Genetics of Exfoliation Syndrome and Glaucoma

Abstract

Exfoliation glaucoma (XFG) is the most common identifiable secondary form of open-angle glaucoma in the world. It is an ocular manifestation of exfoliation syndrome (XFS), an age-related systemic disease characterized by deposition of extracellular fibrillar material in various tissues and organs. XFS/XFG has been studied in populations around the world, which has led to identification of genetic factors that play a significant role in disease pathogenesis. Here, we summarize current knowledge of the genetics of XFS/XFG and identify areas for future research.

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

“…Still, these hypotheses require further research both taken together and individually and in different populations. For example, XFS/XFG has not been detected in Greenlandic Inuit populations, but this can be attributed to narrow lid fissures and thick irises which protect them from ocular UV radiation and, therefore, an environmental-genetic cascade of disease [ 10 , 11 , 189 ].…”

“…In most populations of ED, including Swedish/Icelandic, US Caucasian, Australian, and European populations, rs3825942 (Gly153Asp) is strongly associated with risk for XFS/XFG, as well as for all other populations studied except for South Africans, where the risk allele is reversed [ 171 ]. Meanwhile, rs1048661 has not been associated with XFG risk in Greek and Polish populations [ 11 ]. In a US Caucasian population, LOXL1 promoter region SNPs have also been associated with XFS/XFG [ 193 ].…”

“…Importantly, glaucoma may be classified in different specific subtypes with different pathophysiologic mechanisms, including primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and secondary exfoliation glaucoma (XFG), which have all been shown in the literature to be more prevalent in populations of different races [ 8 , 9 , 10 , 11 ]. Specifically, POAG, which is characterized by increased resistance to aqueous fluid outflow through the trabecular meshwork, has been shown to be more prevalent, to present earlier, and to be more severe in patients of African descent (AD) than patients of European descent (ED).…”

Recent advances in risk factors associated with ocular exfoliation syndrome

“…). Additionally, recombinantly expressed LOXL1, with those specific variants, has been shown to still have amine oxidase activity (Kim & Kim ), implying that a more complex mechanism involving non‐native LOXL1 could be crucial to XFS and XFG pathogenesis (Aboobakar & Allingham ; Aung et al. ).…”

“…Since then several studies have verified the association of genetic variants of LOXL1 with XFS in different populations; however, risk allele for LOXL1 SNP rs3825942 which was consistently reported to be G allele has been found to be the opposite allele (A allele) in the South African black population (Williams et al 2010). Additionally, recombinantly expressed LOXL1, with those specific variants, has been shown to still have amine oxidase activity (Kim & Kim 2012), implying that a more complex mechanism involving non-native LOXL1 could be crucial to XFS and XFG pathogenesis (Aboobakar & Allingham 2014;Aung et al 2015). It is also thought that dysregulations in the expression of this gene could be a contributing factor for XFS development (Zenkel & Schl€ otzer-Schrehardt 2014).…”