The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.
Aged
Aged, 80 and over
Amino Acid Oxidoreductases
/ genetics
Cells, Cultured
Ethnicity
/ genetics
Exfoliation Syndrome
/ enzymology
Gene Expression Regulation
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Membrane Proteins
/ genetics
Middle Aged
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Sequence Analysis, DNA
Signal Transduction
Tretinoin
/ metabolism
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
13
12
2018
revised:
29
03
2019
accepted:
01
04
2019
pubmed:
16
4
2019
medline:
1
9
2021
entrez:
16
4
2019
Statut:
ppublish
Résumé
LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
Identifiants
pubmed: 30986821
pii: 5464630
doi: 10.1093/hmg/ddz075
pmc: PMC6644155
doi:
Substances chimiques
Membrane Proteins
0
STRA6 protein, human
0
Tretinoin
5688UTC01R
Amino Acid Oxidoreductases
EC 1.4.-
LOXL1 protein, human
EC 1.4.3.-
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2531-2548Subventions
Organisme : NEI NIH HHS
ID : P30 EY014104
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY020928
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press.
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