Genetics, Diagnosis, and Monitoring of Pseudoexfoliation Glaucoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Nathan N
PROVIDER: S-EPMC5424603 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
Publications
Genetics, Diagnosis, and Monitoring of Pseudoexfoliation Glaucoma.
Nathan Niraj N Kuchtey Rachel W RW
Current ophthalmology reports 20161011 4
Recent studies have shed new light on the genetic factors underlying pseudoexfoliation syndrome, growing our understanding of the role of the lysyl oxidase-like 1 (LOXL1) gene and its various polymorphisms as well as identifying new genetic associations. Recent years have brought new insight on how these genetic factors interact with other factors, including environmental, to confer risk to individuals and populations worldwide. All of these findings may hold importance to the screening, diagnos ...[more]
Similar Datasets
Project description:Pseudoexfoliation (PEX) syndrome, one of the most common causes of glaucoma, represents a complex, multifactorial, late-onset disease of worldwide significance. The etiopathogenesis involves both genetic and non-genetic factors. The PEX-specific tissue alterations are caused by a generalized fibrotic matrix process, which has been characterized as a stress-induced elastosis associated with the excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. The identification of lysyl oxidase-like 1 (LOXL1) as a major genetic risk factor for PEX syndrome and PEX glaucoma further supports a role of elastogenesis and elastosis in the pathophysiology of PEX, as LOXL1 is a pivotal cross-linking enzyme in elastic fiber formation and stabilization. The available data suggest that LOXL1 is markedly dysregulated depending on the stage of the fibrotic process. While transient upregulation of LOXL1 during the early stages of PEX fibrogenesis participates in the formation and aggregation of abnormal PEX fiber deposits, the decreased expression of LOXL1 during the advanced stages of the disease may affect elastin metabolism and promote elastotic processes, e.g. in the lamina cribrosa, predisposing to glaucoma development. However, in view of the low penetrance of the PEX-associated risk variants of LOXL1, other genetic and/or environmental factors must contribute to the risk of developing the PEX phenotype. Some evidence exists for the contribution of additional genes with relatively small effects, e.g. clusterin (CLU), contactin-associated protein-like 2 (CNTNAP2), apolipoprotein E (APOE), glutathione S-transferases (GSTs), and tumor necrosis factor-alpha (TNFA), in certain study populations. Several environmental conditions associated with PEX, such as oxidative stress as well as pro-fibrotic cytokines and growth factors, can regulate expression of LOXL1 and elastic proteins in vitro and may therefore act as co-modulating external factors. Ultimately, both detection and functional characterization of yet unidentified genetic and non-genetic factors may lead to the development of more precise screening tools for the risk of PEX glaucoma.
| S-EPMC3085149 | biostudies-literature
Project description:Pseudoexfoliation syndrome (XFS) is a late-onset and complex disorder that is strongly associated with the development of glaucoma. The purpose of this review is to discuss the inheritance patterns and recent genetic advances in the study of this disorder.XFS has a strong familial association and recently, the lysyl oxidase-like 1 gene has been strongly associated with this disorder. This gene is involved in the synthesis and maintenance of elastic fibers and therefore has a strong biological rationale for being involved in this disorder. However, the exact relationship between lysyl oxidase-like 1 polymorphisms and the development of XFS has not been elucidated. Also, the value of genetic testing for this disorder has not been validated.XFS is an important risk factor for glaucoma and lysyl oxidase-like 1 polymorphisms are strongly associated with XFS. The mechanisms behind glaucoma development and the value of genetic testing are not clear and further study is needed.
| S-EPMC2674400 | biostudies-literature
Project description:Purpose:To compare long-term effects of trabeculectomy on pseudoexfoliation glaucoma (PXG) and primary open-angle glaucoma (POAG). Methods:This retrospective case-control study included 53 eyes of PXG and 76 eyes of POAG. Intraocular pressure (IOP), number of antiglaucoma medications used, surgical success rate, and occurrence of complications were observed and statistically analyzed in both groups at 3 and 6 months and at 1, 3, and 5 years after trabeculectomy. Surgical success was defined according to the following 3 criteria: (1) IOP???21?mmHg; (2) IOP???18?mmHg; (3) IOP???15?mmHg. Complete success is defined as patients met these criteria without medical treatment, and qualified success is defined as patients met these criteria with medical treatment (?3 medications). Cumulative probabilities of success were compared using the Kaplan-Meier survival analysis. Results:For the 3 criteria, there were no statistically significant differences in complete and qualified success rates between the two groups at 3 and 6 months after trabeculectomy (P > 0.05). For criterion A, complete success rates in PXG at 3 and 5 years after surgery were lower than those in POAG; for criterion B, complete and qualified success rates in PXG at 3 and 5 years after surgery were lower than those in POAG; for criterion C, complete and qualified success rates in PXG at 1, 3, and 5 years after surgery were lower than those in POAG, the differences were statistically significant (P < 0.05). Conclusions:The short-term success rates of both types of glaucoma were similar; however, the long-term success rate of PXG was significantly lower, and it was difficult to achieve long-term control of IOP at a low target level.
| S-EPMC7125473 | biostudies-literature
Project description:Purpose:To investigate the microRNA (miRNA) profile in patients with different stages of pseudoexfoliation (PXF). Methods:Peripheral blood of patients with PXF (naïve to medical therapy and with no systemic disease/drugs) with ocular hypertension (OHT) and pseudoexfoliation glaucoma (PXG) was evaluated in triplicate for miRNA profiling using polymerase chain reaction (PCR) arrays. Those identified in the discovery stage were validated with evaluation of serum transforming growth factor-?1 (TGF-?1) levels by ELISA. The downstream targets of TGF-?1 and unfolded protein response (UPR) were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Predicted targets of the identified miRNA and KEGG pathway analysis were done using miRbase and DIANA tools mirPathv3.1. Results:We found hsa-miR-122-5p, hsa-miR-124-3p and hsa-miR-424-5p to be upregulated in PXG targeting 3 specific pathways namely TGF-?1, fibrosis/ECM and proteoglycan metabolism with common effectors like SMAD/3/2. The unfolded protein response (UPR) genes were significantly downregulated in all stages of PXF suggesting this as the key mechanism for protein aggregates in PXF syndrome. Serum TGF-?1 was significantly upregulated as disease progressed to later stages in PXG. This elevation in advanced stages was associated with significantly differential expression of downstream pathways and fibrotic genes in OHT compared to PXG predominantly through the SMAD3, a canonical pathway marker. Conclusion:Circulatory miRNA differentially regulating TGF-?1 and downstream targets including UPR genes may be the key mechanisms for glaucoma onset in PXF.
| S-EPMC7547124 | biostudies-literature
Project description:Objectives:To investigate the three single nucleotide polymorphisms (SNPs) (rs3825942, rs1048661, and rs2165241) of the LOXL1 gene in pseudoexfoliation syndrome (XFS) and pseudoexfoliation glucoma (XFG) in the Turkish population. Materials and Methods:DNA was obtained from blood samples of 48 XFS, 58 XFG, and 171 control subjects. Three LOXL1 SNPs (rs3825942, rs1048661, rs2165241) were investigated with real time PCR, a probe-based genotyping method, and melting curve analysis. Results:All three SNPs of LOXL1 were significantly associated with XFS (rs3825942 p=3.54x10-6, odds ratio [OR]=?; rs1048661 p=0.008, OR=2.18; rs2165241 p=8.69x10-9, OR=4.30) and XFG (rs3825942 p=3.41x10-7, OR=?; rs1048661 p=1.75x10-5, OR=3.78; rs2165241 p=3.85x10-11 OR=4.90). No significant differences were observed between the XFS and XFG groups for any of the SNPs. The GG genotype of rs3825942 was more valuable for distinguishing pseudoexfoliative cases from healthy individuals. The homozygous TT genotype of rs2165241 was associated with 6-fold increased XFS risk (p=8.15x10-8, OR=6.32) and 7-fold increased XFG risk (p=1.45x10-10 OR=7.95). The GGT haplotype consisting of all three risk alleles was associated with a 7.45-fold higher risk of XFS/XFG (p=8.65x10-14, OR=7.45). Presence of T allele of rs2165241 conferred 3 times higher risk for men than women (p=6.78x10-5, OR=3.202). Conclusion:LOXL1 SNPs are associated with increased risk for pseudoexfoliation in the Turkish population. T allele of rs2165241 was found to be the most important characterized risk factor for our cohort. All SNP distributions were similar to other European and American populations.
| S-EPMC6216538 | biostudies-literature
Project description:The present knowledge on the association of single nucleotide polymorphisms (SNPs) of lysyl oxidase-like 1 (LOXL1) with pseudoexfoliation syndrome (PEXS) and pseudoexfoliation glaucoma (PEXG) is controversial and inconclusive. This meta-analysis sought to derive a more precise estimation of the effects of LOXL1 SNP loci (rs1048661, rs3825942, and rs2165241) on PEXS/PEXG. Literature searches were conducted on the PubMed, EMBASE, ISI Web of Science, and Cochrane Library databases through October 2013. Twelve studies describing 1810 cases and 1790 controls met the inclusion criteria. The strengths of the associations found through the meta-analysis were assessed with pooled odds ratios and their 95% confidence intervals (CI). A meta-regression analysis was also used to examine the influence of the study and population characteristics. The results indicated that rs1048661 TT carriers had 92.1% and 40.4% less risk of developing PEXS/PEXG than did the controls in the Caucasian and Asian populations, respectively. Carriers of rs3825942 AA or rs2165241 CC also had significantly less PEXS/PEXG susceptibility than did the non-carriers. Meta-regression showed that in Caucasians, the male proportion (slope: 0.272; 95% CI: 0.167-0.376; P = 0.0001) and mean age (slope: 0.796; 95% CI: 0.375-1.217; P = 0.0002) of the PEXS/PEXG subjects correlated positively with the effect of rs3825942 on PEXS/PEXG susceptibility. The meta-analysis suggested that LOXL1 rs1048661 TT, rs3825942 AA, and rs2165241 CC were associated with a reduced risk of developing PEXS/PEXG.
| S-EPMC3946061 | biostudies-literature
Project description:Genetic and genomic studies, including genome-wide association studies (GWAS) have accelerated the discovery of genes contributing to glaucoma, the leading cause of irreversible blindness world-wide. Glaucoma can occur at all ages, with Mendelian inheritance typical for the rare early onset disease (before age 40) and complex inheritance evident in common adult-onset forms of disease. Recent studies have suggested possible therapeutic targets for some patients with early-onset glaucoma based on the molecular and cellular events caused by MYOC, OPTN and TBK1 mutations. Diagnostic genetic tests using early-onset glaucoma genes are also proving useful for pre-symptomatic disease detection and genetic counseling. Recent GWAS completed for three types of common adult-onset glaucoma have identified novel loci for POAG (primary-open-angle glaucoma) (ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, TXNRD2); PACG (primary angle-closure glaucoma (EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102); and exfoliation syndrome (XFS) glaucoma (CACNA1A). In total sixteen genomic regions have been associated with POAG (including the normal tension glaucoma (NTG) subgroup), 8 with PACG and 2 with XFS. These studies are defining important biological pathways and processes that contribute to disease pathogenesis.
| S-EPMC6074793 | biostudies-literature
Project description:PURPOSE: Three common sequence variants in the lysyl oxidase-like 1 (LOXL1) gene were recently associated with pseudoexfoliation (PEX) and pseudoexfoliation glaucoma (PEXG) in populations from various parts of the world. In this study, the genetic association of these variants was investigated in Greek patients with PEX and PEXG. METHODS: The three LOXL1 single nucleotide polymorphisms (SNPs), one intronic (rs2165241) and two nonsynonymous coding SNPs (rs1048661: R141L and rs3825942: G153D), were genotyped in a total of 48 unrelated patients with PEX, 35 patients with PEXG, and 52 healthy subjects who had normal findings in repeated ophthalmic examinations. A genetic association study was performed. RESULTS: Between the two coding SNPs, R141L did not show an association with PEX (p=0.297 for allele G, p=0.339 for genotype GG), whereas allele G of G153D showed a significant association (odds ratio [OR]=3.52, 95% confidence interval [CI]=1.735-7.166, p=3.24×10(-4) for allele G, p=0.004 for genotype GG). Likewise, for the intronic SNP of rs2165241, genotype TT (p=0.005) and its corresponding allele T (OR=2.99, 95% CI=1.625-5.527, p=3.53×10(-4)) showed a significant association with PEX. The allele G of G153D showed a significant association with PEXG (OR=3.74, 95% CI=1.670-8.387, p=0.001). The combined haplotype GGT, consisting of all three risk alleles, was associated with PEX (p=0.037), conferring a 1.8-fold of increased risk to the disease (OR=1.799, 95% CI=1.04-3.13). Furthermore, the haplotype GGT presented in 39.8% of the patients with PEX and 26.9% of the controls. CONCLUSIONS: Certain genetic variants in LOXL1 confer risk for PEX in Greek populations, confirming in part findings in patients from Northern Europe.
| S-EPMC3712667 | biostudies-literature
Project description:A systematic literature review was performed evaluating articles examining the effects of pseudoexfoliation syndrome (PEX) and glaucoma (PEXG) on the cornea with a focus on the corneal endothelium. We searched for articles relevant to pseudoexfoliation syndrome, pseudoexfoliation glaucoma and corneal endothelial cell counts using Pubmed, Google Scholar Database, Web of Science and Cochrane Library databases published prior to September of 2016. We then screened the references of these retrieved papers and performed a Web of Science cited reference search. Corneal characteristics analyzed included central corneal thickness (CCT), corneal nerve density, endothelial cell density (ECD), polymegathism, and pleomorphism. These parameters were compared in the following populations: control, PEX, PEXG, and primary open angle glaucoma (POAG). Over 30 observational studies were reviewed. Most studies showed a statistically significant lower ECD in PEX and PEXG populations compared to controls. Overall, PEX eyes had a non-statistically significant trend of lower ECDs compared to PEXG eyes. No consistent trends were found when analyzing differences in CCT amongst control, PEX and PEXG groups. For the few studies that looked at corneal nerve characteristics, the control groups were found to have statistically significantly greater nerve densities than PEX eyes, which had significantly greater densities than PEXG eyes. ECD and corneal nerve densities may be potential metrics for risk-stratifying patients with PEX and PEXG. Our literature review provided further evidence of the significant negative influence PEX has on the cornea, worsening as patients convert to PEXG.
| S-EPMC5525502 | biostudies-literature
Project description:PurposeThe aim of this study was to evaluate differences in the iris and angle parameters in psuedoexfoliation syndrome (PXF) and pseudoexfoliation glaucoma (PXG) using anterior segment optical coherence tomography (ASOCT).MethodsPatients with PXF or PXG were compared using ASOCT with primary open-angle glaucoma POAG eyes as controls in this noninterventional comparative study conducted at a tertiary eye care center in East India. All angle parameters, TM length, and iris thickness were analyzed from the enhanced depth imaging (EDI) single scans obtained. Quadrant scans were used for the calculation of iris volume using a custom-built in-house software. In particular, the software performs multiple operations including edge detection, connected components, and thresholding to localize and segment the iris. Differences in the iris volume/thickness and TM length in PXF and PXG with POAG were analyzed.ResultsA total of 225 eyes were included, which included 75 PXG and 98 PXF cases and 52 POAG with a mean age of 67 ± 9.7 years at presentation. The algorithm repeatability and reproducibility was also established with correlation coefficients more than 99% which was substantiated with Bland-Altman plots. The iris volume (calculated in 197 images of 225 eyes) did not differ significantly in PXF and PXG eyes, although both had significantly greater volume compared to POAG eyes. The iris volume or other angle parameters including TM length did not correlate with clinical variables such as IOP, age, or visual field indices.ConclusionIris parameters or TM length do not explain pathogenesis of glaucoma in pseudoexfoliation.
| S-EPMC8374829 | biostudies-literature