The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome

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 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.

Recent advances in risk factors associated with ocular exfoliation syndrome

“…Protective function of rs7173049‐G allele is believed to be through the upregulation of STRA6 , which is involved in cellular uptake of vitamin A and was shown to be significantly downregulated in XFS eyes (Berner et al. ). Another deep sequencing analysis has been conducted across LOXL1 locus in a collection of 5570 XFS cases and 6279 controls drawn from nine countries.…”

“…A common non-coding variant rs7173049A>G was found downstream of LOXL1, suggested to be associated with decreased risk of XFS in different ethnic groups, where the minor allele G was shown to be constantly enriched in controls. Protective function of rs7173049-G allele is believed to be through the upregulation of STRA6, which is involved in cellular uptake of vitamin A and was shown to be significantly downregulated in XFS eyes (Berner et al 2019). Another deep sequencing analysis has been conducted across LOXL1 locus in a collection of 5570 XFS cases and 6279 controls drawn from nine countries.…”

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

“…25 These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of XFS syndrome. Retinoic acid, the active metabolite involved in the signaling pathway implicated by Berner et al 25 in XFS through regulation of ISLR2, STRA6 and LOXL1, has been shown to control critical checkpoints in inflammation and to promote an inflammatory environment. [111][112][113] In summary, our analysis of predicted gene expression and extensive functional analysis in eye tissue prioritized six genes in association with XFS.…”

“…Some of these non-coding variants regulate expressions of the sentinel LOXL1 and the neighboring STRA6 gene. 7,25,26 After considering all the reports on genetic architecture of XFS to date, we hypothesize that analysis of the contribution of the genetically-determined component of gene expression to XFS risk can provide a powerful method to elucidate genes involved in XFS. We used a genebased method, PrediXcan 27 , implemented on GWAS summary statistics (Summary PrediXcan; S-PrediXcan) 28 to identify genetically determined gene expression traits associated with disease risk.…”

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Exfoliation Syndrome

“…Some of these non-coding variants regulate expressions of the sentinel LOXL1 and the neighboring STRA6 gene. 7,25,26 After considering all the reports on genetic architecture of XFS to date, we hypothesize that analysis of the contribution of the genetically-determined component of gene expression to XFS risk can provide a powerful method to elucidate genes involved in XFS. We used a genebased TWAS method, PrediXcan 27 , implemented on GWAS summary statistics (Summary PrediXcan; S-PrediXcan) 28 to identify genetically determined gene expression traits associated with disease risk.…”