July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Targeted assessment of the chromosome 15 locus identifies a potential protective role for ISLR coding variants in exfoliation syndrome.
Author Affiliations & Notes
  • Mineo Ozaki
    Ophthalmology, Ozaki Eye Hosp, Hyuga, MIYAZAKI, Japan
    Ophthalmology, Faculty of Medicine University of Miyazaki, Miyazaki, Miyazaki, Japan
  • Takanori Mizoguchi
    Ophthalmology, Mizoguchi Eye Hospital, Japan
  • Satoko Nakano
    Ophthalmology, Oita University Faculty of Medicine, Japan
  • Shinichi Manabe
    Ophthalmology, Hayashi Eye Hospital, Japan
  • Kazuhiko Mori
    Ophthalmology, Kyoto Prefectural University of Medicine., Japan
  • Kazunori Miyata
    Ophthalmology, Miyata Eye Hospital, Japan
  • Etsuo Chihara
    Ophthalmology, Sensho-kai Eye Institute, Japan
  • Satoshi Ishiko
    Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Japan
  • Kenji Inoue
    Ophthalmology, Inouye Eye Hospital, Japan
  • Yoshiaki Kiuchi
    Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Japan
  • Masaru Inatani
    Ophthalmology, Faculty of Medical Science, University of Fukui, Japan
  • Kazuhisa Sugiyama
    Ophthalmology & Visual Science, Kanazawa University Graduate School of Medical Science, Japan
  • Toshiaki Kubota
    Ophthalmology, Oita University Faculty of Medicine, Japan
  • Tin Aung
    Singapore Eye Research Institute, Singapore
  • Chiea Chuen Khor
    Genome Institute of Singapore, Singapore
  • Footnotes
    Commercial Relationships   Mineo Ozaki, None; Takanori Mizoguchi, None; Satoko Nakano, None; Shinichi Manabe, None; Kazuhiko Mori, None; Kazunori Miyata, None; Etsuo Chihara, None; Satoshi Ishiko, None; Kenji Inoue, None; Yoshiaki Kiuchi, None; Masaru Inatani, None; Kazuhisa Sugiyama, None; Toshiaki Kubota, None; Tin Aung, None; Chiea Chuen Khor, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2815. doi:
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      Mineo Ozaki, Takanori Mizoguchi, Satoko Nakano, Shinichi Manabe, Kazuhiko Mori, Kazunori Miyata, Etsuo Chihara, Satoshi Ishiko, Kenji Inoue, Yoshiaki Kiuchi, Masaru Inatani, Kazuhisa Sugiyama, Toshiaki Kubota, Tin Aung, Chiea Chuen Khor; Targeted assessment of the chromosome 15 locus identifies a potential protective role for ISLR coding variants in exfoliation syndrome.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2815.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Common genetic polymorphisms within the chromosome 15 locus (where LOXL1 resides) show the strongest evidence of association to date with exfoliation syndrome. However, the signal for genetic association spans >1,000,000 base-pairs and >50 genes, making localization of the causative genes challenging. We hypothesize that apart from LOXL1, there could be other genes within the locus harboring strong association independent of the classical LOXL1 rs3825942 G>A variant.

Methods : We performed whole exome resequencing in 1,000 XFS cases and 1,000 controls from Japan. With this data, we created a reference panel for imputation of low frequency (defined as frequency <5%) coding changes into existing genome-wide association data for 3,000 XFS cases and 3,000 controls, also from Japan. All successfully imputed coding variants passing stringent quality checks were analyzed for association with XFS disease status using logistic regression.

Results : Apart from confirming strong association at LOXL1 rs3825942 and the previously reported protective rare variant (LOXL1 p. Y407F; P<5x10-8 for both), we detected significant association at ISLR p. F142L. This amino acid substitution was found at 0.66% in XFS cases and 2% in controls (Odds Ratio = 0.32, P = 8.4x10-11). This association with ISLR p. F142L remained significant even after adjusting for the classical LOXL1 p. G153D (rs3825942) (OR conditioned = 0.32, P = 4.9 x 10-12) as well as locus-wide conditioning on LOXL1 p.G153D, LOXL1 p. Y407F, LOXL1 p. I516V, as well as LOXL1 rs2165241 )(OR conditioned = 0.36, P = 1.95x 10-8)

Conclusions : Our results suggests that within the chromosome 15 locus, both LOXL1 and ISLR may contribute independent protective effects against XFS in Japanese. Our data provides further biological insights into the XFS disease process, and further improves the genetic resolution within the chromosome 15 locus.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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