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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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Journal Article
TL;DR: Polymorphisms in LOXL1 confer risk to XFS/XFG in the Chinese, and the lower incidence of XFS compared to other populations suggests additional genetic or environmental factors to have a major influence on the phenotypic expression of X FS in theChinese.
Abstract: Purpose Single nucleotide polymorphisms (SNPs) within the lysyl oxidase like-1 gene (LOXL1; rs1048661 and rs3825942) were found to confer risk to pseudoexfoliation glaucoma (XFG) through the pseudoexfoliation syndrome (XFS) in Nordic, Caucasian, and two Asiatic populations (Indian and Japanese). The prevalence (0.2%–0.7%) of XFS in the Chinese is considerably lower compared to Nordic populations. The aim of this study was to determine the association of LOXL1 in Chinese subjects with XFS/XFG.

50 citations


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

  • ...The haplotype formed by protective alleles (T-A) was also not observed in the Chinese case-control groups, similar to data from other Asian populations (Indian and Japanese) as well as Scandinavian and Caucasian populations [19-30]....

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  • ...Subsequent studies replicated the association of LOXL1 SNPs with XFS/XFG in different populations including Caucasians, Germans, Italians, Central Europeans, Indians, and Japanese [20-30]....

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Journal ArticleDOI
TL;DR: At present there are no known medical indications that infer an increased systemic vascular risk or imply a need for the complete internal medical examination of a symptom‐free patient with newly diagnosed ES in the eye, and further large‐scale, randomized clinical studies are required.
Abstract: Exfoliation syndrome (ES) is an age-related disorder in which greyish-white flakes accumulate in different tissues in the anterior eye. Its pathogenesis is not completely known, but it results in electron-dense microfibrils. The finding that these can be seen outside the eye in many visceral organs inspired the theory that ES might be a part of a generalized disorder. It was postulated that ES might contribute to increased morbidity, mainly of systemic vascular diseases. This review is a summary of the existing knowledge. The prevalence of arterial hypertension (AHT) in elderly populations is > 30%. No differences have been found in the frequency of AHT among patients with ES or exfoliative glaucoma (EG) compared with those with primary open-angle glaucoma (POAG) or no ES. There are conflicting reports of frequencies of ischaemic heart disease (IHD). A recent registry-based study that used uniform criteria for IHD found no difference in the rate of IHD between patients with EG and those with POAG. However, findings of elevated homocysteine levels in the plasma and aqueous humour of patients with ES or EG suggest an increased vascular risk. No studies have yet been conducted to assess possible links between ES and systemic vascular diseases. In a single-blind study, ES was associated with abdominal aortic aneurysm, but this was not found in a large, cross-sectional investigation. The frequency of ES in patients with diabetes mellitus (DM) is only about half of that when compared in patients with no ES or with POAG. This finding warrants further studies. Molecular genetics research has found no common denominator for ES and the vascular diseases. There is no evidence that ES or EG are related to increased mortality for cardiovascular diseases. Further large-scale, randomized clinical studies are required. At present there are no known medical indications that infer an increased systemic vascular risk or imply a need for the complete internal medical examination of a symptom-free patient with newly diagnosed ES in the eye.

48 citations


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

  • ...A large, prospective population study carried out in Greece in subjects aged 20–86 years found that 40.2% of men and 38.9% of women had AHT (Psaltopoulou et al. 2004)....

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Journal ArticleDOI
TL;DR: It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance the understanding of neuropsychiatric genetics.
Abstract: Hundreds of genome-wide association studies have been performed in recent years in order to try to identify common variants that associate with complex disease These have met with varying success Some of the strongest effects of common variants have been found in late-onset diseases and in drug response The major histocompatibility complex has also shown very strong association with a variety of disorders Although there have been some notable success stories in neuropsychiatric genetics, on the whole, common variation has explained little of the high heritability of these traits In contrast, early studies of rare copy number variants have led rapidly to a number of genes and loci that strongly associate with neuropsychiatric disorders It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance our understanding of neuropsychiatric genetics

41 citations

Journal Article
TL;DR: The “G” allele of both rs1048661 and rs3825942 SNPs were associated with the risk of PEG in the Saudi Arab population, similar to almost all non-African populations tested thus far.
Abstract: Purpose: To investigate whether single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene are associated with pseudoexfoliation glaucoma (PEG) in the Saudi Arabian population. Methods: The coding regions of LOXL1 were fully sequenced in 93 clinically diagnosed PEG patients and 101 healthy controls. Both groups were Saudi Arabs. Previously reported and newly identified SNPs were evaluated for possible association with PEG and their pathological consequences on the gene were assessed. Results: The “G” allele frequencies of both rs1048661 and rs3825942 SNPs differed between PEG patients and control subjects from Saudi Arabia (p=0.0056 and p=0.000005, respectively). This significance remained after applying the Bonferroni correction. Two non-synonymous novel SNPs in LOXL1 were detected in the PEG patients and not in the controls. One of these SNPs was in exon 4 (g.25722 C>G; codon change D484E) of LOXL1 and was predicted to be nonpathological; the other was in exon 6 of LOXL1 (g.28084 T>G; codon change Y559D) and was predicted to be probably damaging. All alleles of SNPs (rs28706550, rs35203737, rs41429348, rs12906373, rs41435250, and rs13329473) were monoallelic in this population. No allele frequency difference for rs8818 and rs3522 SNP between patients and controls (p values were 0.126 and 0.994 respectively). Conclusions: Similar to almost all non-African populations tested thus far, the “G” allele of both rs1048661 and rs3825942 SNPs were associated with the risk of PEG in the Saudi Arab population. Pseudoexfoliation syndrome (XFS) is characterized by deposits of grayish-white material seen primarily in the anterior segment of the eye. The deposits are primarily found along the pupillary border and often produce a characteristic pattern on the anterior lens surface [1]. XFS is frequently associated with pseudoexfoliation glaucoma (PEG), which often has a more aggressive clinical course and worse prognosis than the more common primary open angle glaucoma (POAG) [2]. The incidence of PEG in XFS patients varies and seems highest among individuals with Scandinavian and Northern European ancestry and lower among African Americans and in West Africa [3-5]. The prevalence of PEG in Saudi Arabia is unknown. The Glaucoma unit at King Abdulaziz University Hospital (where most PEG patients were recruited for this study) sees around 600 new glaucoma patients every year, and about 10% of those are PEG.

38 citations


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

  • ...The “G” allele frequency of 0.876 observed in Saudi Arabian PEG patients was comparable to the rate observed in Icelandic (0.781), Swedish (0.834), Americans (0.819), Austrians (0.841), Germans (0.818), Italians (0.825), Finnish (0.825), and South Africans (0.990) [17]....

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  • ...The significant association of the “G” allele of SNP rs1048661 with PEG in the Saudi Arab population mirrors the rate observed in the Icelandic, Swedish, American, Australian, Austrian, German, Italian, Finnish, Japanese, and South African populations and differ from that observed in the Indian [14] and Chinese [15] populations (Table 5)....

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  • ...The association of LOXL1 SNPs (in particular rs1048661 and rs3825942) with XFS/PEG has now been studied in Caucasian populations in the USA [8], Australia [9], Austria [10], Germany [11], Italy [12], and Finland and in other ethnic groups, including Japanese [13], Indian [14], Chinese [15], and recently black South Africans [16]....

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Journal ArticleDOI
TL;DR: It is revealed that in the German population the LOXL1 genetic predisposition is limited to exfoliation glaucoma and does not include normal tension glauca, and that 1 nonsynonymous polymorphism may serve as a predictor of age at disease onset in pigmentary glau coma.
Abstract: PURPOSE To evaluate the association between lysyl-oxidase-like 1 (LOXL1) gene polymorphisms and exfoliation glaucoma, pigmentary glaucoma and normal tension glaucoma in a case-control cohort of German patients. METHODS Six single nucleotide polymorphisms in a 22 kb genomic region encompassing the LOXL1 gene plus an additional "outlier" single nucleotide polymorphism located approximately 1.1 Mb upstream of LOXL1 were genotyped in 128 exfoliation glaucoma patients, 88 pigmentary glaucoma patients, 273 normal tension glaucoma patients, and 280 healthy control subjects either with TaqMan allelic discrimination assays or by direct sequencing, and a genetic association study was performed. RESULTS For the exfoliation glaucoma cases, case-control allelic association for 6 single nucleotide polymorphisms were highly significant. In contrast, there were no genotypic differences between pigmentary glaucoma cases, normal tension glaucoma cases and controls. However, an association between rs1048661 genotype and age at disease onset was suggested for pigmentary glaucoma patients. CONCLUSIONS Our study reveals that in the German population the LOXL1 genetic predisposition is limited to exfoliation glaucoma and does not include normal tension glaucoma. In addition, our study implicates that LOXL1 polymorphisms are not likely to have a major influence on the pathophysiology of pigmentary glaucoma. However, 1 nonsynonymous polymorphism may serve as a predictor of age at disease onset in pigmentary glaucoma.

36 citations

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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