Our previous data suggested that three single-nucleotide polymorphisms (SNPs), rs1048661, rs3825942, and rs2165241, of the lysyl oxidase-like 1 gene (<i>LOXL1</i>) are significantly associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG).
The two nonsynonymous single-nucleotide polymorphisms rs1048661 (R141L) and rs3825942 (rs3825942" genes_norm="4016">G153D) within exon 1 of LOXL1 gene have been found to confer risk of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in different geographical populations.
It covers the known genetic associations at the LOXL1 locus, potential mechanisms of gene regulation, implications of LOXL1 in XFS-associated fibrosis and connective tissue homeostasis, its role in the development of glaucoma and associated systemic diseases, and the currently available LOXL1-based in vivo and in vitro models.
In contrast, in nearly all tissues of the posterior segment, XFM seems to be absent and differential gene expression is confined to the lamina cribrosa, characterized by a stage-independent, primary, and XFS-specific downregulation of LOXL1 and elastic components in XFS eyes.
In addition to the discovery of lysyl oxidase-like 1, further genetic associations have been identified and knowledge related to XFS etiology and pathophysiology has markedly increased over the past 10 years.
The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model.
While questions remain regarding how LOXL1 gene variants contribute to XFS pathogenesis, it is clear that the frequencies of disease-related alleles do not track with the varying disease burden throughout the world, prompting a search for environmental risk factors.
Genome-wide association studies have identified robust genetic associations with LOXL1, CACNA1A, and 5 additional genes including POMP and TMEM136, which provide new biological insights into the pathology of XFS and highlight a role for abnormal matrix cross-linking processes, Ca channel deficiency, blood-aqueous barrier dysfunction, and abnormal ubiquitin-proteasome signaling in XFS pathophysiology.
These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
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.
The results suggested that the LOXL1 variants, which are well-established markers for EX, are not likely genetic markers for CRVO in Japanese subjects.
At the very least, the discovery of the association between LOXL1 variants and XFS has opened the door to the discovery of environmental risk factors for this condition.
LOXL1 variants are highly associated with XFS in most populations; however, the high frequency of risk alleles in normal individuals and the reversal of risk alleles in different ethnic populations suggest that other factors contribute to XFS pathogenesis.