title: Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.
abstract: 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.
authors: Department of Medicine, Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA, Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore, Duke, National University of Singapore, Singapore, Singapore, mike.hauser@duke.edu.
authors: Michael A
authors: MA
authors: Hauser
authors: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
authors: Inas F
authors: IF
authors: Aboobakar
authors: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
authors: Yutao
authors: Y
authors: Liu
authors: Department of Medicine.
authors: Shiroh
authors: S
authors: Miura
authors: Department of Medicine.
authors: Benjamin T
authors: BT
authors: Whigham
authors: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
authors: Pratap
authors: P
authors: Challa
authors: Department of Medicine.
authors: Joshua
authors: J
authors: Wheeler
authors: Michigan State University College of Human Medicine, Grand Rapids, MI, USA.
authors: Andrew
authors: A
authors: Williams
authors: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
authors: Cecelia
authors: C
authors: Santiago-Turla
authors: Department of Medicine.
authors: Xuejun
authors: X
authors: Qin
authors: Division of Ophthalmology, Department of Surgical Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors: Robyn M
authors: RM
authors: Rautenbach
authors: Division of Ophthalmology, Department of Surgical Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors: Ari
authors: A
authors: Ziskind
authors: Division of Human Genetics, NHLS and School of Pathology and Sydney Brenner Institute for Molecular Bioscience, University of Witwatersrand, Johannesburg, South Africa.
authors: Michèle
authors: M
authors: Ramsay
authors: Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Steffen
authors: S
authors: Uebe
authors: Center for Genomic and Computational Biology and Department of Pediatrics, Duke University, Durham, NC, USA.
authors: Lingyun
authors: L
authors: Song
authors: Center for Genomic and Computational Biology and Department of Pediatrics, Duke University, Durham, NC, USA.
authors: Alexias
authors: A
authors: Safi
authors: Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore.
authors: Eranga N
authors: EN
authors: Vithana
authors: Mizoguchi Eye Hospital, 6-13 Tawara-machi, Sasebo, Nagasaki 857-0016, Japan.
authors: Takanori
authors: T
authors: Mizoguchi
authors: Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.
authors: Satoko
authors: S
authors: Nakano
authors: Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.
authors: Toshiaki
authors: T
authors: Kubota
authors: Hayashi Eye Hospital, 23-35, Hakataekimae-4, Hakata-ku, Fukuoka, Japan.
authors: Ken
authors: K
authors: Hayashi
authors: Hayashi Eye Hospital, 23-35, Hakataekimae-4, Hakata-ku, Fukuoka, Japan.
authors: Shin-ichi
authors: S
authors: Manabe
authors: Shinjo Eye Clinic, 889-1, Mego, Simokitakatamachi, Miyazaki-shi, Miyazaki 880-0035, Japan.
authors: Shigeyasu
authors: S
authors: Kazama
authors: Miyata Eye Hospital, 6-3, Kurahara, Miyakonojo, Miyazaki 885-0051, Japan.
authors: Yosai
authors: Y
authors: Mori
authors: Miyata Eye Hospital, 6-3, Kurahara, Miyakonojo, Miyazaki 885-0051, Japan, University of Miyazaki, Miyazaki, Japan.
authors: Kazunori
authors: K
authors: Miyata
authors: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Nagahisa
authors: N
authors: Yoshimura
authors: Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Andre
authors: A
authors: Reis
authors: Center for Genomic and Computational Biology and Department of Pediatrics, Duke University, Durham, NC, USA.
authors: Gregory E
authors: GE
authors: Crawford
authors: Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors: Francesca
authors: F
authors: Pasutto
authors: Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa and.
authors: Trevor R
authors: TR
authors: Carmichael
authors: Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa and.
authors: Susan E I
authors: SE
authors: Williams
authors: Ozaki Eye Hospital, 1-15, Kamezaki, Hyuga, Miyazaki 883-0066, Japan.
authors: Mineo
authors: M
authors: Ozaki
authors: Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore.
authors: Tin
authors: T
authors: Aung
authors: Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore.
authors: Chiea-Chuen
authors: CC
authors: Khor
authors: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
authors: W Daniel
authors: WD
authors: Stamer
authors: Department of Medicine.
authors: Allison E
authors: AE
authors: Ashley-Koch
authors: Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA, Singapore Eye Research Institute, Singapore National Eye Center, Singapore, Singapore, Duke, National University of Singapore, Singapore, Singapore.
authors: R Rand
authors: RR
authors: Allingham
mesh_terms: D000368:Aged; D000483:Alleles; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D016022:Case-Control Studies; D017889:Exfoliation Syndrome / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D062085:RNA, Long Noncoding; D000594:Amino Acid Oxidoreductases; C445313:LOXL1 protein, human