Commentary: The genetics of pseudoexfoliation syndrome/glaucoma.
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SUBMITTER: Behera G
PROVIDER: S-EPMC9359298 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Commentary: The genetics of pseudoexfoliation syndrome/glaucoma.
Behera Geeta G Kaliaperumal Subashini S
Indian journal of ophthalmology 20220601 6
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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: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, diagnosis, and monitoring of pseudoexfoliation and may also help lead to the identification of novel therapeutic targets. This review serves as an update on the recent trends and findings in pseudoexfoliation syndrome.
| S-EPMC5424603 | biostudies-literature
Project description:Purpose of reviewPseudoexfoliation 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.Recent findingsXFS 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.SummaryXFS 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: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: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:ObjectivesTo 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 methodsDNA 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.ResultsAll 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).ConclusionLOXL1 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:Pseudoexfoliation (PEX) is a multifactorial age-related disease involving deposition of extracellular proteinaceous aggregates on anterior ocular tissues. The present study aims to identify functional variants in fibulin-5 (FBLN5) as risk factors for the development of PEX. Thirteen tag single-nucleotide polymorphisms (SNPs) in FBLN5 were genotyped using TaqMan SNP genotyping technology to identify association between SNPs of FBLN5 and PEX in an Indian cohort comprising 200 control and 273 PEX patients (169 PEXS and 104 PEXG). Functional analysis of risk variants was done through luciferase reporter assays and electrophoretic mobility shift assay (EMSA) using human lens epithelial cells. Genetic association and risk haplotype analysis showed a significant association of rs17732466:G>A (NC_000014.9:g.91913280G>A) and rs72705342:C>T (NC_000014.9:g.91890855C>T) within FBLN5 as risk factors with the advanced severe stage of the disease, pseudoexfoliation glaucoma (PEXG). Reporter assays showed allele-specific regulatory effect of rs72705342:C>T on gene expression, wherein, construct containing the risk allele showed a significant decrease in the reporter activity compared with the one with protective allele. EMSA further validated higher binding affinity of the risk variant to nuclear protein. In silico analysis predicted binding sites for two transcription factors, GR-α and TFII-I with risk allele at rs72705342:C>T, which were lost in the presence of protective allele. The EMSA showed probable binding of both these proteins to rs72705342. In conclusion, the present study identified the novel association of two genetic variants in FBLN5 with PEXG but not with PEXS, distinguishing between the early and the later forms of PEX. Further, rs72705342:C>T was found to be a functional variant.
| S-EPMC9995586 | biostudies-literature
Project description:PURPOSE:To evaluate the elastin gene (ELN) as a secondary risk factor for pseudoexfoliation syndrome (PXFS) and the associated glaucoma pseudoexfoliation glaucoma (PXFG). METHODS:One hundred seventy-eight unrelated patients with PXFS, including 132 patients with PXFG, and 113 unrelated controls were recruited from the Massachusetts Eye and Ear Infirmary. All the patients and controls were white of European ancestry. Three tag SNPs (rs2071307, rs3823879, and rs3757587) that capture the majority of alleles in ELN were genotyped. Single-SNP association was analyzed using Fisher exact test. Haplotype analysis and the set-based test were used to assess the association for the whole gene. Interaction analysis was done between the ELN SNP rs2071307 and LOXL1 SNP rs2165241 using logistic regression. Multiple comparisons were corrected using the Bonferroni method. RESULTS:All 3 ELN tag SNPs were not significantly associated with PXFS and PXFG (P>0.20). The minor allele frequencies in PXFS, PXFG, and controls were 40.7%, 39.8%, and 45.6%, respectively for rs2071307, 6.7%, 6.3%, and 5.4% for rs3823879, and 14.8%, 16.2%, and 13.6% for rs3757587. Haplotype analysis and the set-based test did not find significant association of ELN with PXFS (P=0.94 and 0.99, respectively). No significant interaction effects on PXFS were identified between the ELN and LOXL1 SNPs (P=0.55). CONCLUSIONS:Our results suggest that common polymorphisms of ELN are not associated with PXFS and PXFG in white populations. Further studies are required to identify secondary genetic factors that contribute to PXFS.
| S-EPMC6748032 | biostudies-literature
Project description:PurposeThree 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.MethodsThe 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.ResultsBetween 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.ConclusionsCertain 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: Not available
| S-EPMC4157521 | biostudies-literature