Novel common variants and susceptible haplotype for exfoliation glaucoma specific to Asian population

Abstract

The common variants in lysyl oxidase-like 1 gene (LOXL1) are associated with exfoliation glaucoma (XFG) patients developed through exfoliation syndrome (XFS). However, the risk allele of a variant in LOXL1 has been found to be inverted between Asian and Caucasian populations. Therefore, we newly performed a genome-wide association study using 201 XFS/XFG and 697 controls in Japanese, and identified 34 genome-wide significant single-nucleotide polymorphisms (SNPs) distributing in not only LOXL1 but also TBC1D21 and PML at the 15q24.1 locus. These SNPs were confirmed by an independent population consisted of 121 XFS/XFG and 263 controls in Japanese. Moreover, further analyses revealed a unique haplotype structure only from the combination of TBC1D21 and LOXL1 variants showing a high XFS/XFG susceptibility specific for the Asian population. Although there still should be other gene(s) in the other region(s) contributing to the disease process, these results suggested that the combination of newly discovered variants in these genes might be useful for precise XFG risk assessment, as well as for elucidating the molecular mechanism of XFG pathogenesis through XFS.

Recent advances in risk factors associated with ocular exfoliation syndrome

“…Research on the genetic risk factors for XFS is an area of intense research, and other susceptibility loci and SNPs have been identified in association with this syndrome in certain populations (Krumbiegel et al 2011;Wiggs et al 2012;Nakano et al 2014;Zagajewska et al 2018;Ma et al 2019). Genomewide association study (GWASs) and next-generation sequencing technologies have been used to elucidate potential genetic causal variants underlying XFS, which could help better understanding the disease mechanism and provide specific treatment approaches (Schl€ otzer-Schrehardt 2018).…”

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

“…Realizing that large and inclusive international collaborative efforts are essential in providing new biological leads in complex disease pathogenesis [15][16][17][18][19][20] , we report here a world-wide collaborative XFS study aimed at further understanding the genetic basis of the disorder. Firstly, due to the allele reversals seen at LOXL1 common polymorphisms led by rs3825942 G>A (p.153Gly>Asp) and to a lesser extent, rs1048661 T>G (p.141Leu>Arg) 12,[21][22][23][24][25][26][27][28] (Supplementary Figure 1), we aimed to refine the LOXL1 genetic landscape by performing deep sequencing of the entire gene in 5,570 XFS and XFG cases and 6,279 controls from 9 countries (Supplementary Table 1). The previously reported CACNA1A locus was also sequenced to assess if rare non-synonymous amino acid substitutions within the gene could provide further insights [29][30][31] .…”

Advances in Vision Research, Volume I

“…LOXL1 codes for an enzyme that is essential for the formation, maintenance, and remodeling of elastic fibers and prevents age-related loss of tissue elasticity. The association of LOXL1 with XFS has been confirmed in populations from throughout the world including Asian populations of Chinese, Indian, and Japanese [186][187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205]. The association of LOXL1 with XFS has been confirmed in populations from throughout the world including Asian populations of Chinese, Indian, and Japanese [186][187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205].…”