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Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1.
Nat. Commun. 8:15466 (2017)
Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Lysyl Oxidase-like; Single Nucleotide Polymorphism; Abdominal Aortic-aneurysms; Common Sequence Variants; Genome-wide Association; Pelvic Organ Prolapse; Messenger-rna Decay; Exfoliation Syndrome; Risk Allele; Glaucoma
ISSN (print) / ISBN
2041-1723
e-ISSN
2041-1723
Journal
Nature Communications
Quellenangaben
Volume: 8,
Article Number: 15466
Publisher
Nature Publishing Group
Publishing Place
London
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Epidemiology II (EPI2)