The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome
| Autor: | Fotis Topouzis, Daniel Berner, Susan Williams, Yury S. Astakhov, Francesca Pasutto, Trevor R. Carmichael, Steffen Uebe, Farah Akhtar, Tin Aung, Raheel Qamar, James Julian Ross, Matthias Zenkel, Friedrich E. Kruse, Mineo Ozaki, Periasamy Sundaresan, Michael V. Dubina, Paolo Frezzotti, Robyn M. Rautenbach, André Reis, Ursula Schlötzer-Schrehardt, Anthi Chatzikyriakidou, Alexandros Lambropoulos, Marisa Cruz-Aguilar, Daniela Paoli, Chiea Chuen Khor, Juan Carlos Zenteno, Ursula Hoja, Michèle Ramsay, Ari Ziskind, Janey L. Wiggs, Humaira Ayub |
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| Rok vydání: | 2018 |
| Předmět: |
Retinoic acid
Exfoliation Syndrome chemistry.chemical_compound 0302 clinical medicine GLAUCOMA GENETIC-VARIANTS Ethnicity LYSYL OXIDASE STRA6 Promoter Regions Genetic Genetics (clinical) Cells Cultured RISK Aged 80 and over 0303 health sciences VITAMIN-A-DEFICIENCY High-Throughput Nucleotide Sequencing General Medicine Middle Aged THYROID-HORMONE RECEPTORS Amino Acid Oxidoreductases General Article medicine.drug Signal Transduction EXPRESSION INDUCED PULMONARY-FIBROSIS Locus (genetics) Tretinoin Biology Polymorphism Single Nucleotide Thyroid hormone receptor beta 03 medical and health sciences Downregulation and upregulation Genetics medicine Humans Genetic Predisposition to Disease Allele Molecular Biology 030304 developmental biology Aged Thyroid hormone receptor EXFOLIATION SYNDROME Membrane Proteins Sequence Analysis DNA Molecular biology Retinoic acid receptor chemistry Gene Expression Regulation 030221 ophthalmology & optometry |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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