Genetic Associations of Primary Angle-Closure Disease: A Systematic Review and Meta-Analysis.

Importance: Effects of genetic variants on primary angle-closure disease remained uncertain. Objective: To systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression. Data Sources: Eligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen. Study Selection: Studies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression. Data Extraction and Synthesis: PRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I2 statistics. Main Outcomes and Measures: SNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized. Results: Sixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease-associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified. Conclusions and Relevance: This study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

Phenotypic and Genetic Links between Body Fat Measurements and Primary Open-Angle Glaucoma.

The phenotypic and genetic links between body fat phenotypes and primary open-angle glaucoma (POAG) are unclear. We conducted a meta-analysis of relevant longitudinal epidemiological studies to evaluate the phenotypic link. To identify genetic links, we performed genetic correlation analysis and pleiotropy analysis of genome-wide association study summary statistics datasets of POAG, intraocular pressure (IOP), vertical cup-to-disc ratio, obesity, body mass index (BMI), and waist-to-hip ratio. In the meta-analysis, we first established that obese and underweight populations have a significantly higher risk of POAG using longitudinal data. We also discovered positive genetic correlations between POAG and BMI and obesity phenotypes. Finally, we identified over 20 genomic loci jointly associated with POAG/IOP and BMI. Among them, the genes loci CADM2, RP3-335N17.2, RP11-793K1.1, RPS17P5, and CASC20 showed the lowest false discovery rate. These findings support the connection between body fat phenotypes and POAG. The newly identified genomic loci and genes render further functional investigation.

Genetic associations of central serous chorioretinopathy: a systematic review and meta-analysis.

AIMS: To identify single-nucleotide polymorphisms (SNPs) associated with central serous chorioretinopathy (CSCR) by a systematic review and meta-analysis, and to compare the association profiles between CSCR, neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We searched the EMBASE, PubMed and Web of Science for genetic studies of CSCR from the starting dates of the databases to 12 September 2020. We then performed meta-analyses on all SNPs reported by more than two studies and calculated the pooled OR and 95% CIs. We also conducted sensitivity analysis and adopted the funnel plot to assess potential publication bias. RESULTS: Totally 415 publications were reviewed, among them 10 were eligible for meta-analysis. We found 10 SNPs that have been reported at least twice. Meta-analysis and sensitivity analysis confirmed significant associations between CSCR and six SNPs in three genes, namely age-related maculopathy susceptibility 2 (ARMS2) (rs10490924, OR=1.37; p=0.00064), complement factor H (CFH) (rs800292, OR=1.44; p=7.80×10-5; rs1061170, OR=1.34; p=0.0028; rs1329428, OR=1.40; p=0.012; and rs2284664, OR=1.36; p=0.0089) and tumour necrosis factor receptor superfamily, member 10a (TNFRSF10A) (rs13278062, OR=1.34; p=1.44×10-15). Among them, only TNFRSF10A rs13278062 showed the same trend of effect on CSCR, nAMD and PCV, while the SNPs in ARMS2 and CFH showed opposite trends in the SNP associations. CONCLUSIONS: This study confirmed the associations of ARMS2, CFH and TNFRSF10A with CSCR, and revealed that ARMS2, CFH and TNFRSF10A may affect different phenotypic expressions of CSCR, nAMD and PCV.

A hidden structural variation in a known IRD gene: a cautionary tale of two new disease candidate genes.

Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1 in 3500 people. More than 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% of IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with RCD. Family members were given a full ophthalmic exam at the Retinal Service at Massachusetts Eye and Ear and consented to genetic testing. Whole-exome sequencing (WES) was performed and variants of interest were Sanger-validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function. WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187 + 3A > C and c.1568-8C > A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G > A (p.Glu1290Lys) and c.4603G > A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins); however, the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94-bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant. Our study demonstrates the importance of thorough functional characterization of new disease candidate genes and the value of reanalyzing next-generation sequencing sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Anti-fibrosis potential of pirarubicin via inducing apoptotic and autophagic cell death in rabbit conjunctiva.

This study investigated the potential efficacy of pirarubicin (THP) in modulating rabbit conjunctival fibrosis both in vitro and in vivo and characterized the underlying mechanisms. Primary rabbit conjunctival fibroblasts (RCF) were cultured and treated with THP or mitomycin C (MMC) for 5 min, followed by assaying for cell viability, cell cycle distribution, apoptotic and autophagic pathways. The production of reactive oxygen species (ROS) and chemotaxis of macrophages by RCF were evaluated using 2',7'-dichlorofluorescein diacetate (DCFH-DA) labeling and transwell migration assay, respectively. Limbal stem cell excision in combination with alkali burn was performed on the rabbits to establish a model of limbal deficiency and conjunctival fibro-vascular invasion. After three months, the modeled fibro-vascular tissue was excised combined with topical subconjunctival 5-min exposure to THP compared with MMC intraoperatively. The recurrence of postoperative fibrosis and the expression of apoptosis, autophagy, and inflammation markers were evaluated by immunohistochemistry. All modeled rabbits developed conjunctival fibro-vascular lesions, which were similar to human recurrent pterygium (HRP). Both THP and MMC inhibited RCF proliferation and arrested cell cycle at the G0/G1 phase. In particular, 7.5 µmol/L THP remarkably promoted RCF autophagy by upregulating the levels of Beclin 1, Atg 5/12 conjugate, and LC3B, whereas, 15 µmol/L THP significantly triggered a cascade of mitochondrial-associated RCF apoptosis. THP induced the production of ROS and enhanced the chemoattraction of macrophages by RCF. Similar to 600 µmol/L MMC, both 7.5 µmol/L and 15 µmol/L THP attenuated postoperative conjunctival fibrosis in the models; 7.5 µmol/L THP preferentially enhanced autophagy while causing fewer side effects. THP exerted its antifibrotic action by modulating autophagy in RCF, inducing cell cycle arrest, and mitochondrial-mediated apoptosis. THP at the dose of 7.5 µmol/L prevented postoperative conjunctival fibrosis in an animal model.

Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese.

BACKGROUND: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese. METHODS: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis. RESULTS: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (Pmeta = .0019, OR = 4.55, I2 = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (Pmeta = .81, OR = 1.05; I2 = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects. CONCLUSIONS: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.

Rationale, Design, Methodology and Baseline Data of Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT).

Purpose: To describe the rationale, design, methodology and baseline characteristics of Fushun Diabetic Retinopathy Cohort Study (FS-DIRECT), a community-based prospective cohort study in patients with type 2 diabetes mellitus (T2DM) living in northeast China.Methods: Patients with T2DM, aged 30 years and above from communities of Fushun city, Liaoning province, China, were recruited. The presence and severity of the diabetic retinopathy (DR) were determined by a modified Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy scale of 6 fields fundus photographs. Detailed ocular examinations and questionnaires were collated, in addition to blood and urine sample collection.Results: Of the 2224 subjects eligible for the FS-DIRECT, 2033 (91.4%) participated in the study. The majority of participants were female (58.9%), the average age was 62.1 ± 9.1 years. The overall prevalence rates of DR, non-proliferative DR, proliferative DR, diabetic macular edema, and vision-threatening retinopathy were 44.3%, 40.0%, 4.3%, 15.2%, and 12.3%, respectively. Compared to the patients without DR, patients with DR had lower income, an earlier onset of diabetes, a longer duration of diabetes, higher proportion of insulin use, higher fasting plasma glucose, HbA1c, systolic blood pressure, total cholesterol and high density lipoprotein, as well as a higher level of urine protein (all P < .05).Conclusion: The baseline data of FS-DIRECT showed a high prevalence of DR in a community of northeast China. Further investigation will provide key information about the risk factors, impact, and trends of DR in this region.

Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis.

AIM: To determine the association between dementia and age-related macular degeneration (AMD) using meta-analysis. METHODS: We searched in the MEDLINE, EMBASE, Web of Knowledge, PsycInfo and Cochrane database of systematic reviews for studies published from March 1959 to March 2018. We included cross-sectional, case-control and cohort studies that evaluated the association of dementia/Alzheimer's disease (AD) with AMD (as outcome) and the association of AMD with dementia/AD (as outcome). Studies that compared cognitive functions between AMD and controls were also included. The summary outcomes, namely odds ratio (OR), relative risk, mean differences and corresponding 95% CIs, were estimated using random effects models. We performed sensitivity analysis based on study quality and individual study effect to control for potential biases. RESULTS: Among 2159 citation records, we identified 21 studies consisting of 7 876 499 study subjects for meta-analysis. Patients with dementia (padjusted≤0.017, OR≥1.24, I2≤9%) or AD (p=0.001, ORunadjusted=2.22, I2=50%) were at risk for AMD, particularly for late AMD (padjusted<0.001, OR=1.37, I2=0). AMD was also significantly associated with increased risk of AD/cognitive impairment (padjusted=0.037, OR=2.42, I2=38%). Moreover, patients with AMD had poorer cognitive functions when compared with controls, including Mini-Mental State Examination (p<0.001, I2≤79%) and Trail Making Test A (p<0.001, I2=0). Sensitivity analysis and Egger's test indicated our results were less likely biased. CONCLUSIONS: A significant association between dementia/AD and AMD calls for greater clinical awareness. The cost-effectiveness of routine screening for the other condition in patients with primary diagnosis of dementia/AD or AMD requires further study.

Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese.

The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (Pcombined = 4.3 × 10-5, OR = 0.72, I2 = 0). Additionally, we replicated the association of one known SNP, rs33912345 (Pcombined = 0.0061, OR = 0.69, I2 = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (Pcombined = 0.017, OR = 0.70, I2 = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (Pcombined<0.005). Furthermore, two haplotypes, C-C (Pcombined = 1.13 × 10-5, OR = 1.41, I2 = 0) and A-A (Pcombined = 0.045, OR = 0.68, I2 = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG.