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Journal Article

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

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
TL;DR: Surprisingly, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG and is found with a strong association with the opposite allele in the South African population.
Abstract: PURPOSE To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa. METHODS Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher's exact test. RESULTS A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2 x 10(-13) and 1.7 x 10(-5), respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects. CONCLUSIONS This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG.

94 citations


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

  • ...These findings have subsequently been replicated in numerous populations globally [16-34], but to date there has not been a study of Molecular Vision 2010; 16:705-712 <http://www....

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Journal ArticleDOI
Tin Aung1, Tin Aung2, Tin Aung3, Mineo Ozaki  +178 moreInstitutions (49)
TL;DR: In this paper, the authors conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents.
Abstract: Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

81 citations

Journal ArticleDOI
TL;DR: 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.
Abstract: 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.

72 citations

Journal Article
TL;DR: LOXL1 is a susceptibility gene of XFS/XFG in the Chinese population, and the association is mainly attributed to SNP rs1048661, which was found to be opposite to that of Caucasians.
Abstract: PURPOSE: To evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with exfoliation syndrome in a Chinese population. METHODS: Fifty unrelated patients with exfoliation syndrome and 125 control subjects were included. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed by direct sequencing, and a case-control association study was performed. RESULTS: The three SNPs were significantly associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) individually. After controlling for rs3825942 and rs2165241, the association between rs1048661 and XFS/XFG remained significant (p=3.6 x 10(-7)). At this SNP, the T allele and TT genotype conferred a 7.59-(95% confidence interval [CI]: 3.87-14.89, p=6.95 x 10(-11)) and 8.69-(95% CI: 4.15-18.20, p<1.00 x 10(-7)) fold increased risk to the disease. The alleles of T at rs1048661 and C at rs2165241 were found to be risk alleles in Chinese subjects, which were opposite to Caucasian individuals. The haplotypes T-G, defined by SNPs rs1048661 and rs3825942, and T-C by SNPs rs1048661 and rs2165241, were also significantly associated with the disorder. However when the genotypic or allelic frequencies of the three SNPs were compared between XFS and XFG, no significant difference was detected. CONCLUSIONS: LOXL1 is a susceptibility gene of XFS/XFG in the Chinese population, and the association is mainly attributed to SNP rs1048661. The risk alleles of rs1048661 and rs2165241 in Chinese subjects were found to be opposite to that of Caucasians. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG.

72 citations

Journal Article
TL;DR: The association of rs3825942, but not rs2165241 or rs1048661, with XFS/XFG is consistent in different ethnic populations in the recessive model, and LOXL1 is not associated with POAG in all study populations.
Abstract: PURPOSE: To investigate the association and ethnic heterogeneity of lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) with exfoliation syndrome (XFS)/exfoliation glaucoma (XFG) and other types of glaucoma. METHODS: We performed meta-analysis and ethnicity-based subgroup analyses according to published studies. Allele and genotype frequencies of SNPs rs1048661, rs2165241, and rs3825942 were extracted for analysis in Reviewer Manager: (1) comparison of the allelic distributions between XFS and XFG, (2) allelic association of LOXL1 SNPs with XFS/XFG, (3) associations in homozygote, heterozygote, and dominant and recessive models, and (4) allelic association with primary open angle glaucoma (POAG). RESULTS: In total 24 reported articles were retrieved, including Caucasian, African, Japanese, Indian, and Chinese populations. There was no significant difference in the distributions of rs1048661, rs2165241, and rs3825942 between XFS and XFG. The G allele of rs3825942 was the common at-risk allele for XFS/XFG in all populations with a total odds ratio (OR) of 10.89. The total homozygote OR of rs3825942 was 9.06 for XFS/XFG combined, but the total heterozygote OR was not significant. We also found that in the recessive model, the total OR was 14.70. There was no association of the three SNPs with POAG. CONCLUSIONS: The association of rs3825942, but not rs2165241 or rs1048661, with XFS/XFG is consistent in different ethnic populations in the recessive model. LOXL1 is not associated with POAG in all study populations.

67 citations


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

  • ...In most reported studies on LOXL1 and XFS/XFG, the three SNPs (rs1048661, rs2165241, and rs3825942) have been investigated together [11-23,25-28]....

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  • ...Since then the association of LOXL1 SNPs with XFS/ XFG has been reported in Caucasian populations in the USA [12-16], Australia [17], Austria [18], Germany [19,20], Italy [20], and Finland [21] and in other ethnic groups, including Japanese [22-27], Indian [28], and Chinese [29,30]....

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  • ...On the other hand, the allelic and genotypic distributions of the three SNPs were found to be drastically different among different populations [11-23,25-28]....

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  • ...Cohorts whose allele counting data were calculated from the frequencies data, Challa’s Duke (US) cohort [13] and Hewitt’s Austrian cohort [17], were removed....

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References
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Journal ArticleDOI
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 ArticleDOI
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]....

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  • ...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 ArticleDOI
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 ArticleDOI
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 ArticleDOI
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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