Major review: Exfoliation syndrome; advances in disease genetics, molecular biology, and epidemiology

Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets We focus on a 35-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression

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Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1

Purpose
To summarize various topics and the cutting edge approaches to refine XFS pathogenesis that were discussed at the 21st annual Glaucoma Foundation Think Tank meeting in New York City, Sept. 19–20, 2014.

Methods
The highlights of three categories of talks on cutting edge research in the field were summarized.

Results
Exfoliation syndrome (XFS) is a systemic disorder with a substantial ocular burden, including high rates of cataract, cataract surgery complications, glaucoma and retinal vein occlusion. New information about XFS is akin to puzzle pieces that do not quite join together to reveal a clear picture regarding how exfoliation material (XFM) forms.

Conclusion
Meeting participants concluded that it is unclear how the mild homocysteinemia seen in XFS might contribute to the disarrayed extracellular aggregates characteristic of this syndrome. Lysyl oxidase-like 1 (LOXL1) variants are unequivocally genetic risk factors for XFS but exactly how these variants contribute to the assembly of exfoliation material (XFM) remains unclear. Variants in a new genomic region, CACNA1A associated with XFS, may alter calcium concentrations at the cell surface and facilitate XFM formation but much more work is needed before we can place this new finding in proper context. It is hoped that various animal model and ex vivo systems will emerge that will allow for proper assembly of the puzzle pieces into a coherent picture of XFS pathogenesis. A clear understanding of XFS pathogenesis may lead to ‘upstream solutions’ to reduce the ocular morbidity produced by XFS.

Exfoliation syndrome: assembling the puzzle pieces

Pseudoexfoliation (PEX) is an age-related disorder of the extracellular matrix; it is strongly associated with glaucoma, the leading cause of irreversible blindness worldwide. We conducted an ethnic-based meta-analysis of the association of LOXL1 polymorphisms with PEX/pseudoexfoliative glaucoma (PEXG). Association studies were retrieved systematically from PubMed, EMBASE, and Web of Knowledge. Allelic and genotype frequencies of rs3825942, rs1048661, and rs2165241 were compared between PEX/PEXG and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model. Overall, 39 independent cohorts were included. Rs3825942 (G) was an at risk allele for PEX/PEXG in Caucasians, Japanese, Koreans, Chinese, South Asians, and Middle Easterners, but protective in Black South Africans (OR = 0.10, 95%CI:0.06-0.16). Rs1048661 (G) was an at risk allele for PEX/PEXG in Caucasians, South Asians, Middle Easterners and Black South Africans, but was protective in Japanese (OR = 0.03, 95%CI:0.02-0.06) and Koreans (OR = 0.10, 95%CI:0.05-0.22). These associations we-re confirmed for the genotypic recessive models. Rs2165241 (C) was a protective allele for PEX/PEXG in Caucasians, but was an at risk allele in Japanese (OR = 7.49, 95%CI:3.22-17.41) and Koreans (OR = 6.63, 95%CI:2.60-16.90). This was confirmed for the genotypic dominant model. Other genetic and/or environmental factors may modify the effect of LOXL1 polymorphisms in certain ethnic groups.

Ethnicity‐Based Differences in the Association of LOXL1 Polymorphisms with Pseudoexfoliation/Pseudoexfoliative Glaucoma: A Meta‐Analysis

Lysyl Oxidase Like 1: Biological roles and regulation.

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.

ping liu

Papers

LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta-Analysis.