 years to 12 years old, were enrolled in the study. The ChT of subfovea and peripheral locations 0.5, 1.5, and 2.5 mm away from the fovea were evaluated by enhanced depth imaging optical coherence tomography. The association between subfoveal ChT and systemic, as well as ocular factors, including age, sex, height, weight, body mass index, axial length, refractive error, intraocular pressure, preterm history, and the refractive status of parents were studied. RESULTS: The mean subfoveal ChT was 302 ± 63 µm. In the nasal, superior, and inferior areas, the ChT of locations closer to the fovea was thicker than those farther away from the fovea (all P < 0.05); however, ChT was not significantly different among different locations in the temporal area (P = 0.16). The ChT of the nasal quadrant was significantly thinner than that of other areas (P < 0.01). Subfoveal ChT decreased with age, axial length, preterm history, and increased with height. Sex was not statistically associated with subfoveal ChT. CONCLUSION: In Chinese children, the ChT is thinnest in the nasal quadrant and thicker in central regions than in peripheral areas. The subfoveal ChT independently decreases with age, axial length, preterm history, and increases with height.

Choroidal and Retinal Thickness in Children With Different Refractive Status Measured by Swept-Source Optical Coherence Tomography.

PURPOSE: To investigate the choroidal and retinal thickness in myopic, emmetropic, and hyperopic Chinese children by swept-source longer-wavelength optical coherence tomography. DESIGN: Cross-sectional study. METHODS: Two-hundred and seventy-six schoolchildren aged 7-13 years underwent comprehensive ophthalmic examinations, including cycloplegic refraction, and swept-source optical coherence tomography measurements. The thickness of the choroid, retina, ganglion cell layer, and nerve fiber layer were compared among children of different refractive status. The topographic variation and factors related to the thickness of the choroid and retinal layers were analyzed. RESULTS: Compared to emmetropic subjects, those with myopia had a significantly thinner choroid in all regions (P < .01), and hyperopic subjects had a thicker choroid in most regions (P < .05). The myopic retinas were thinner than those of emmetropic or hyperopic subjects in the superior parafoveal and all 4 perifoveal subfields (P < .05), but no other subfields differed significantly among different refractive groups (P > .05). The axial length and refractive diopters were independently related to central foveal choroidal thickness (R(2) = 0.17, P < .01), while age and intraocular pressure were independently associated with central fovea retinal (R(2) = 0.15, P < .01) and ganglion cell layer thicknesses (R(2) = 0.10, P < .01) after adjustment for other systematic and ocular factors. Central foveal choroidal and retinal thickness were unrelated in children of different refractive status (P > .05). CONCLUSIONS: Choroidal thickness, but not retinal thickness, correlated closely with axial length and refractive diopters in Chinese children. Choroid thinning occurs before retina thinning early in myopic progression.

Anterior-Chamber Angle and Axial Length Measurements in Normal Chinese Children.

PURPOSE: To establish the physiological distribution of anterior-chamber angle parameters and axial length (AL) in a randomly sampled cohort of Chinese children. PATIENTS AND METHODS: This was a prospective, cross-sectional study on randomly sampled Chinese children ages 7 to 15 years. Complete ophthalmologic examination was carried out on all participants; anterior-segment parameters and ALs were measured using Fourier-domain optical coherence tomography and automated biometers. Associations between the age, the sex, the refractive error, the iris thickness, the AL, and anterior-chamber depth (ACD) and angle measurements were analyzed using multiple correlation and regression tests. The relationship between the AL and other factors was studied by a linear regression analysis. Only the right eye data were analyzed for statistical purpose. RESULTS: A total of 541 children were enrolled in this study. There were no differences in angle parameters between sexes (P>0.05), but boys had a longer AL (P<0.01). The AL increased logarithmically with age in children (P<0.01, R=0.5552, b=6.18). Although the magnitude of myopia also increased with AL, this association was less robust (P<0.05, R=0.0917, b=-0.88). A multiple regression test indicated that the age and the ACD were independently associated with the increase in angle width (b=0.37 to 0.50 and 0.51 to 0.60, respectively; P<0.001). CONCLUSIONS: All angle measurements increased with age and were positively correlated with the ACD in children 7 to 15 years of age. The AL increased logarithmically with age.

A five-year prospective study of diabetic retinopathy progression in chinese type 2 diabetes patients with "well-controlled" blood glucose.

PURPOSE: To determine the progression rate and risk factors for diabetic retinopathy (DR) in Chinese type 2 diabetic patients who have reached the target hemoglobin A1c (HbA1c) level recommended by the American Diabetes Association. METHODS: This was a 5-year community-based prospective study. The study population consisted of patients with type 2 diabetes with HbA1c less than 7.0%. Demographic information, systemic examination results and ophthalmological test results for each participant were collected. The outcome of this study was the progression of DR, which was defined as an increase in DR grade in one or both eyes at the final visit in comparison to the baseline status. The association between each potential risk factor and DR progression was studied. RESULTS: A total of 453 patients with HbA1c less than 7.0% were included in the study group. In 146 patients (32.22%), DR developed or progressed during the five-year follow-up. Baseline HbA1c level was the only independent risk factor for DR progression (p<0.01, OR = 2.84, 95%CI: 2.11~3.82). The logistic regression function suggested that the possibility of DR progression increased fastest when baseline HbA1c increased from 5.2% to 6.4%. The 5-year DR progression rate in patients with baseline HbA1c less than 5.2%, between 5.2% and 6.4%, and over 6.4% were 19.62%, 24.41%, and 76.83%, respectively. CONCLUSIONS: To slow the progression of DR in Chinese patients with type 2 diabetes, more intensive glucose control is recommended.

Screening for significant refractive error using a combination of distance visual acuity and near visual acuity.

PURPOSE: To explore the effectiveness of using a series of tests combining near visual acuity (NVA) and distance visual acuity (DVA) for large-scale screenings for significant refractive error (SRE) in primary school children. METHOD: Each participant underwent DVA, NVA and cycloplegic autorefraction measurements. SREs, including high myopia, high hyperopia and high astigmatism were analyzed. Cycloplegic refraction results were considered to be the gold standard for the comparison of different screening measurements. Receiver-operating characteristic (ROC) curves were constructed to compare the area under the curve (AUC) and the Youden index among DVA, NVA and the series combined tests of DVA and NVA. The efficacies (including sensitivity, specificity, positive predictive value, and negative predictive value) of each test were evaluated. Only the right eye data of each participant were analysed for statistical purpose. RESULT: A total of 4416 children aged 6 to 12 years completed the study, among which 486 students had right eye SRE (SRE prevalence rate = 11.01%). There was no difference in the prevalence of high hyperopia and high astigmatism among different age groups. However, the prevalence of high myopia significantly increased with the age (χ² = 381.81, p<0.01). High hyperopia was the biggest SRE factor associated with amblyopia（p＜0.01，OR = 167.40, 95% CI: 75.14∼372.94). The DVA test was better than the NVA test for detecting high myopia (Z = 2.71, p<0.01), but the NVA test was better for detecting high hyperopia (Z = 2.35, p = 0.02) and high astigmatism (Z = 4.45, p<0.01). The series combined DVA and NVA test had the biggest AUC and the highest Youden Index for detecting high hyperopia, myopia, astigmatism, as well as all of the SREs (all p<0.01). CONCLUSION: The series combined DVA and NVA test was more accurate for detecting SREs than either of the two tests alone. This new method could be applied to large-scale SRE screening of children, aged 6 to 12, in areas that are less developed.

The 5-year onset and regression of diabetic retinopathy in Chinese type 2 diabetes patients.

PURPOSE: To determine the rate and risk factors of diabetic retinopathy (DR) onset and regression in Chinese type 2 diabetes mellitus patients. METHODS: This is a 5-year community-based prospective study. The demographic information, systemic examination results and ophthalmological test results of each participant were collected. The study outcomes were DR incidence, defined as the onset of DR in at least one eye, and DR regression, defined as full regression from existing DR to no retinopathy without invasive treatments. The associations between each potential risk factor and the outcomes were studied. RESULTS: In total, 778 participants were enrolled. There were 322 patients without DR at baseline, of which 151 participants developed DR during follow-up (DR incidence rate = 46.89%). Baseline hyperglycemia and high blood pressure were two independent risk factors associated with DR incidence. Among the 456 participants with existing DR at entry, 110 fully recovered after 5 years (DR regression rate = 24.12%). Low baseline glucose and low serum triglyceride were two independent factors associated with DR regression. CONCLUSIONS: DR incidence occurred more frequently in patients with hyperglycemia and high blood pressure. DR regression occurred mostly in patients with lower glucose and lower serum triglyceride levels among Chinese type 2 diabetes patients.