TY - JOUR
T1 - Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus
AU - Hauser, Michael A.
AU - Aboobakar, Inas F.
AU - Liu, Yutao
AU - Miura, Shiroh
AU - Whigham, Benjamin T.
AU - Challa, Pratap
AU - Wheeler, Joshua
AU - Williams, Andrew
AU - Santiago-Turla, Cecelia
AU - Qin, Xuejun
AU - Rautenbach, Robyn M.
AU - Ziskind, Ari
AU - Ramsay, Michële
AU - Uebe, Steffen
AU - Song, Lingyun
AU - Safi, Alexias
AU - Vithana, Eranga N.
AU - Mizoguchi, Takanori
AU - Nakano, Satoko
AU - Kubota, Toshiaki
AU - Hayashi, Ken
AU - Manabe, Shin Ichi
AU - Kazama, Shigeyasu
AU - Mori, Yosai
AU - Miyata, Kazunori
AU - Yoshimura, Nagahisa
AU - Reis, Andre
AU - Crawford, Gregory E.
AU - Pasutto, Francesca
AU - Carmichael, Trevor R.
AU - Susan, Susan E.
AU - Ozaki, Mineo
AU - Aung, Tin
AU - Khor, Chiea Chuen
AU - Stamer, W. Daniel
AU - Ashley-Koch, Allison E.
AU - Allingham, R. Rand
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (~40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a welldefined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1.We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1.We showthat this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.
AB - Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (~40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a welldefined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1.We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1.We showthat this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.
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U2 - 10.1093/hmg/ddv347
DO - 10.1093/hmg/ddv347
M3 - Article
C2 - 26307087
AN - SCOPUS:84949057843
SN - 0964-6906
VL - 24
SP - 6552
EP - 6563
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -