Genetics of exfoliation syndrome and glaucoma.
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ABSTRACT:
SUBMITTER: Aboobakar IF
PROVIDER: S-EPMC4157521 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Genetics of exfoliation syndrome and glaucoma.
Aboobakar Inas F IF Allingham R Rand RR
International ophthalmology clinics 20140101 4
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Project description:The multifunctional protein clusterin (CLU) is a secreted glycoprotein ubiquitously expressed throughout the body, including in the eye. Its primary function is to act as an extracellular molecular chaperone, preventing the precipitation and aggregation of misfolded extracellular proteins. Clusterin is commonly identified at fluid-tissue interfaces, and has been identified in most body fluids. It is a component of exfoliation material, and CLU mRNA is reduced in eyes with exfoliation syndrome compared with controls. SNPs located in the CLU genomic region have been associated with Alzheimer disease (AD) at the genome-wide level and several CLU SNPs located in an apparent regulatory region have been nominally associated with XFS/XFG in Caucasians with European ancestry and in south Indians. Interestingly, clusterin associates with altered elastic fibers in human photoaged skin and prevents UV-induced elastin aggregation in vitro. In light of the known geographic risk factors for XFS/XFG, which could include UV light, investigations of CLU-geographic interactions could be of interest. Future studies investigating rare CLU variation and other complex interactions including gene-gene interactions in XFS/XFG cases and controls may also be fruitful. Although CLU has been considered as a therapeutic target in AD, cancer and dry eye, a role for clusterin in XFS/XFG needs to be better defined before therapeutic approaches involving CLU can be entertained.
| S-EPMC8035929 | biostudies-literature
Project description:Exfoliation syndrome and exfoliation glaucoma comprise a unique age-related ocular aggregopathy characterized by the accumulation of protein complex aggregates in different ocular structures. Recent literature and studies have expanded our knowledge of the clinical characteristic features, phenotypical variations, and molecular pathophysiology associated with disease onset or development of glaucoma. Despite years of studies on the various epidemiological, clinical, and molecular facets of the disease, the exact mechanism of disease onset, formation of aggregates, and the events that trigger the development of glaucoma marking irreversibility in the disease remains elusive. This review elaborates on the existing and new insights that we have gained over the years and highlights gaps in the knowledge about the disease that need future exploration.
| S-EPMC11329824 | biostudies-literature
Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). We have shown that these SNPs are not associated with the primary glaucomas such as primary open-angle (POAG) glaucoma and primary angle-closure glaucoma (PACG). To further establish the specificity of LOXL1 SNPs for XFS and XFG, we determined whether these SNPs were involved in pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). METHODS: Three SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in a cohort of 78 unrelated and clinically well characterized glaucoma cases comprising of PG (n=44) and PDS (n=34) patients as well as 108 ethnically matched normal controls of Caucasian origin. The criteria for diagnosis of PDS/PG were Krukenberg spindle, hyperpigmentation of the trabecular meshwork, and wide open angle. Transillumination defects were detected by infrared pupillography, and the presence of a Zentmayer ring was considered as a confirmatory sign. All three SNPs were genotyped in cases and controls by resequencing the genomic region of LOXL1 harboring these variants and were further confirmed by polymerase chain reaction (PCR)-based restriction digestions. Haplotypes were generated from the genotype data, and the linkage disequilibrium (LD) and haplotype analysis were done with Haploview software that uses the expectation maximization (EM) algorithm. RESULTS: The LOXL1 SNPs showed no significant association with PDS or PG. There was no significant difference in the frequencies of the risk alleles of rs1048661 ('G' allele; p=0.309), rs3825942 ('G' allele' p=0.461), and rs2165241 ('T' allele; p=0.432) between PG/PDS cases and controls. Similarly, there was no involvement of the XFS/XFG-associated haplotypes, 'G-G' (p=0.643; [OR=1.08, 95%CI, 0.59-1.97]) and 'T-G' (p=0.266; [OR=1.35, 95%CI, 0.70-2.60]), with the PDS/PG phenotypes. The risk haplotype 'G-G' was observed in ~55% of the normal controls. CONCLUSIONS: There was no involvement of the LOXL1 SNPs in patients with PDS and PG. The results further indicate that the associations of these SNPs are specific to XFS/XFG.
| S-EPMC2447814 | biostudies-literature
Project description: Not available
| S-EPMC2268854 | biostudies-literature
Project description:PURPOSE: To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients. METHODS: A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1 -1607 1G/2G (rs1799750) and MMP3 -1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression. RESULTS: The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03-2.10]), since after correction for multiple comparisons, this association was no longer statistically significant. CONCLUSIONS: Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients.
| S-EPMC2797043 | biostudies-literature
Project description:Exfoliation syndrome presents as an accumulation of insoluble fibrillar aggregates that commonly correlates with age and causes ocular complications, most notably open-angle glaucoma. Despite advances in understanding the pathogenesis and risk factors associated with exfoliation syndrome, there has been no significant progress in curative pharmacotherapy of this disease. It is thought that the ability to target the fibrillar aggregates associated with exfoliation may offer a new therapeutic approach, facilitating their direct removal from affected tissues. Phage display techniques yielded two peptides (LPSYNLHPHVPP, IPLLNPGSMQLS) that could differentiate between exfoliative and non-affected regions of the human lens capsule. These peptides were conjugated to magnetic particles using click chemistry to investigate their ability in targeting and removing exfoliation materials from the anterior human lens capsule. The behavior of the fibrillar materials upon binding to these magnetic particles was assessed using magnetic pins and rotating magnetic fields of various strengths. Ex vivo studies showed that the magnetic particle-peptide conjugates could generate enough mechanical force to remove large aggregates of exfoliation materials from the lens capsule when exposed to a low-frequency rotating magnetic field (5000 G, 20 Hz). Biocompatibility of targeting peptides with and without conjugated magnetic particles was confirmed using MTT cell toxicity assay, live/dead cell viability assay, and DNA fragmentation studies on primary cultured human trabecular meshwork cells. This is a novel, minimally invasive, therapeutic approach for the treatment of exfoliation glaucoma via the targeting and removal of exfoliation materials that could be applied to all tissues within the anterior segment of the eye.
| S-EPMC9615239 | biostudies-literature
Project description:Exfoliation syndrome is a common cause of open-angle glaucoma. It is characterized by microscopic flakes of protein-rich material being deposited in both ocular and non-ocular tissues. While its mechanism is poorly understood, family- and population-based studies have established that the disorder has a strong genetic component. A further understanding of the relevant gene variants might help reveal the molecular mechanism behind exfoliation. The most-strongly associated genetic variants are found in the lysyl oxidase-like 1 (LOXL1) gene. However, two major risk alleles in the LOXL1 coding region are reversed between ethnic groups. It now appears the strong association between LOXL1 and XFS is due to non-coding variants that have not yet been identified. Such variants might alter LOXL1 expression, which is decreased in the late stages of exfoliation syndrome/glaucoma. Here we discuss LOXL1 as a risk gene for exfoliation syndrome and glaucoma.
| S-EPMC3729321 | biostudies-literature
Project description:BackgroundSingle nucleotide polymorphisms (SNPs) in the gene encoding LOXL1 are risk factors for exfoliation syndrome and exfoliation glaucoma. This meta-analysis comprehensively investigated the association between LOXL1 gene polymorphisms (rs1048661, rs3825942, and rs2165241) and the risk of exfoliation syndrome/exfoliation glaucoma (XFS)/(XFG).MethodsAll eligible case-control studies, published before August 17, 2020, were searched on Medline (Ovid), PubMed, CNKI, EMBASE, and Wanfang databases.ResultsIn total, 5022 cases and 8962 controls were included in this meta-analysis. Significant associations between LOXL1 gene polymorphisms and XFS/XFG risk was observed in the disease types-based subgroups. In addition, in the subgroup analysis of ethnicity, positive associations between LOXL1 gene polymorphisms (rs1048661, rs3825942, and rs2165241) and XFS/XFG risk were found in Caucasians. Furthermore, rs1048661 and rs3825942 polymorphisms were related to XFS/ XFG risk in Asians; however, no significant association was observed between the LOXL1 gene rs2165241 polymorphism and XFS/XFG risk in Asians. In addition, rs1048661 and rs3825942 correlated with XFS/XFG susceptibility in Africans.ConclusionsOur results implicate LOXL1 gene polymorphisms as XFS/XFG risk factors, especially in Caucasians.
| S-EPMC8081202 | biostudies-literature
Project description:PurposeWe compared cytokines, chemokines, and growth factors in the aqueous humor (AH) of patients with exfoliation syndrome (XFS), with exfoliation glaucoma (XFG), with primary open angle glaucoma (POAG), and healthy controls.MethodsAH samples were collected from 21 patients with XFS, 28 with XFG, 14 with POAG, and 17 healthy controls during routine cataract surgery. The protein levels of 21 cytokines and growth factors, together with TGF-β1, 2, and 3, were quantified using the multiplex immunoassay. The levels of each protein in the four groups were compared using the Kruskal-Wallis test.ResultsAmong the 24 cytokines and growth factors, 16 were out of the detectable range in >50% of samples in at least one group; the remaining 8 cytokines and growth factors (IL-8, MIP-1α, fractalkine, Flt3 ligand, PDGF-AA, VEGF, TGF-β1, and TGF-β2) were included in the analysis. TGF-β1 and TGF-β2 levels were the highest in patients with XFG and those with POAG, respectively. Expression levels of the inflammatory chemokines IL-8, MIP-1α, and fractalkine, as well as levels of the immune cell growth factor Flt3 ligand, were significantly higher in the XFG group than in the other groups. The protein levels of PDGF-AA and VEGF were not significantly different among the 4 groups.ConclusionsBoth TGF-β1 and inflammatory cytokines were highly expressed in the AH of patients with XFG. Considering that the levels of these cytokines are increased by oxidative stress and that they regulate the extracellular matrix, they may also play a role in intraocular pressure elevation in XFG.
| S-EPMC8662569 | biostudies-literature
Project description:Exfoliation syndrome (XFS) is a condition characterized by the production of insoluble fibrillar aggregates (exfoliation material; XFM) in the eye and elsewhere. Many patients with XFS progress to exfoliation glaucoma (XFG), a significant cause of global blindness. We used quantitative mass spectrometry to analyze the composition of XFM in lens capsule specimens and aqueous humor samples from XFS and XFG patients and individuals without XFS. Pieces of lens capsule and samples of aqueous humor were obtained with consent from patients undergoing cataract surgery. Tryptic digests of capsule or aqueous samples were analyzed by HPLC-mass spectrometry and relative differences between samples were quantified using the tandem mass tag technique. The distribution of XFM on the capsular surface was visualized by scanning electron microscopy and super-resolution light microscopy. A small set of proteins was consistently upregulated in XFS samples, including microfibril components fibrillin-1 (FBN1), latent TGFBeta-binding protein-2 (LTBP-2), and LTBP-3. Lysyl oxidase-like 1 (LOXL1), a protein linked strongly to XFS in genetic studies, was an abundant XFM protein. Ligands of the TGFBeta superfamily were prominent, including LEFTY2, a protein known for its role in establishing the embryonic body axis. Elevated levels of LEFTY2 were also detected in aqueous humor from XFG patients and confirmed by ELISA. This analysis verified the presence of several suspected XFM proteins and identified novel components. Quantitative comparisons between patient samples revealed a consistent XFM proteome. The expression of FBN1, LOXL1, and LEFTY2 was particularly strong in XFG patients in comparison to XFS patients.
2022-02-17 | PXD026764 | Pride