Journal Article•
Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population
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.
Citations
More filters
TL;DR: This is the first study to demonstrate the association of rs41435250 with PEX as well as reversal of the promoter risk allele, and the role of the LOXL1 gene in PEX pathogenesis will facilitate early detection in individuals at risk for this condition.
Abstract: Importance This study was necessary to establish the association between common genetic variants in the lysyl oxidase–like 1 ( LOXL1 ) gene with pseudoexfoliation (PEX) syndrome and emphasize the reversal of promoter risk allele in a South Indian population. Objective To investigate the potential association of genetic variants across the LOXL1 gene in South Indian patients with PEX syndrome and glaucoma. Design, Setting, and Participants A case-control study of individuals from Madurai, India, with PEX syndrome and glaucoma as well as healthy people serving as controls. Three hundred unrelated people with PEX syndrome and 225 age- and ethnically matched controls were recruited for genetic analysis. Main Outcomes and Measures Four single-nucleotide polymorphisms in LOXL1 (rs16958477, rs1048661, rs3825942, and rs2165241) were genotyped by direct sequencing in all participants. Regulatory regions and 7 coding exons of LOXL1 were directly sequenced in 50 patients and 50 controls. A case-control association analysis was performed using the Golden Helix SVS suite. Results An association between 4 LOXL1 single-nucleotide polymorphisms with PEX syndrome and glaucoma was observed (rs16958477, P = 4.77 × 10 −6 [odds ratio, 0.50]; rs1048661, P = 4.28 × 10 −5 [1.79]; rs3825942, P = 4.68 × 10 −30 [9.19]; and rs2165241, P = 1.98 × 10 −15 [2.88]). Sequencing of 7 exons and regulatory regions of LOXL1 identified 11 additional sequence variants; only rs41435250 showed an association ( P = 3.80 × 10 −5 [0.49]) with PEX syndrome and glaucoma. Conclusions and Relevance Genetic variants in LOXL1 are associated with PEX syndrome and glaucoma in the South Indian population. To our knowledge, this is the first study to demonstrate the association of rs41435250 with PEX as well as reversal of the promoter risk allele. Understanding the role of the LOXL1 gene in PEX pathogenesis will facilitate early detection in individuals at risk for this condition.
20 citations
TL;DR: SNPs of the LOXL1 gene are associated with XFG in the Spanish population and this information adds new support to the distinct risk association frequencies of LO XL1 alleles with X FG in Western European and Asian populations.
Abstract: LOXL1 gene is the most important genetic risk factor known so far for pseudoexfoliation glaucoma (XFG). Our purpose was to evaluate the potential association of individual genetic variants of the lysyl oxidase-like 1 (LOXL1) gene and haplotypes with XFG in Spanish patients. Blood samples were collected from a total of 105 Spanish patients with XFG and 200 healthy controls. The entire LOXL1 gene along with the promoter, coding and non-coding regions including the 5´- and 3´-untranslated regions, were sequenced using next-generation sequencing in 99 XFG patients. SNPs rs16958477 (promoter), rs1048661 (exon 1), rs3825942 (exon 1), rs2165241 (intron 1) and rs3522 (exon 7) in LOXL1 were genotyped by restriction fragment-length polymorphism (RFLP) in all Spanish control participants and in six additional XFG patients, and a case–control association study was performed. Comparisons of the allelic and genotypic frequencies were performed using standard χ2 test with Bonferroni and Pearson corrections. Logistic regression analyses were permormed using Sigmaplot v11. Haplotypes frequencies were performed using HaploView 4.0. Sequencing of the LOXL1 gene in XFG participants identified a total of 212 SNPs, of which 49 exhibited allelic frequencies with significant differences between cases and controls, and 66 were not previously described. The allele frequencies of SNPs rs16958477, rs1048661, rs3825942, rs2165241, were significantly associated with an increased risk for XFG, however the SNP rs3522 was not. The haplotype frequencies of SNPs rs16958477, rs1048661, rs3825942 and rs2165241 and their association with XFG indicated that the CGGT haplotype, containing all four risk alleles, and the AGGT haplotype, which carries the protective allele of rs16958477 and three risk alleles of the other three SNPs, were significantly associated with XFG (p = 4.5×10−6, and p = 8.8×10−6), conferring more than 2-fold increased disease susceptibility. SNPs of the LOXL1 gene are associated with XFG in the Spanish population. This information adds new support to the distinct risk association frequencies of LOXL1 alleles with XFG in Western European and Asian populations. Identification and validation of additional SNPs along the entire LOXL1 gene of XFG cases may provide insightful information on their potential role in the pathogenesis of this disease.
17 citations
TL;DR: The results do not support LOXL1 as being a major risk gene for AD and evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found.
Abstract: Aggregation of amyloid-beta is one of the major characteristics in brains of patients with Alzheimer’s disease (AD). Although several mechanisms behind the formation of such aggregates have been suggested the regulatory factors are still unknown. The present study aimed at investigating the association of lysyl oxidase-like 1 (LOXL1) polymorphisms with AD diagnosis and cerebrospinal fluid biomarkers (CSF) for the disease. Proteins of the lysyl oxidase (LOX) family are involved in cross-linking extracellular matrix proteins to insoluble fibers and have been associated with neurodegenerative diseases including AD. Genetic polymorphisms in LOXL1 (rs1048661, rs3825942, and rs2165241) have been linked to exfoliation syndrome and exfoliation glaucoma, conditions that have shown association with AD. The polymorphisms were genotyped by Taqman allelic discrimination in a study sample including AD patients (n = 318) and controls (n = 575). In a subgroup of the population, the polymorphisms were analyzed in relation to APOE e4 genotype and to CSF (T-tau, P-tau, and Aβ1–42). No evidence for associations of these polymorphisms with risk for AD or any of the studied CSF biomarkers measured was found. These results do not support LOXL1 as being a major risk gene for AD.
17 citations
Cites methods from "Lysyl oxidase-like protein 1 (LOXL1..."
...…et al. 2008; Chen et al. 2009, 2010; Fan et al. 2008; Fuse et al. 2008; Hayashi et al. 2008; Lee et al. 2009; Lemmela et al. 2009; Mori et al. 2008; Mossbock et al. 2008; Ozaki et al. 2008; Pasutto et al. 2008; Ramprasad et al. 2008; Tanito et al. 2008; Thorleifsson et al. 2007; Williams et al.…...
[...]
...In the present study, analyses of patients with AD and healthy controls were performed for genotypes of three XFS/XFG-associated SNPs in LOXL1 (Aragon-Martin et al. 2008; Challa et al. 2008; Chen et al. 2009, 2010; Fan et al. 2008; Fuse et al. 2008; Hayashi et al. 2008; Lee et al. 2009; Lemmela et al. 2009; Mori et al. 2008; Mossbock et al. 2008; Ozaki et al. 2008; Pasutto et al. 2008; Ramprasad et al. 2008; Tanito et al. 2008; Thorleifsson et al. 2007; Williams et al. 2010; Yang et al. 2008)....
[...]
TL;DR: Overall, LURIC data confirmed that there is no major cardiovascular risk associated with CYP2C8 and CYP3C9 variants in a cardiovascular risk population of patients having undergone coronary angiography.
Abstract: Aims: As data on the cardiovascular risk associated with CYP2C8 and CYP2C9 polymorphisms is controversial, we performed a cross-sectional analysis of subjects enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Materials & methods: CYP2C8 and CYP2C9 genetic polymorphisms were determined with real-time PCR in 2827 patients. Based on angiography, 1052 of these patients had coronary artery disease (CAD) and 615 did not; 1160 patients had signs or a history of myocardial infarction (MI) in addition to CAD. The association of genotypes with CAD and MI was determined by logistic regression analysis, adjusted for age, sex, dyslipidemia, hypertension, diabetes mellitus and smoking status. Results: Frequencies of CYP2C8 and 2C9 variants were neither significantly different between CAD and control patients, nor between MI and control patients. Men carrying the CYP2C9*3 allele had an increased risk of MI (odds ratio [OR]: 1.67; 95% CI: 1.06–2.63; p = 0.03) and women carrying the CYP2C9*3 allel...
16 citations
TL;DR: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe.
Abstract: Purpose: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG).Materials and methods: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing.Results: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p = 3.36 × 10−5, OR = 5.71, 95% CI: 2.30–14.18; p = 3.38 × 10−5, OR = 6.91, 95% CI: 2.51–19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p = 2.50 × 10−4, OR = 2.18, 95% CI: 1.43–3.33; p = 1.21 × 10−2, OR = 2.13, 95% CI: 1.7...
15 citations
References
More filters
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
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]....
[...]
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]....
[...]
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]....
[...]
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]....
[...]