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Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Publication ,  Journal Article
Hauser, MA; Aboobakar, IF; Liu, Y; Miura, S; Whigham, BT; Challa, P; Wheeler, J; Williams, A; Santiago-Turla, C; Qin, X; Rautenbach, RM ...
Published in: Hum Mol Genet
November 15, 2015

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 well-defined 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 show that 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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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 15, 2015

Volume

24

Issue

22

Start / End Page

6552 / 6563

Location

England

Related Subject Headings

  • RNA, Long Noncoding
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Oxidative Stress
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Gene Frequency
  • Gene Expression
 

Citation

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Hauser, M. A., Aboobakar, I. F., Liu, Y., Miura, S., Whigham, B. T., Challa, P., … Allingham, R. R. (2015). Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum Mol Genet, 24(22), 6552–6563. https://doi.org/10.1093/hmg/ddv347
Hauser, Michael A., Inas F. Aboobakar, Yutao Liu, Shiroh Miura, Benjamin T. Whigham, Pratap Challa, Joshua Wheeler, et al. “Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.Hum Mol Genet 24, no. 22 (November 15, 2015): 6552–63. https://doi.org/10.1093/hmg/ddv347.
Hauser MA, Aboobakar IF, Liu Y, Miura S, Whigham BT, Challa P, et al. Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum Mol Genet. 2015 Nov 15;24(22):6552–63.
Hauser, Michael A., et al. “Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.Hum Mol Genet, vol. 24, no. 22, Nov. 2015, pp. 6552–63. Pubmed, doi:10.1093/hmg/ddv347.
Hauser MA, Aboobakar IF, Liu Y, Miura S, Whigham BT, Challa P, Wheeler J, Williams A, Santiago-Turla C, Qin X, Rautenbach RM, Ziskind A, Ramsay M, Uebe S, Song L, Safi A, Vithana EN, Mizoguchi T, Nakano S, Kubota T, Hayashi K, Manabe S-I, Kazama S, Mori Y, Miyata K, Yoshimura N, Reis A, Crawford GE, Pasutto F, Carmichael TR, Williams SEI, Ozaki M, Aung T, Khor C-C, Stamer WD, Ashley-Koch AE, Allingham RR. Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum Mol Genet. 2015 Nov 15;24(22):6552–6563.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 15, 2015

Volume

24

Issue

22

Start / End Page

6552 / 6563

Location

England

Related Subject Headings

  • RNA, Long Noncoding
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Oxidative Stress
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Gene Frequency
  • Gene Expression