scispace - formally typeset
Search or ask a question
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.

Content maybe subject to copyright    Report

Citations
More filters
Journal Article•
Evaluation of LOXL1 polymorphisms in primary open-angle glaucoma in southern and northern Chinese

[...]

Wei Fen Gong1, Sylvia W. Y. Chiang, Li Jia Chen, Pancy O. S. Tam, Li Yun Jia, Dexter Y L Leung, Yi Qun Geng, Clement C Y Tham, Dennis S.C. Lam, Robert Ritch, Ningli Wang, Chi Pui Pang •
The Chinese University of Hong Kong1
19 Dec 2008-Molecular Vision
TL;DR: Individual LOXL1 SNPs, rs1048661, rs3825942, and rs2165241, were not associated with POAG in the Chinese population, however, a minor haplotype T-G-T was found to be associated with the disorder in the southern Chinese.
Abstract: Purpose: The lysyl oxidase-like protein 1 (LOXL1) gene is strongly associated with exfoliation glaucoma, which is very rare in the Chinese population. The implicated LOXL1 polymorphisms have not been associated with primary open-angle glaucoma (POAG). In this study, we investigated three of the LOXL1 polymorphisms in POAG in a southern Chinese population of Hong Kong and northern Chinese from Beijing. Methods: The Hong Kong group included 293 POAG patients and 250 controls, and the Beijing group included 169 POAG patients and 197 controls. LOXL1 single nucleotide polymorphisms (SNPs), rs1048661, rs3825942, and rs2165241, were genotyped by direct DNA sequencing. Individual association was analyzed using the χ 2 test, and haplotype-based association analysis was performed in WHAP. Results: Each of the candidate SNPs was not statistically associated with POAG in either group (p>0.017, Bonferroni correction). Haplotype-based association analysis had identified a significant omnibus association (Omnibus χ2=18.16, p=0.00115) between these SNPs and POAG in the Hong Kong group. A minor haplotype (T-G-T) showed significant statistical association with POAG. It presented in 2.1% of cases and 0.4% of controls, conferring a 5.24 fold of increased risk to the disease (95% CI: 1.17–23.54, Pperm=0.00108). However, this haplotype was absent in the Beijing group. Conclusions: Individual LOXL1 SNPs, rs1048661, rs3825942, and rs2165241, were not associated with POAG in the Chinese population. However, a minor haplotype T-G-T was found to be associated with the disorder in the southern Chinese. The low frequencies of the at-risk alleles at rs1048661 and rs2165241 may be one of the factors that led to the low prevalence of exfoliation syndrome in the general populations of the Chinese. Glaucoma is a group of heterogeneous disorders that can lead to progressive optic neuropathy and loss of vision with or without the association of elevated intraocular pressure

26 citations

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

  • ...LOXL1 is so far the most strongly associated gene with XFS/XFG having been reported in various populations [21-32]....

    [...]

  • ...Subsequent studies have replicated the association of LOXL1 SNPs with XFG and XFS among populations in different regions including the United States [22-24], Central Europe [25,26], India [27], and Japan [28-31]....

    [...]

Journal Article•DOI•
Lysyl Oxidase Like 1: Biological roles and regulation.

[...]

Alison G Greene1, Sarah B. Eivers1, Edward Dervan2, Colm O'Brien2, Deborah Wallace1 •
University College Dublin1, Mater Misericordiae University Hospital2
01 Apr 2020-Experimental Eye Research
TL;DR: Environmental factors such as hypoxia, oxidative stress and ultraviolet radiation exposure alter LOXL1 expression, and it is likely a combination of these genetic and environmental factors that influence disease development and progression.

23 citations

Journal Article•
TNF-α -308 G>A and -238 G>A polymorphisms are not major risk factors in Caucasian patients with exfoliation glaucoma

[...]

Georg Mossböck1, Wilfried Renner, Yosuf El-Shabrawi, Christoph Faschinger, Otto Schmut, Andreas Wedrich, Christina Zimmermann, Martin Weger •
University of Graz1
09 Mar 2009-Molecular Vision
TL;DR: Investigating a hypothesized association between two common functional polymorphisms in the promoter region of the TNF-α gene and the presence of XFG in a Caucasian population of Caucasian descent suggests that both of these polymorphisms are unlikely to be major risk factors for XFG.
Abstract: Purpose: TNF-α has been suggested to participate in the pathogenesis of exfoliation glaucoma (XFG). The purpose of the present study was to investigate a hypothesized association between two common functional polymorphisms in the promoter region of the TNF-α gene (TNF-α –308 G>A, rs1800629, and TNF-α –238 G>A, rs361525) and the presence of XFG in a Caucasian population. Methods: The present case-control study comprised 408 participants (204 patients with XFG and 204 control subjects). Control subjects were matched for age and sex. Genotypes of the TNF-α –308 G>A and TNF-α –238 G>A polymorphisms were determined by polymerase chain reaction (restriction fragment length polymorphism). Results: No significant differences regarding genotype distribution or allelic frequencies were found between patients and control subjects (p>0.025). The presence of the TNF-α –308 G-allele was associated with an insignificant odds ratio of 0.98 (95% confidence interval [CI]: 0.66–1.46; p=0.99) while the presence of the TNF-α –238 G-allele was associated with an insignificant odds ratio of 0.64 (95% CI: 0.33–1.23; p=0.25). Conclusions: Our data suggest that both the TNF-α –308 G>A and the TNF-α –238 G>A polymorphisms are unlikely to be major risk factors for XFG in an European population of Caucasian descent.

23 citations

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

  • ...However, as the prevalences of these polymorphisms are also high in individuals without XFS, other, as yet unkown genetic or enviromental factors may be involved [10-16]....

    [...]

Journal Article•
Evaluation of LOXL1 polymorphisms in exfoliation syndrome in the Uygur population.

[...]

Mayinu1, Xueyi Chen•
First Affiliated Hospital of Xinjiang Medical University1
28 Jun 2011-Molecular Vision
TL;DR: In this paper, the association profiles of LOXL1 gene polymorphisms with exfoliation syndrome (XFS) in the Uygur population were evaluated by direct sequencing, and a case-control association study was performed.
Abstract: Purpose: In Uygur populations, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occurred at a high frequency. In this study, we evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with XFS in the Uygur population. Methods: Sixty-four unrelated Uygur patients with XFS and 127 Uygur control subjects were included in this study. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs2165241, and rs3825942) were analyzed by direct sequencing, and a case-control association study was performed. Results: The three SNPs were significantly associated with XFS and XFG individually. The G allele of rs1048661 (OR [95%CI]: 1.92 [1.14–3.22]), G of rs3825942 (OR [95%CI]: 4.86 [2.02–11.68]), and T of rs2165241 (OR [95%CI]: 3.98 [2.54–6.25]) were risk alleles for the disorder. The genotypes GG for rs1048661 (OR [95%CI]: 2.13 [1.14–3.97]), GG for rs3825942 (OR [95%CI]: 5.68 [2.28–14.17]), and TT for rs2165241 (OR [95%CI]: 6.13 [2.68–14.01]) were risk genotypes for the disease. The haplotypes G-G for the SNPs rs1048661and rs3825942, G-T for the SNPs rs1048661 and rs2165241, and SNPs rs3825942 and rs2165241 were found to be significantly associated with XFS/G. The haplotypes G-G-T for the three SNPs were determined to be significantly associated with XFS/G. There were significant differences of the allelic and genotypic proportion in different gender/age patients and controls for all three SNPs. T allele of rs2165241 and G of rs3825942 were risk alleles for the disorder in both the male and female groups. G allele of rs1048661 was a risk allele for the disorder in the below 65-year-old group. T of rs2165241 was a risk allele for the disorder in both age groups. G of rs3825942 was a risk allele for the disorder in the over 65-year-old group. The genotypes also showed significant differences in the below 65-year-old group of rs1048661, both groups of rs2165241, and over 65-year-old group of rs3825942. Conclusions: LOXL1 is a susceptibility gene of XFS/XFG in Uygur populations. The risk alleles of rs1048661, rs3825942 and rs2165241 in Uygur subjects were found to be similar to those of populations in Iceland and the United States and different from Han populations in China. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG.

22 citations

Journal Article•DOI•
Review: The role of LOXL1 in exfoliation syndrome/glaucoma

[...]

Benjamin T. Whigham1, R. Rand Allingham1•
Duke University1
01 Oct 2011-Saudi Journal of Ophthalmology
TL;DR: It now appears the strong association between LOXL1 and XFS is due to non-coding variants that have not yet been identified, which might alter LO XL1 expression, which is decreased in the late stages of exfoliation syndrome/glaucoma.

20 citations

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

  • ...…et al., 2007; Yang et al., 2008), Australian (Hewitt et al., 2008), German (Wolf et al., 2010), Italian (Pasutto et al., 2008), Central European (Mossbock et al., 2008), Finnish (Lemmela et al., 2009), Chinese (Chen et al., 2009; Lee et al., 2009), Japanese (Fuse et al., 2008; Hayashi et al.,…...

    [...]

  • ...The relationship between the LOXL1 SNPs and XFS has now been studied in numerous populations including Swedish (Thorleifsson et al., 2007), US Caucasian (Aragon-Martin et al., 2008; Challa et al., 2008; Fan et al., 2008; Fingert et al., 2007; Yang et al., 2008), Australian (Hewitt et al., 2008), German (Wolf et al., 2010), Italian (Pasutto et al., 2008), Central European (Mossbock et al., 2008), Finnish (Lemmela et al., 2009), Chinese (Chen et al., 2009; Lee et al., 2009), Japanese (Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008; Ozaki et al., 2008; Tanito et al., 2008), Indian (Ramprasad et al., 2008), South African (Rautenbach et al., 2011; Williams et al., 2010), and Saudi Arabian (Abu-Amero et al., 2010)....

    [...]

  • ..., 2008), Central European (Mossbock et al., 2008), Finnish (Lemmela et al....

    [...]

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]....

    [...]

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]....

    [...]

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

    [...]

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]....

    [...]

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 
Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma.

[...]

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

[...]

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