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Yoko Ikeda, Masakazu Nakano, Kazuhiko Mori, Morio Ueno, Kojiro Imai, Natue Omi, Yuichi Tokuda, Hiroko Adachi, Kei Tashiro, Shigeru Kinoshita; New susceptible genetic variants of exfoliation syndrome/exfoliation glaucoma in a Japanese population . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3680.
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© ARVO (1962-2015); The Authors (2016-present)
Exfoliation glaucoma (XFG) is clinically characterized by a large fluctuation of intraocular pressure, and it is often hard to treat due to its difficult clinical course. The common variants in lysyl oxidase-like 1 gene (LOXL1) at chromosome 15q24.1 are well known to be associated with XFG patients arising from exfoliation syndrome [XFS (MIM 177650)]. However, LOXL1 alone does not appear to sufficiently explain the molecular mechanism of XFG pathogenesis. Moreover, the risk allele of a variant (rs1048661) in exon 1 of LOXL1 has been found to be inverted between Asian and Caucasian populations, suggesting that the variants in other genes should also be contributing to the genetic heritability of XFS/XFG. Therefore, we recently conducted a genome-wide association study (GWAS) using a Japanese population in an attempt to discover genetic markers for XFS/XFG.
We conducted a discovery GWAS using Japanese subjects, and analyzed 652,792 autosomal common single-nucleotide polymorphisms (SNPs) in 201 XFS/XFG patients and 697 controls. We then replicated the results of the GWAS using an independent population that consisted of 121 XFS/XFG patients and 263 controls. We also performed a conditional analysis to analyze the combinational effect of the variants identified from the different genes. Finally, we confirmed the expression of the identified genes in human ocular tissues.
The results of the GWAS identified 34 genome-wide significant SNPs (p = 5.56 × 10-8 - 3.46 × 10-54) as a cluster only from chromosome 15q24.1. However, the significant SNPs were distributed in not only LOXL1 but also in TBC1D21 and PML, two other adjacent genes in the locus. The significance of these SNPs was confirmed by replication analysis. We also identified a suggested association between the variants of TBC1D21 and LOXL1 by conditional analysis. Both TBC1D21 and PML were expressed in the human retina and anterior capsule.
We successfully identified novel variants associated with XFS/XFG. The results suggested that the combination of newly discovered variants in<br /> these genes would be useful for precise XFG risk assessment, especially in the Asian population, as well as for elucidating the molecular mechanism of XFG pathogenesis<br /> through XFS.
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