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Journal Article•

Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population

Georg Mossböck1, Wilfried Renner, Christoph Faschinger, Otto Schmut, Andreas Wedrich, Martin Weger •
University of Graz1
09 May 2008-Molecular Vision (Emory University)-Vol. 14, pp 857-861
TL;DR: The data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend the knowledge to a Central European population.
Abstract: PURPOSE Exfoliation syndrome (XFS) is characterized by an accumulation of abnormal extracellular material in the anterior part of the eye that frequently leads to increased intraocular pressure and glaucomatous optic neuropathy. Recently, two non-synonymous polymorphisms (rs1048661 G>T and rs3825942 G>A) of lysyl oxidase-like protein 1 (LOXL1), a monoamine oxidase that catalyzes the polymerization of tropoelastin to elastin, were found to be associated with increased risk for XFS and exfoliation glaucoma (XFG). The aim of the present study was to investigate the role of these LOXL1 variants in a Central European cohort of Caucasian patients with XFG. METHODS The present case-control study comprised of 167 unrelated patients with XFG and 170 control subjects. Genotyping of the LOXL1 rs1048661 and rs3825942 polymorphisms was done using polymerase chain reaction. RESULTS The frequency of allele G of rs1048661 as well as rs3825942 was significantly higher in patients than in controls (rs1048661: 0.841 in patients versus 0.669; p<0.001; rs3825942: 0.994 in patients versus 0.817; p<0.001). Odds ratios of 52.1 (95% confidence interval [CI]: 13.85-195.6) and 14.67 (95% CI: 3.81-56.2), respectively, were calculated for the two high-risk haplotypes GG and TG compared to the haplotype GA. CONCLUSIONS Our data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend our knowledge to a Central European population.

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Citations
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Journal Article•DOI•
Role of an extracellular chaperone, Clusterin in the pathogenesis of Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.

[...]

Biswajit Padhy, Gargi Gouranga Nanda, Mahasweta Chowdhury, Debanand Padhi, Aparna Rao, Debasmita Pankaj Alone 
01 Oct 2014-Experimental Eye Research
TL;DR: The results reveal that rs2279590 was found to be associated with PEX in Indian population and the risk allele mediates an allele specific upregulation of the clusterin mRNA.

36 citations

Journal Article•DOI•
Association of TNFA –308 G/A and TNFRI +36 A/G Gene Polymorphisms with Glaucoma

[...]

Mohammad Reza Razeghinejad1, Feisal Rahat, Eskandar Kamali-Sarvestani•
Shiraz University of Medical Sciences1
24 Jun 2009-Ophthalmic Research
TL;DR: The results of the present study showed that inheritance of the high producer TNFA –308 A allele might be a susceptibility factor for the development of open-angle glaucoma.
Abstract: Objective: TNF-α is one of the most important factors recognized in the pathogenesis of open-angle glaucoma. Therefore, the association of single nucleotide polymorphisms in the <

35 citations

Journal Article•DOI•
Ethnicity‐Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta‐Analysis

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Panayiota Founti1, Panayiota Founti2, Anna-Bettina Haidich2, Anthoula Chatzikyriakidou2, Angeliki Salonikiou2, Eleftherios Anastasopoulos2, Theofanis Pappas2, Alexandros Lambropoulos2, Ananth C. Viswanathan3, Fotis Topouzis2 •
Moorfields Eye Hospital1, Aristotle University of Thessaloniki2, University College London3
01 Nov 2015-Annals of Human Genetics
TL;DR: An ethnic‐based meta‐analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG) found that other genetic and/or environmental factors may modify the effect of LO XL1 polymorphism in certain ethnic groups.
Abstract: Pseudoexfoliation (PEX) is an age-related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic-based meta-analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06-0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02-0.06) and Koreans (OR = 0.10, 95%CI:0.05-0.22). These associations we-re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22-17.41) and Koreans (OR = 6.63, 95%CI:2.60-16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.

34 citations

Cites background from "Lysyl oxidase-like protein 1 (LOXL1..."

  • ...Among these, 37 studies met the inclusion criteria and were included in the meta-analysis (Thorleifsson et al., 2007; Fingert et al., 2007; Fan et al., 2008; Hewitt et al., 2008; Fuse et al., 2008; Ozaki et al., 2008; Mossböck et al., 2008; Challa et al., 2008; Pasutto et al., 2008; Schlötzer-Schrehardt et al., 2008; Aragon-Martin et al., 2008; Yang et al., 2008; Hayashi et al., 2008; Tanito et al., 2008; Mabuchi et al., 2008; Mori et al., 2008; Ramprasad et al., 2008; Lee et al., 2009; Chen et al., 2009; Lemmelä et al., 2009; Wolf et al., 2010; AbuAmero et al., 2010; Williams et al., 2010; Mayinu & Chen et al., 2011; Malukiewicz et al., 2011; Sagong et al., 2011; Abu-Amero et al., 2011; Rautenbach et al., 2011; Jaimes et al., 2012; Micheal et al., 2012; Chiras et al., 2013; Metaxaki et al., 2013; Kasım et al., 2013; Park et al., 2013; Anastasopoulos et al., 2014; Dubey et al., 2014; de Juan-Marcos et al., 2014)....

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  • ...S34), nine studies were outside the 95% CI from the lnOR (Thorleifsson et al., 2007; Fan et al., 2008; Mossböck et al., 2008; Pasutto et al., 2008; Wolf et al., 2010; Chiras et al., 2013; Kasim et al., 2013), causing the heterogeneity in the results....

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  • ...…in the meta-analysis (Thorleifsson et al., 2007; Fingert et al., 2007; Fan et al., 2008; Hewitt et al., 2008; Fuse et al., 2008; Ozaki et al., 2008; Mossböck et al., 2008; Challa et al., 2008; Pasutto et al., 2008; Schlötzer-Schrehardt et al., 2008; Aragon-Martin et al., 2008; Yang et al., 2008;…...

    [...]

  • ...S34), nine studies were outside the 95% CI from the lnOR (Thorleifsson et al., 2007; Fan et al., 2008; Mossböck et al., 2008; Pasutto et al., 2008; Wolf et al., 2010; Chiras et al., 2013; Kasim et al., 2013), causing the heterogeneity in the results....

    [...]

Journal Article•DOI•
The genetics of pigment dispersion syndrome and pigmentary glaucoma.

[...]

Gerassimos Lascaratos1, Ameet Shah1, David F. Garway-Heath1•
UCL Institute of Ophthalmology1
01 Mar 2013-Survey of Ophthalmology
TL;DR: The inheritance patterns and recent genetic advances in the study of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) are reviewed.

33 citations

Journal Article•
Role of functional single nucleotide polymorphisms of MMP1, MMP2, and MMP9 in open angle glaucomas

[...]

Georg Mossböck1, Martin Weger, Christoph Faschinger, Christine Zimmermann, Otto Schmut, Wilfried Renner, Yosuf El-Shabrawi •
Medical University of Graz1
28 Aug 2010-Molecular Vision
TL;DR: The data suggest that the MMP1 −1607 1G/2G, MMP2 −1306 C/T, M MP2 −1575 G/A, and MMP9 Q279R polymorphisms themselves are unlikely major risk factors among Caucasian patients with either POAG or XFG.
Abstract: Purpose: Matrix metalloproteinases (MMPs) play an essential role in the turnover of the extracellular matrix and cellular behavior. MMP1, MMP2, and MMP9 have previously been implicated in the pathogenesis of primary open angle glaucoma (POAG) and open angle glaucoma secondary to exfoliation syndrome (XFG), respectively. Functional gene polymorphisms of these MMPs such as MMP1 −1607 1G/2G (rs1799750), MMP2 −1306 C/T (rs243865), MMP2 −1575 G/A (rs243866), and MMP9 Q279R (rs17576) are thus plausible candidates as risk factors for open angle glaucomas. The purpose of the present study was to investigate hypothesized associations between these polymorphisms and the presence of POAG and XFG in a Caucasian population. Methods: The present case-control study included 322 patients with POAG, 202 patients with XFG, and 248 control subjects. Genotyping of polymorphisms was done using polymerase chain reaction. Results: No significant differences in either genotype distributions or allelic frequencies of MMP1 −1607 1G/2G, MMP2 −1306 C/T, MMP2 −1575 G/A, and MMP9 Q279R were found between patients with POAG and control subjects and patients with XFG and control subjects, respectively (p>0.05). The presence of POAG or XFG was not predicted by any of the investigated polymorphisms. Conclusions: Our data suggest that the MMP1 −1607 1G/2G, MMP2 −1306 C/T, MMP2 −1575 G/A, and MMP9 Q279R polymorphisms themselves are unlikely major risk factors among Caucasian patients with either POAG or XFG.

33 citations

Cites background from "Lysyl oxidase-like protein 1 (LOXL1..."

  • ...Mutations in the myocilin gene (MYOC) in the case of POAG and as for XFG polymorphisms in the lysyl oxidase like protein 1 (LOXL1) gene are the most prominent among them [6-16]....

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References
More filters
Journal Article•DOI•
Haploview: analysis and visualization of LD and haplotype maps

[...]

Jeffrey C. Barrett1, Ben Fry1, Julian Maller1, Mark J. Daly1•
Massachusetts Institute of Technology1
15 Jan 2005-Bioinformatics
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. Availability: http://www.broad.mit.edu/mpg/haploview/ Contact: jcbarret@broad.mit.edu

13,862 citations

Journal Article•DOI•
Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

[...]

Gudmar Thorleifsson1, Kristinn P. Magnusson1, Patrick Sulem1, G. Bragi Walters1, Daniel F. Gudbjartsson1, Hreinn Stefansson1, Thorlakur Jonsson1, Adalbjorg Jonasdottir1, Aslaug Jonasdottir1, Gerdur Stefansdottir1, Gisli Masson1, Gudmundur A. Hardarson1, H. Petursson1, Arsaell Arnarsson2, Mehdi Motallebipour3, Ola Wallerman3, Claes Wadelius3, Jeffrey R. Gulcher1, Unnur Thorsteinsdottir1, Augustine Kong1, Fridbert Jonasson2, Kari Stefansson1 •
deCODE genetics1, University of Iceland2, Uppsala University3
07 Sep 2007-Science
TL;DR: Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association with glaucoma, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS).
Abstract: Glaucoma is a leading cause of irreversible blindness A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q241 region associated with glaucoma Further investigation revealed that the association is confined to exfoliation glaucoma (XFG) Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS) About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes The population-attributable risk is more than 99% The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG

654 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background or result in this paper

  • ...Most importantly, a recent genome-wide association study from Icelandic and Swedish patients with XFS and XFG found two common non-synonymous single nucleotide polymorphisms in exon 1 of the lysyl oxidase-like protein 1 gene (LOXL1; OMIM 153456) conferring increased risk for the development of XFS and XFG (rs1048661 and rs3825942) [10]....

    [...]

  • ...Beside the original study from Thorleifsson and coworkers [10] that included an Icelandic and a Swedish cohort, four studies from the United States, one study from Australia, one study from Japan, and one from India investigating LOXL1 polymorphisms in XFS and XFG have been performed [10,15-21]....

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Journal Article•DOI•
Elastic fiber homeostasis requires lysyl oxidase-like 1 protein.

[...]

Xiao-Qing Liu1, Yun Zhao1, Jiangang Gao, Basil S. Pawlyk1, Barry Starcher2, Jeffrey A. Spencer3, Hiromi Yanagisawa, J. Zuo, Tiansen Li1 •
Harvard University1, University of Texas Health Science Center at Tyler2, University of Texas Southwestern Medical Center3
25 Jan 2004-Nature Genetics
TL;DR: It is shown that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation.
Abstract: Elastic fibers are components of the extracellular matrix and confer resilience1. Once laid down, they are thought to remain stable2, except in the uterine tract where cycles of active remodeling occur3. Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema4,5,6,7. Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance8, but little is known about the role of renewal. Here we show that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. Thus elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a cross-linking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin.

629 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...Mice lacking LOXL1 display tropoelastin accumulation in multiple tissues, which leads to pelvic organ prolapse, emphysematous changes, and vascular abnormalities [13]....

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  • ...This deamination leads to the polymerization of tropoelastin to elastin, which is the first step of elastogenesis [12,13]....

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Journal Article•DOI•
Pseudoexfoliation syndrome, ocular manifestation of a systemic disorder?

[...]

Ursula Schlötzer-Schrehardt1, Mahmut R. Koca, Gottfried O. H. Naumann, Hildegard Volkholz•
University of Erlangen-Nuremberg1
01 Dec 1992-Archives of Ophthalmology
TL;DR: Findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.
Abstract: The pseudoexfoliation syndrome has recently been suggested to represent the local manifestation of a more widespread disorder. In this study, a case of classic bilateral pseudoexfoliation syndrome with systemic distribution of pseudoexfoliation material involving a variety of organ systems is described. Using transmission electron microscopy, typical pseudoexfoliation fibers were identified in autopsy tissue specimens of skin, heart, lungs, liver, kidney, and cerebral meninges in addition to the classic intraocular locations. The pseudoexfoliation material was mainly localized to connective-tissue portions or septa traversing the various organs. The pseudoexfoliation fibers were consistently associated with connective-tissue components, particularly fibroblasts and collagen and elastic fibers; myocardial tissue specimens; and heart-muscle cells. These findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.

400 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...Mainstay of the pathogenesis of exfoliation syndrome is the accumulation of pathognomonic fibrils in the anterior segment of the eye as well as in extraocular locations [1]....

    [...]

  • ...Exfoliation syndrome (XFS; OMIM 177650) is characterized by an accumulation of abnormal extracellular fibrillar material not only in different structures of the eye but also in various extraocular tissues [1]....

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Journal Article•DOI•
Why is glaucoma associated with exfoliation syndrome

[...]

Robert Ritch1, Ursula Schlötzer-Schrehardt, Anastasios G. P. Konstas•
New York Eye and Ear Infirmary1
01 May 2003-Progress in Retinal and Eye Research
TL;DR: Exfoliation syndrome is an age-related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar material in tissues throughout the anterior segment and also in connective tissue portions of various visceral organs.

218 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...These fibrils are partly composed of components of the elastic fiber system like elastin, tropoelastin, amyloid P, and latent TGF-β binding proteins [2,4]....

    [...]

  • ...Secondary open-angle glaucoma due to XFS (exfoliation glaucoma, XFG) develops as a consequence of deposition of exfoliation material and of liberated iris pigment in the trabecular meshwork leading to elevated intraocular pressure and consecutively glaucomatous optic neuropathy [4]....

    [...]

Related Papers (5)
Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

[...]

07 Sep 2007-Science
Gudmar Thorleifsson, Kristinn P. Magnusson, Patrick Sulem, G. Bragi Walters, Daniel F. Gudbjartsson, Hreinn Stefansson, Thorlakur Jonsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Gerdur Stefansdottir, Gisli Masson, Gudmundur A. Hardarson, H. Petursson, Arsaell Arnarsson, Mehdi Motallebipour, Ola Wallerman, Claes Wadelius, Jeffrey R. Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Fridbert Jonasson, Kari Stefansson 
Association of LOXL1 common sequence variants in german and italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma

[...]

01 Apr 2008-Investigative Ophthalmology & Visual Science
Francesca Pasutto, Mandy Krumbiegel, Christian Y. Mardin, Daniela Paoli, Robert Lämmer, Bernhard H. F. Weber, Friedrich E. Kruse, Ursula Schlötzer-Schrehardt, André Reis 
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29 Jan 2008-Molecular Vision
Pratap Challa, Silke Schmidt, Yutao Liu, Xuejun Qin, Robin Vann, Pedro Gonzalez, R. Rand Allingham, Michael A. Hauser 
Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India

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09 Feb 2008-Molecular Vision
Vedam L. Ramprasad, Ronnie George, Nagasamy Soumittra, Ferdinamarie Sharmila, Lingam Vijaya, Govindasamy Kumaramanickavel 
Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people.

[...]

16 Nov 2007-Human Molecular Genetics
Alex W. Hewitt, Alex W. Hewitt, Shiwani Sharma, Kathryn P. Burdon, Jie Jin Wang, Paul N. Baird, David P. Dimasi, David A. Mackey, David A. Mackey, Paul Mitchell, Jamie E Craig