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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•
Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma.

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Kollu N. Rao1, Robert Ritch2, Syril Dorairaj, Inderjeet Kaur1, Jeffrey M. Liebmann2, Ravi Thomas1, Subhabrata Chakrabarti1 •
L V Prasad Eye Institute1, New York Eye and Ear Infirmary2
09 Jul 2008-Molecular Vision
TL;DR: There was no involvement of the LOXL1 SNPs in patients with PDS and PG, and the results indicate that the associations of these SNPs are specific to XFS/XFG.
Abstract: 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).

33 citations

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

  • ...Since most studies had demonstrated a significant risk with haplotypes generated with the rs1048661 and rs3825942 SNPs [9-15, 17-19], a similar exercise was conducted to draw a comparison of the haplotype structure in the present cohort with other studies....

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  • ...00) SNPs, similar to earlier studies [11-15,17-20]....

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  • ...Two non-synonymous SNPs in exon 1 of LOXL1 (rs1048661 [R141L] and rs3825942 [G135D]) were demonstrated to exhibit a strong association with XFS and XFG in an Icelandic and Swedish population [9] that was later replicated across multiple populations worldwide [10-19]....

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  • ...Several studies conducted on XFS and XFG worldwide were able to independently replicate these findings in geographically and ethnically diverse cohorts [10-19]....

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Journal Article•DOI•
Prevalence of high-risk alleles in the LOXL1 gene and its association with pseudoexfoliation syndrome and exfoliation glaucoma in a Latin American population.

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Martha Jaimes, David Rivera-Parra, Antonio Miranda-Duarte, Gerardo Valdés, Juan Carlos Zenteno 
19 Jan 2012-Ophthalmic Genetics
TL;DR: LOXL1 variants are associated with an elevated risk for XFS/XFG in the Mexican population and a higher risk was conferred by the T allele of the intronic rs2165241 SNP rather than by the worldwide “high-risk” G allele of rs3825942.
Abstract: Purpose: Pseudoexfoliation syndrome (XFS) is a major risk factor for exfoliation glaucoma (XFG). A significant association exists between XFG and several SNPs in the lysyl oxidase-like 1 (LOXL1) gene. The purpose of this study was to report the results of the first association study between LOXL1 polymorphisms and XFS and/or XFG in a Latin American population.Methods: Genotypes of three high-risk SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed by direct sequencing. A case-control study was conducted with 102 unrelated XFS/XFG Mexican patients (42 XFS/60 XFG) as well as 97 control subjects. Allele frequencies, Hardy-Weinberg equilibrium, and haplotype association analysis were assessed with the Haplo View software.Results: The T allele of the intronic SNP rs2165241 was more frequent in XFS/XFG patients than in controls (OR [95% CI] = 2.41 [1.59–3.64]; p = 0.00001). The G allele of rs3825942 was found in a higher frequency in XFS/XFG than in controls (100% vs 95% respectively, p = 0.0019)....

31 citations

Journal Article•DOI•
LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta-Analysis.

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Lin Wang1, Yongbin Yu, Songbin Fu, Wencheng Zhao, ping liu •
Harbin Medical University1
01 Jan 2016-Journal of Glaucoma
TL;DR: A meta-analysis of the associations between lysyl oxidase-like 1 gene polymorphism and the susceptibility to exfoliation syndrome (XFS)/exfoliation glaucoma (XFG) indicates that rs1048661 had weak association with XFG/XFS; rs3825942 (“G” alleles) had strongly association withXFG/ XFS; and rs2165241 had significant risk with XFS in some ethnicity.
Abstract: AIM There were several studies that have researched the associations between lysyl oxidase-like 1 (LOXL1) gene polymorphism and the susceptibility to exfoliation syndrome (XFS)/exfoliation glaucoma (XFG), but results have been inconclusive. MATERIALS AND METHODS A meta-analysis was performed for deriving more exact estimation of the relationship. Twenty-five studies were selected for studying rs1048661 and rs3825942. Sixteen studies were selected for studying rs2165241. RESULTS Single nucleotide polymorphism (SNP) rs1048661 was found to be associated with XFS/XFG, but the risk allele in white populations was found to be G, as opposite to the T allele in Japanese, Chinese, and Korean populations. The SNP rs3825942 was significantly associated with XFS in this black South African population. However, the AA genotype of rs3825942 confers XFS risk in this population, as opposed to the GG genotype described in all other populations. SNP rs2165241 was found to be associated with XFS/XFG, but the risk allele in white populations was found to be T, as opposite to the "C" allele in Japanese and Korean populations. CONCLUSIONS Our meta-analysis indicates that rs1048661 ("G" alleles) had weak association with XFG/XFS; rs3825942 ("G" alleles) had strongly association with XFG/XFS; and rs2165241("T" alleles) had significant risk with XFG/XFS in some ethnicity.

31 citations

Journal Article•
Association of LOXL1 gene polymorphisms with exfoliation syndrome/glaucoma and primary open angle glaucoma in a Turkish population.

[...]

Burcu Kasım1, Murat Irkec1, Mehmet Alikasifoglu1, Mehmet Orhan1, Mehmet C. Mocan, Dilek Aktas1 •
Hacettepe University1
28 Jan 2013-Molecular Vision
TL;DR: The findings of the current study indicate that in a logistic regression analysis model the T allele of rs1048661 is the most important risk-modifying factor for the development of XFS and XFG.
Abstract: ) and XFG (OR=0.366, 95% CI: 0.219–0.611, p=8.56×10 −5 ) compared to the control subjects. None of the patients with XFS or XFG had the A allele of rs3825942, whereas 16% of the control subjects had that variant (OR=0.025, 95% CI: 0.003–0.188, p=3.69×10 −9 ). No association was observed between the SNPs studied and POAG. By using logistic regression analysis, the effect of rs1048661 remained significant (p=8.45×10 −8 ) after controlling for the effect of rs3825942, whereas rs3825942 was not significant with conditioning on rs1048661. Female gender was protective against the disease controlling with the effect of the two SNPs (OR=0.527, 95% CI: 0.358–0.776, p=0.001). Conclusions: The findings of the current study indicate that in a logistic regression analysis model the T allele of rs1048661 is the most important risk-modifying factor for the development of XFS and XFG. Our results also confirm in a Turkish population the findings of previous reports describing the association between LOXL1 polymorphisms and XFS/ XFG but not with POAG. The allele and genotype distribution in this cohort appear to be similar to those of Caucasians.

29 citations

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

  • ...The association was confirmed in the United States [5,6], Australia [7], Austria [8], Finland [9], Germany [10], Italy [10], Poland [11], Pakistan [12], Saudi Arabia [13] and India [14]....

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  • ...Our findings appear to be similar to those in Caucasians [4-14] and differ from Chinese [15,16], Japanese [17-19], Korean [20], and South African [22,23] populations (Table 4)....

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  • ...Our findings appear to be similar to those in Caucasians [4-14] and differ from Chinese [15,16], Japanese [17-19], Korean [20], and South African [22,23] populations (Table 4)....

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  • ...However, in Chinese [15,16], Japanese [17-19] and Korean [20] populations, the risk allele was inverse for the rs1048661 SNP in contrast to Caucasians [5-13]....

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  • ...These findings suggest that the variants of rs3825942 may have functional effects on LOXL1, such as substrate targeting or enzyme activity when the common variant of rs1048661 exists [4-13,15-20]....

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Journal Article•
Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma

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Baojian Fan1, Teresa Chia-Ching Chen1, Cynthia L. Grosskreutz1, Louis R. Pasquale1, Douglas J. Rhee1, E. DelBono1, Jonathan L. Haines2, Janey L. Wiggs1 •
Harvard University1, Vanderbilt University2
26 Dec 2008-Molecular Vision
TL;DR: Five genes that are critical components of the homocysteine metabolism pathway were evaluated as secondary factors for PXFS and PXFG and suggest that these genes are not significant risk factors for the development of these conditions.
Abstract: Purpose: To evaluate genes involved in homocysteine metabolism as secondary risk factors for pseudoexfoliation syndrome (PXFS) and the associated glaucoma (PXFG). Methods: One hundred eighty-six unrelated patients with PXFS, including 140 patients with PXFG and 127 unrelated control subjects were recruited from the Massachusetts Eye and Ear Infirmary. All the patients and controls were Caucasian of European ancestry. Seventeen tag SNPs from 5 genes (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], methylenetetrahydrofolate dehydrogenase [MTHFD1], and cystathionine β-synthase [CBS]) were genotyped. Single-SNP association was analyzed using Fisher’s exact test (unconditional) or logistic regression after conditioning on the effects of age and three LOXL1 SNPs (rs1048661, rs3825942, and rs2165241). Interaction analysis was performed between the homocysteine and LOXL1 SNPs using logistic regression. Haplotype analysis and the set-based test were used to test for association of individual genes. Multiple comparisons were corrected using the Bonferroni method. Results: One SNP (rs8006686) in MTHFD1 showed a nominally significant association with PXFG (p=0.015, OR=2.23). None of the seventeen SNPs tested were significantly associated with PXFS or PXFG after correcting for multiple comparisons (Bonferroni corrected p>0.25). After controlling for the effects of age and three associated LOXL1 SNPs, none of the seventeen tested SNPs were associated with PXFS (p>0.12). No significant interaction effects on PXFS were identified between the homocysteine and LOXL1 SNPs (p>0.06). Haplotype analysis and the set-based test did not find significant association of individual genes with PXFS (p>0.23 and 0.20, respectively). Conclusions: Five genes that are critical components of the homocysteine metabolism pathway were evaluated as secondary factors for PXFS and PXFG. Our results suggest that these genes are not significant risk factors for the development of these conditions.

29 citations

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

  • ...This association has been replicated in our study of a USA clinic-based population with broad ethnic diversity [9] and in other studies using ethnic populations of Caucasian [10-16], Indian [17], and Japanese [18-22]....

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  • ...All the patients and controls were Caucasian of European ancestry....

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  • ...This study population (cases and controls) included only Caucasian participants of European ancestry....

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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?

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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]....

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  • ...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]....

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  • ...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]....

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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.

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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