Primary Open-angle Glaucoma Susceptibility Research Articles

Targeting mechanics-induced trabecular meshwork dysfunction through YAP-TGFβ Ameliorates high myopia-induced ocular hypertension

High myopia is a risk factor for primary open angle glaucoma (POAG). The pathological mechanism of high myopia induced POAG occurrence is not fully understood. In this study, we successfully established the guinea pig model of ocular hypertension with high myopia, and demonstrated the susceptibility of high myopia for the occurrence of microbead-induced glaucoma compared with non-myopia group and the effect of YAP/TGF-β signaling pathway in TM pathogenesis induced by high myopia. Moreover, we performed stretching treatment on primary trabecular meshwork (TM) cells to simulate the mechanical environment of high myopia. It was found that stretching treatment disrupted the cytoskeleton, decreased phagocytic function, enhanced ECM remodeling, and promoted cell apoptosis. The experiments of mechanics-induced human TM cell lines appeared the similar trend. Mechanically, the differential expressed genes of TM cells caused by stretch treatment enriched YAP/TGF-β signaling pathway. To inhibit YAP/TGF-β signaling pathway effectively reversed mechanics-induced TM damage. Together, this study enriches mechanistic insights of high myopia induced POAG susceptibility and provides a potential target for the prevention of POAG with high myopia.

Association between optic atrophy 1 polymorphisms and primary open angle glaucoma risk: Based on a meta-analysis.

Emerging evidence suggested a significant association between optic atrophy 1 (OPA1) polymorphisms and primary open angle glaucoma (POAG) risk. However, the current data are inconsistent or even contradictory. Given these, we conducted a meta-analysis to examine the precise association between OPA1 polymorphisms and POAG risk. Online databases were retrieved, and the related studies were reviewed from inception to December 1, 2022. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to examine the statistical power of each genetic model. In addition, heterogeneity, sensitivity, cumulative analysis, and publication bias were analyzed to guarantee statistical power. Overall, 14 studies within 11 publications (involving 2,413 POAG patients and 1,904 controls) were included and some significant association between OPA1 rs166850 C/T (T vs. C: OR = 1.24, 95%CI = 1.06-1.45, P = 0.01, I2 = 39.0%; CT vs. CC: OR = 1.37, 95%CI = 1.05-1.79, P = 0.02, I2 = 41.6%; CT + TT vs. CC: 1.37, 95%CI = 1.06-1.77, P = 0.02, I2 = 41.6%), rs10451941T/C (TC + CC vs. TT: OR = 1.79, 95%CI = 1.41-2.28, P < 0.01, I2 = 71.9%) polymorphisms and POAG susceptibility. In addition, further significant associations were also observed in the stratified analysis, especially in normal tension glaucoma groups and Caucasian descendants. The observed evidences suggest that OPA1 polymorphisms may be associate with POAG susceptibility significantly.

Genetic association between CDKN2B-AS1 polymorphisms and the susceptibility of primary open-angle glaucoma (POAG): a meta-analysis from 21,775 subjects

BackgroundPrimary open-angle glaucoma (POAG) is affected by both genetics and environmental factors. CDKN2B-AS1 polymorphisms have been reported to be involved in the pathogenesis of POAG. However, the results of the genetic associations between the CDKN2B-AS1 polymorphisms and POAG risk were inconclusive.AimsThis study aimed to evaluate the correlation of CDKN2B-AS1 polymorphisms and POAG susceptibility using a meta-analysis.MethodsMeta-analysis was performed by searching PubMed, Web of science, the Cochrane database of system reviews, CNKI, and Embase databases. The relationship of CDKN2B-AS1 rs4977756, rs10120688, rs2157719, and rs7049105 polymorphisms and POAG risk was evaluated by the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsEleven studies with 8290 cases and 13,485 controls were included in the present meta-analysis. The alleles of rs4977756 and rs10120688 significantly increased the risk of POAG (rs4977756: OR = 1.20, 95%CI = 1.03–1.39, p = 0.02; rs10120688: OR = 1.36, 95%CI = 1.29–1.44, p < 0.00001). As for ethnicity, rs4977756 polymorphism significantly increased POAG risk in Caucasians (OR = 1.33, 95%CI = 1.12–1.57, p = 0.0009), but not in Asians. In addition, the rs2157719 allele was significantly associated with POAG risk in Asians (OR = 0.66, 95%CI = 0.55–0.80, p < 0.0001), but not in Caucasians (p > 0.05).ConclusionsThe CDKN2B-AS1 rs4977756 might increase the POAG risk in Caucasian population, and rs2157719 might decrease the POAG risk in Asian population, while rs10120688 might increase the risk of POAG.

Clinical implications of recent advances in primary open-angle glaucoma genetics.

Over the last decade, genetic studies, including genome-wide association studies (GWAS), have accelerated the discovery of genes and genomic regions contributing to primary open-angle glaucoma (POAG), a leading cause of irreversible vision loss. Here, we review the findings of genetic studies of POAG published in English prior to September 2019. In total, 74 genomic regions have been associated at a genome-wide level of significance with POAG susceptibility. Recent POAG GWAS provide not only insight into global and ethnic-specific genetic risk factors for POAG susceptibility across populations of diverse ancestry, but also important functional insights underlying biological mechanisms of glaucoma pathogenesis. In this review, we also summarize the genetic overlap between POAG, glaucoma endophenotypes, such as intraocular pressure and vertical cup-disc ratio(VCDR), and other eye disorders. We also discuss approaches recently developed to increase power for POAG locus discovery and to predict POAG risk. Finally, we discuss the recent development of POAG gene-based therapies and future strategies to treat glaucoma effectively. Understanding the genetic architecture of POAG is essential for an earlier diagnosis of this common eye disorder, predictive testing of at-risk patients, and design of gene-based targeted medical therapies none of which are currently available.

The association of toll-like receptor 4 gene polymorphisms with primary open angle glaucoma susceptibility: a meta-analysis.

Primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) cause irreversible blindness while current medications cannot completely inhibit disease progression. An understanding of immunopathogenesis is thus a keystone to develop novel drug targets and genetic markers are still required for early diagnosis. Toll-like receptor 4 (TLR4) is an essential player in inflammation in various diseases. However, the TLR4 polymorphisms have not been completely elucidated in both types of glaucoma. The aim of the present study was to identify the association between TLR4 polymorphism and glaucoma (POAG and NTG) via the use of a comprehensive review and meta-analysis. The relevant studies were collected from PubMed, Excerpta Medica Database (EMBASE), and Web of Science to identify eight included articles, assessed for quality by a modified Newcastle-Ottawa Scale (NOS) for gene association study. A meta-analysis was applied to calculate the pooled odds-ratio and 95% confidence intervals (CIs) to evaluate the association between TLR4 polymorphism and glaucoma. The results revealed that TLR4 rs1927911 A/G, rs12377632 C/T, and rs2149356 G/T significantly decrease the risk of POAG and NTG in allele contrast models 0.71-, 0.71-, and 0.67-fold, respectively. Moreover, rs4986790 A/G and rs4986791 C/T showed a stringent association with POAG in allele contrast, heterozygous, recessive, and overdominant models. In conclusion, this meta-analysis represented a significant correlation between TLR4 polymorphisms and both types of glaucoma suggesting that TLR4 might be involved in the pathogenesis of glaucoma and may be applied as a genetic marker for disease screening.

Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7.

PurposeTo test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis.MethodsGenetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients.ResultsAmong 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (β = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (β = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (β = -2.16 and -2.82 μm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (β = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (β = 0.03 mm3, P = 4.60E-02) and mean cup depth (β = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (β = -0.87 dB, P = 2.44E-02; dominant model).ConclusionThe association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

Primary open angle glaucoma (POAG) is a leading cause of blindness world-wide. To identify new susceptibility loci, we meta-analyzed GWAS results from 8 independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significant SNPs in two Australian studies (1,252 cases and 2,592 controls), 3 European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of top SNPs identified three novel loci: rs35934224[T] within TXNRD2 (odds ratio (OR) = 0.78, P = 4.05×10−11 encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] within ATXN2 (OR = 1.17, P = 8.73×10−10), and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76×10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest novel targets for preventative therapies.

Association of Common Variants in eNOS Gene with Primary Open Angle Glaucoma: A Meta-Analysis.

Purpose. To clarify the association of endothelial nitric oxide synthase (eNOS) polymorphisms and primary open angle glaucoma (POAG). Methods. After a systematic literature search in the MEDLINE, EMBASE, and ISI Web of Science databases, all relevant studies evaluating the association between the polymorphisms (rs2070744 and rs1799983) of eNOS gene and POAG were screened and included. The pooled odds ratios (ORs) and the 95% confidence interval (CI) of each single-nucleotide polymorphism (SNP) in five genetic models were estimated using fixed-effect model if I 2 < 50% in the test for heterogeneity; otherwise the random-effects model was used. Results. Thirty-one records were obtained, with five being suitable for meta-analysis. The overall results showed that both TT genotype in rs2070744 and GG genotype in rs1799983 are associated with decreased risk of POAG susceptibility. Stratified analysis based on ethnicity showed that the association of rs2070744 with POAG remained only in Caucasians. Results of subgroup analysis by sex indicated association between both polymorphisms and POAG in female group, but not in male group. Conclusions. TT genotype and/or T-allele in rs2070744, as well as GG genotype and/or G-allele in rs1799983, was associated with decreased risk for POAG overall and in female group.

DNA copy number variants of known glaucoma genes in relation to primary open-angle glaucoma.

We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG). Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC. Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls. The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.

Family‐based analysis identified CD 2 as a susceptibility gene for primary open angle glaucoma in Chinese Han population

Primary open angle glaucoma (POAG) is characterized by optic disc cupping and irreversible loss of retinal ganglion cells. Few genes have been detected that influence POAG susceptibility and little is known about its genetic architecture. In this study, we employed exome sequencing on three members from a high frequency POAG family to identify the risk factors of POAG in Chinese population. Text-mining method was applied to identify genes associated with glaucoma in literature, and protein–protein interaction networks were constructed. Furthermore, reverse transcription PCR and Western blot were performed to confirm the differential gene expression. Six genes, baculoviral inhibitors of apoptosis protein repeat containing 6 (BIRC6), CD2, luteinizing hormone/choriogonadotropin receptor (LHCGR), polycystic kidney and hepatic disease gene 1 (PKHD1), phenylalanine hydroxylase (PAH) and fucosyltransferase 7 (FUT7), which might be associated with POAG, were identified. Both the mRNA expression levels and protein expression levels of HSP27 were increased in astrocytes from POAG patients compared with those from normal control, suggesting that mutation in CD2 might pose a risk for POAG in Chinese population. In conclusion, novel rare variants detected by exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.

Role of the APOE ε2/ε3/ε4 Polymorphism in the Development of Primary Open-Angle Glaucoma: Evidence from a Comprehensive Meta-Analysis

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The association between the APOE ε2/ε3/ε4 polymorphism and the risk of POAG has been widely reported, but the results of previous studies remain controversial. To comprehensively evaluate the APOE ɛ2/ɛ3/ε4 polymorphism on the genetic risk for POAG, we performed a systematic review and meta-analysis of previously published studies. The PubMed and Web of Science databases were systematically searched to identify relevant studies. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Stratified analyses according to ethnicity and sensitivity analyses were also conducted for further confirmation. A total of nine studies were eligible for the meta-analysis, and these studies included data on 1928 POAG cases and 1793 unrelated match controls. The combined results showed that there were no associations between the APOE ε2/ε3/ε4 polymorphism and POAG risk in any of the 10 comparison models. The analysis that was stratified by ethnicity subgroups also failed to reveal a significant association. The sensitivity analysis confirmed the stability and reliability of the findings. There was no risk of publication bias. Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations.

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

Three human chromosome loci (1q43, 10p12.31, and 12q21.31) were recently associated with the susceptibility to primary open-angle glaucoma (POAG) in a Japanese population; however, this was not replicated in three subsequent studies using South Indian, Afro-Caribbean, and Chinese populations. To identify genetic markers that are robustly associated across ethnic populations, numerous markers in addition to the six in the three reported loci were examined in this study. A total of 31 single-nucleotide polymorphism (SNP) markers were genotyped for 1115 Korean participants, and many neighboring SNPs were imputed using the Korean HapMap Project genotype data. Each SNP was statistically tested for association with POAG susceptibility by comparisons among 211 POAG patients with 904 unaffected controls. A strong and statistically significant association was found with a previously unreported SNP, rs7098387 (odds ratio, OR=2.0 (1.4-3.0), P=0.00038) at the 10p12.31 locus (where 11 SNPs were typed and 38 imputed) in contrast to the reported rs7081455, which was too poorly correlated with newly associated rs7098387 (r2=0.003, D'=0.40) to show association. Additionally, a modest association was observed with the reported rs693421 (OR=1.4 (1.1-1.7), P=0.0082) and several other SNPs located within and around ZP4 at the 1q43 locus (10 SNPs typed and 14 imputed). However, no association was observed with the reported rs7961953 SNP or any other SNPs at the 12q21.31 locus, upstream of TMTC2 (10 SNPs typed and 29 imputed). Accordingly, POAG susceptibility association was replicated using rs7098387 (C) rather than rs7081455 (T) at the 10p12.31 locus and additionally with rs693421 (T) at the 1q43 locus.

Myocilin Polymorphisms and Primary Open-Angle Glaucoma: A Systematic Review and Meta-Analysis

BackgroundGlaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations.MethodsA meta-analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out.ResultsIn meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02–10.85) for Q368X and 2.17 (95% CI, 1.32–3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37–3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16–12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32–3.57).ConclusionsThere is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I.

Association of OPA1 Polymorphisms with NTG and HTG: A Meta-Analysis

BackgroundGenetic polymorphisms of the Optic atrophy 1 gene have been implicated in altering the risk of primary open angle glaucoma (POAG), especially the susceptibility to normal tension glaucoma (NTG), but the results remain controversial.MethodsMultiple electronic databases (up to January 20, 2012) were searched independently by two investigators. A meta-analysis was performed on the association between Optic atrophy 1 polymorphisms (rs 166850 and rs 10451941) and normal tension glaucoma (NTG)/high tension glaucoma (HTG). Summary odds ratios (ORs) and 95% confidence intervals (CI) were estimated.ResultsSeven studies of 713 cases and 964 controls for NTG and five studies of 1200 cases and 971 controls for HTG on IVS8+4C>T (rs 166850) and IVS8+32T>C (rs10451941) were identified. There were significant associations between the OPA1 rs10451941polymorphism and NTG susceptibility for all genetic models(C vs. T OR = 1.26, 95% CI 1.09–1.47, p = 0.002; CC vs. TT: OR = 1.52, 95% CI 1.04–2.20, p = 0.029; CC vs. CT+TT: OR = 1.64, 95% CI 1.16–2.33, p = 0.005; CC+CT vs. TT: OR = 1.21, 95% CI 1.02–1.44, p = 0.032). However, no evidence of associations was detected between the OPA1 IVS8+32C>T polymorphism and POAG susceptibility to HTG. Similarly, clear associations between the rs 166850 variant and NTG were observed in allelic and dominant models (T vs. C OR = 1.52, 95% CI 1.16–1.99, p = 0.002; TT+TC vs. CC OR = 1.50, 95% CI 1.13–2.01, p = 0.006) but not to HTG. In subgroup analyses by ethnicity, we detected an association between both OPA1 polymorphisms and risk for NTG in Caucasians but not in Asians. By contrast, no significant findings were noted between OPA1 variants for HTG, either in Caucasians or in Asians.ConclusionsBoth the IVS8+4C>T and IVS8+32T>C variants may affect individual susceptibility to NTG. Moreover, stratified analyses for NTG detecting the effects of both OPA1 polymorphisms seemed to vary with ethnicity. Further investigations are needed to validate the association.

Genome-Wide Analysis of Central Corneal Thickness in Primary Open-Angle Glaucoma Cases in the NEIGHBOR and GLAUGEN Consortia

To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia. A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n = 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n = 6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis. Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P = 0.001; β = -5.08 μm/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P = 0.00099; Odds Ratio [OR] = 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; P = 0.018; OR = 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues. The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases.

The Cell and Molecular Biology of Complex Forms of Glaucoma: Updates on Genetic, Environmental, and Epigenetic Risk Factors

Glaucoma is a clinically and genetically heterogeneous disease. First-degree relatives of primary open-angle glaucoma (POAG) patients have a disease prevalence that is between 4 and 10 times higher than that of the general population, 1–3 and there is a higher disease concordance in monozygotic twins than in dizygotic twins. 4,5 These studies indicate the significant heritability of POAG; however, a simple mode of inheritance is not likely and cannot be assumed in genetic studies designed to identify POAG susceptibility genes. POAG is also complex clinically. The relationship between intraocular pressure (IOP) elevation and retinal ganglion cell degeneration is not simple, 6 as many individuals have IOP elevation without optic nerve damage, 7 and in some individuals, optic nerve degeneration develops without elevated IOP. 8 Recent studies have shown that POAG-related clinical features, including optic nerve parameters, 9,10 central corneal thickness, 11–14 and IOP, 15 are influenced by different sets of genes. Genetic and environmental risk factors and epigenetics are thought to influence complex traits such as POAG, normal tension glaucoma (NTG) and exfoliation syndrome–related glaucoma (Fig. 1). GENETIC RISK FACTORS FOR POAG The identification and characterization of POAG susceptibility genes would elucidate the molecular pathogenesis and could suggest new methods of diagnosis and treatment. The demonstration that the function of a particular enzyme or structural protein is impaired in POAG patients may lead to the development of novel drug therapies. The identification of DNA sequence changes associated with the disease could form the basis of diagnostic tests that are useful in identifying individuals at risk. The availability of such tests would provide a mechanism for early detection and timely treatment. Those individuals at risk who are identified early in the course of the disease and who begin therapy before significant damage to the optic nerve have the best chance of maintaining useful sight. Although POAG has a significant heritability, family-based linkage studies have not revealed POAG genes with significant population effect. The lack of such findings suggests that novel POAG genes have modest effect sizes and that large data sets with well-defined phenotypes are necessary for discovery. The formation of multiple consortia and collaborations has been crucial in the success of the genome-wide association studies approach by increasing sample sizes, thereby increasing statistical power, enabling replication of findings from individual studies, and establishing common methods of analysis. Common complex diseases often require more than 10,000 cases and controls for successful identification of the predisposing genes. 16 Genome-wide association studies have recently shown promising results for POAG gene discovery. Using an Icelandic population of 1,263 cases and 34,877 population controls, two single-nucleotide polymorphisms (SNPs) in an intergenic region between the CAV1 and CAV2 genes were found to confer modest risk for POAG (odds ratio [OR] 1.3). This finding was replicated in Caucasians of European ancestry and in a Chinese

Keeping an Eye on Myocilin: A Complex Molecule Associated with Primary Open-Angle Glaucoma Susceptibility

MYOC encodes a secretary glycoprotein of 504 amino acids named myocilin. MYOC is the first gene to be linked to juvenile open-angle glaucoma (JOAG) and some forms of adult-onset primary open-angle glaucoma (POAG). The gene was identified as an up-regulated molecule in cultured trabecular meshwork (TM) cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (TIGR). Elevated intraocular pressure (IOP), due to decreased aqueous outflow, is the strongest known risk factor for POAG. Increasing evidence showed that the modulation of the wild-type (wt) myocilin protein expression is not causative of glaucoma while some misfolded and self-assembly aggregates of mutated myocilin may be associated with POAG in related or unrelated populations. The etiology of the disease remains unclear. Consequently, a better understanding of the molecular mechanisms underlyingPOAG is required to obtain early diagnosis, avoid potential disease progression, and develop new therapeutic strategies. In the present study, we review and discuss the most relevant studies regarding structural characterizations, expressions, molecular interactions, putative functions of MYOC gene and/or its corresponding protein in POAG etiology.

The Path to Open-Angle Glaucoma Gene Discovery: Endophenotypic Status of Intraocular Pressure, Cup-to-Disc Ratio, and Central Corneal Thickness

PURPOSE. Primary open-angle glaucoma (POAG) is a complex disease with a genetic architecture that can be simplified through the investigation of individual traits underlying disease risk. It has been well studied in twin models, and this study was undertaken to investigate the heritability of some of these key endophenotypes in extended pedigrees. METHODS. These data are derived from a large, multicenter study of extended, Caucasian POAG families from Australia and the United States. The study included 1181 people from 22 extended pedigrees. Variance components modeling was used to determine the heritabilities of maximum intraocular pressure (IOP), maximum vertical cup-to-disc ratio (VCDR), and mean central corneal thickness (CCT). Bivariate quantitative genetic analysis between these eye-related phenotypes and POAG itself was performed to determine whether any of these traits represent true endophenotypes. RESULTS. Heritability estimates for IOP, VCDR, and CCT (0.42, 0.66, and 0.72, respectively) were significant and show strong concordance with data in previous studies. Bivariate analysis revealed that both IOP (RhoG = 0.80; P = 9.6 x 10(-6)) and VCDR (RhoG = 0.76; P = 4.8 x 10(-10)) showed strong evidence of genetic correlation with POAG susceptibility. These two traits also correlated genetically with each other (RhoG = 0.45; P = 0.0012). Alternatively, CCT did not correlate genetically with risk of POAG. CONCLUSIONS. All the proposed POAG-related traits have genetic components. However, the significant genetic correlations observed between IOP, VCDR, and POAG itself suggest that they most likely represent true endophenotypes that could aid in the identification of genes underlying POAG susceptibility. CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.

Confirmation of the Adult-Onset Primary Open Angle Glaucoma Locus GLC1B at 2cen-q13 in an Australian Family

Primary open-angle glaucoma (POAG) is genetically heterogeneous, with 6 named POAG loci GLC1A-F mapped and genes myocilin (MYOC) and optineurin (OPTN) identified at 2 of the loci. Using penetrance-model-free methods, we screened the POAG loci GLC1A-F in an extended Australian pedigree, using 3–5 markers within each locus. p values of less than 0.05 were obtained empirically using SimWalk2 and exactly using Genehunter for 2 markers within the GLC1B region on chromosome 2. Fine mapping of this region produced pvalues of 0.01 or less at 5 markers flanked by D2S1897 and D2S2269. The 9 cM haplotype of interest overlaps the original GLC1B region. These results provide supportive evidence for the GLC1B locus on chromosome 2cen-q13 and verify the existence of POAG susceptibility gene in this region, increasing the likelihood of gene identification.

A genome-wide scan for primary open-angle glaucoma (POAG): the Barbados Family Study of Open-Angle Glaucoma

Primary open-angle glaucoma (POAG) is characterized by damage to the optic nerve with associated loss of vision. Six named genetic loci have been identified as contributing to POAG susceptibility by genetic linkage analysis of mostly Caucasian families, and two of the six causative genes have been identified. The Barbados Family Study of Open-Angle Glaucoma (BFSG) was designed to evaluate the genetic component of POAG in a population of African descent. A genome-wide scan was performed on 1327 individuals from 146 families in Barbados, West Indies. Linkage results were based on models and parameter estimates derived from a segregation analysis of these families, and on model-free analyses. Two-point LOD scores >1.0 were identified on chromosomes 1, 2, 9, 10, 11, and 14, with increased multipoint LOD scores being found on chromosomes 2, 10, and 14. Fine mapping was subsequently carried out and indicated that POAG may be linked to intervals on chromosome 2q between D2S2188 and D2S2178 and chromosome 10p between D10S1477 and D10S601. Heterogeneity testing strongly supports linkage for glaucoma to at least one of these regions and suggests possible linkages to both. Although TIGR/myocilin and optineurin mutations have been shown to be causally linked to POAG in other populations, findings from this study do not support either of these as causative genes in an Afro-Caribbean population known to have relatively high rates of POAG.