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Jibril Hirbo, Francesca Pasutto, Julia Sealock, Patrick Evans, Priyanka Pawar, Ran Tao, Peter Straub, Max Breyer, Daniel Berner, Andre Reis, Ursula Schlötzer-Schrehardt, CC Khor, Eric Gamazon, Milam A Brantley, Karen M Joos, Nancy Cox; Analysis of genetically determined gene expression suggest role of inflammatory processes in etiology of exfoliation syndrome. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1255.
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© ARVO (1962-2015); The Authors (2016-present)
Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestation. It is the most common cause of secondary glaucoma resulting in widespread global blindness. Global multi-ethnic genome-wide association (GWAS) summary data of XFS in 123,457 individuals identified 7 loci with strongest signal in chromosome 15 involving 54 potentially causal variants near LOXL1 gene. While the biological importance of the coding mutations on LOXL1 were elucidated, the mechanisms underlying associations with non-coding variants are not clear. The non-coding variants might play a regulatory role, thus we hypothesized that the correlation of genetically determined components of gene expression with XFS may provide a powerful method to identify additional genes involved in the etiology of the XFS.
We applied S-PrediXcan using models trained on 48 GTEx tissues to estimate the correlation of genetically determined gene expression with XFS risk by leveraging multi-ethnic GWAS summary statistics. We then analyzed GWAS data from 13,202 individuals from 4 European ancestry populations conditioning on predicted gene expressions of strongest association signals. We did enrichment analysis of the XFS associated genes. We further performed functional validation in diseased and normal human iris tissues of the top prioritized genes. Finally, we explored other health consequences of high genetic risk to XFS in a large electronic health record.
A total of 28 genes on chr15 showed statistically significant associations. Conditional analysis in European dataset confirmed association with 6 genes, all of which are expressed in eye tissues. All transcript levels decreased in iris tissues derived from XFS patients compared to control samples, with significant differences for NEO1, CD276, LOXL1, UBL7, ARID3B and SCAMP2. Genes that show predicted changes in expression in XFS are enriched for genes associated with inflammatory conditions. We also observed higher incidence of XFS comorbidity with inflammatory and connective tissue diseases.
Our results further confirm the role of connective tissues and suggest inflammation in etiology of XFS. Perhaps inflammation control may be a potential therapeutic option to reduce progression in XFS.
This is a 2020 ARVO Annual Meeting abstract.
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