@article {1435395,
	title = {The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome},
	journal = {Hum Mol Genet},
	year = {2019},
	month = {2019 Apr 15},
	abstract = {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 noncoding sequence variant, rs7173049A\&gt;G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (OR=0.63, p=6.33x10-31) 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 receptor 6), apparently mediated by allele-specific binding of the transcription factor THRβ (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 retinoic acid signaling pathway. siRNA-mediated downregulation of retinoic acid 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 metabolismare 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.},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddz075},
	author = {Berner, Daniel and Hoja, Ursula and Zenkel, Matthias and Ross, James Julian and Uebe, Steffen and Paoli, Daniela and Frezzotti, Paolo and Rautenbach, Robyn M and Ziskind, Ari and Williams, Susan E and Carmichael, Trevor R and Ramsay, Michele and Topouzis, Fotis and Chatzikyriakidou, Anthi and Lambropoulos, Alexandros and Sundaresan, Periasamy and Ayub, Humaira and Akhtar, Farah and Qamar, Raheel and Zenteno, Juan C and Cruz-Aguilar, Marisa and Astakhov, Yury S and Dubina, Michael and Wiggs, Janey and Ozaki, Mineo and Kruse, Friedrich E and Aung, Tin and Reis, Andr{\'e} and Khor, Chiea Chuen and Pasutto, Francesca and Schl{\"o}tzer-Schrehardt, Ursula}
}
