Contributors: Pasutto, F.; Zenkel, M.; Hoja, U.; Berner, D.; Uebe, S.; Ferrazzi, F.; Schodel, J.; Liravi, P.; Ozaki, M.; Paoli, D.; Frezzotti, P.; Mizoguchi, T.; Nakano, S.; Kubota, T.; Manabe, S.; Salvi, E.; Manunta, P.; Cusi, D.; Gieger, C.; Wichmann, H. -E.; Aung, T.; Khor, C. C.; Kruse, F. E.; Reis, A.; Schlotzer-Schrehardt, U.
نبذة مختصرة : 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. © The Author(s) 2017.
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