Identification and activity of the functional complex between hnRNPL and the pseudoexfoliation syndrome-associated lncRNA, LOXL1-AS1.
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ABSTRACT:
SUBMITTER: Schmitt HM
PROVIDER: S-EPMC7390937 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objectives:To investigate the three single nucleotide polymorphisms (SNPs) (rs3825942, rs1048661, and rs2165241) of the LOXL1 gene in pseudoexfoliation syndrome (XFS) and pseudoexfoliation glucoma (XFG) in the Turkish population. Materials and Methods:DNA was obtained from blood samples of 48 XFS, 58 XFG, and 171 control subjects. Three LOXL1 SNPs (rs3825942, rs1048661, rs2165241) were investigated with real time PCR, a probe-based genotyping method, and melting curve analysis. Results:All three SNPs of LOXL1 were significantly associated with XFS (rs3825942 p=3.54x10-6, odds ratio [OR]=?; rs1048661 p=0.008, OR=2.18; rs2165241 p=8.69x10-9, OR=4.30) and XFG (rs3825942 p=3.41x10-7, OR=?; rs1048661 p=1.75x10-5, OR=3.78; rs2165241 p=3.85x10-11 OR=4.90). No significant differences were observed between the XFS and XFG groups for any of the SNPs. The GG genotype of rs3825942 was more valuable for distinguishing pseudoexfoliative cases from healthy individuals. The homozygous TT genotype of rs2165241 was associated with 6-fold increased XFS risk (p=8.15x10-8, OR=6.32) and 7-fold increased XFG risk (p=1.45x10-10 OR=7.95). The GGT haplotype consisting of all three risk alleles was associated with a 7.45-fold higher risk of XFS/XFG (p=8.65x10-14, OR=7.45). Presence of T allele of rs2165241 conferred 3 times higher risk for men than women (p=6.78x10-5, OR=3.202). Conclusion:LOXL1 SNPs are associated with increased risk for pseudoexfoliation in the Turkish population. T allele of rs2165241 was found to be the most important characterized risk factor for our cohort. All SNP distributions were similar to other European and American populations.
| S-EPMC6216538 | biostudies-literature
Project description: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 RXR? (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.
| S-EPMC5457519 | biostudies-literature
Project description:To study lysyl oxidase-like 1 (LOXL1) expression in freshly collected lens capsules from pseudoexfoliation syndrome (XFS), pseudoexfoliation glaucoma (XFG), and normal cataract control individuals. We also investigated the effects of four glaucoma drug medications on LOXL1 expression in primary human lens epithelial cell cultures to see if they could affect LOXL1 expression.Lens capsules were collected at the time of cataract surgery. Controls were matched to age, sex, and ethnicity. Total RNA was isolated from individual lens capsule samples and real-time PCR was performed on each sample using primers flanking the sixth exon of the LOXL1 gene. Cell cultures were grown to confluence in four separate six-well plates at 37 °C in 5% CO2. Each plate was then treated with one of four different glaucoma drugs (brinzolamide 1%, brimonidine tartrate 0.1%, timolol maleate 0.5%, and latanoprost 0.005%) once daily for seven days (at both 1:1,000 and 1:100 concentrations relative to media). Controls were not treated with any drug but media was changed in the same manner. After one week of treatment, cells were harvested and total RNA isolated. Real-time PCR was performed on each group of cells.Seven XFS, seven XFG, and ten cataract control specimens were analyzed. LOXL1 expression was detected in the lens capsule specimens from each of the four groups. Significant expression differences were found between the control and XFG groups and XFS and XFG groups. No significant difference was observed between the control and XFS group. No significant decrease in LOXL1 expression was seen with drug incubation of the four medications (Brinzolamide, Timolol, Latanoprost, and Brimonidine) at the 1:1,000 drug:media concentrations versus controls. At 10-fold higher concentrations (1:100 drug:media), brinzolamide, timolol maleate, and latanoprost showed small increases in LOXL1 expression relative to controls. This effect was not observed with brimonidine tartrate.These results establish that LOXL1 expression is reduced in lens capsule specimens from XFG individuals but not XFS. The drug treatment incubation studies suggest that the change in LOXL1 expression observed in XFG is not attributable to glaucoma drug therapy. If a causative functional relationship can be validated, modification of LOXL1 expression in affected tissues may represent a novel treatment strategy for this disorder.
| S-EPMC2994419 | biostudies-literature
Project description:PURPOSE: Single nucleotide polymorphisms (SNPs) within the lysyl oxidase like-1 gene (LOXL1; rs1048661 and rs3825942) were found to confer risk to pseudoexfoliation glaucoma (XFG) through the pseudoexfoliation syndrome (XFS) in Nordic, Caucasian, and two Asiatic populations (Indian and Japanese). The prevalence (0.2%-0.7%) of XFS in the Chinese is considerably lower compared to Nordic populations. The aim of this study was to determine the association of LOXL1 in Chinese subjects with XFS/XFG. METHODS: Chinese subjects with clinically diagnosed XFS/XFG and normal controls were recruited. Genomic DNA was extracted, and the two LOXL1 SNPs (rs1048661 and rs3825942) were genotyped by bidirectional sequencing. Allele and genotype frequencies were compared between cases and unrelated controls using PLINK. Linkage disequilibrium (LD) calculations and haplotype association analysis were done using the Haploview package and WHAP package, respectively. RESULTS: Sixty-two Chinese patients (17 XFG and 45 XFS) and 171 Chinese controls were studied. The G allele of LOXL1 SNP rs3825942 was moderately associated (OR=10.97, p=0.0018) with pseudoxfoliation in the Chinese. The frequency of the G allele of rs1048661 was not significantly different in cases compared to controls (p=0.142) in the allelic association test. However, the genotype test showed marginal association for rs1048661 (p=0.030). Only three haplotypes were observed (T-G, G-G, and G-A) with G-G as a risk haplotype (p=0.0034) and G-A as a protective haplotype (p=0.00039). T-G, which was a risk haplotype in the Japanese, was not associated with XFG in the Chinese (p=0.124). CONCLUSIONS: Polymorphisms in LOXL1 confer risk to XFS/XFG in the Chinese. The lower incidence of XFS compared to other populations suggests additional genetic or environmental factors to have a major influence on the phenotypic expression of XFS in the Chinese. The G allele of rs3825942 has been shown to be associated with XFS/XFG in all populations studied to date.
| S-EPMC2690963 | biostudies-literature
Project description:PURPOSE: In the Icelandic and Swedish populations, pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) has been significantly associated with LOXL1 exon 1 polymorphisms - allele G of rs1048661 (R141L) and allele G of rs3825942 (G135D). In this study, we looked at the association of rs1048661 and rs3825942 in a southern Indian population. METHODS: Fifty-two cases with XFS (including XFG) and 97 matched controls that had thorough glaucoma evaluations were included in the study. Exon 1 of the LOXL1 gene with the single nucleotide polymorphisms (SNPs) were amplified and sequenced. For statistical significance, Pearson's Chi(2) test was performed. The HAPLOVIEW program v4.0 was used to determine the Hardy-Weinberg equilibrium and haplotype association. RESULTS: In our study population, there was a significant association of allele G of rs3825942 with XFS (p=0.0001) and genotype GG (p=0.000305) with XFS. CONCLUSIONS: Out of the two non-synonymous SNPs in exon 1 of the LOXL1 gene, rs3825942 has a significant association with XFS cases in the patients of the southern Indian population. To the best of our knowledge, this is the first Asian study replicating the European studies.
| S-EPMC2255024 | biostudies-literature
Project description: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.
| S-EPMC6644155 | biostudies-literature
Project description:Liver cancer is becoming one of the most lethal malignancies due to its high incidence and mortality. Accumulating studies have indicated that long non-coding RNAs (lncRNAs) are critical regulators of the tumorigenesis and development of various types of cancer, including liver cancer. LncRNA LOXL1-antisense RNA 1 (LOXL1-AS1) has been identified as an oncogene in some types of human cancer; however, its role in liver cancer remains obscure. Reverse transcription-quantitative PCR was used to measure LOXL1-AS1 expression in liver cancer tissues and cells. Western blot, MTT, colony formation, glucose uptake and wound healing assays were used to explore the biological function of LOXL1-AS1 in liver cancer cells. Bioinformatics analysis and RNA pull-down and luciferase reporter assays were used to explore the molecular mechanism of LOXL1-AS1 in liver cancer cells. Statistical analysis was used to compare the experimental results of different groups. In the present study, LOXL1-AS1 expression was significantly upregulated in liver cancer tissues and cells compared with in normal liver tissues and cells, respectively. High LOXL1-AS1 expression was associated with poor clinical outcomes in patients with liver cancer. Furthermore, LOXL1-AS1-knockdown suppressed glucose metabolism, proliferation, migration and epithelial-mesenchymal transition (EMT) of liver cancer cells. Subsequently, LOXL1-AS1 acted as a microRNA (miR)-377-3p sponge, and nuclear factor I B (NFIB) was confirmed as the downstream target of miR-377-3p in liver cancer cells. Additionally, rescue assays suggested that NFIB overexpression countervailed the inhibitory influence of LOXL1-AS1 silencing on liver cancer cellular processes. The present study demonstrated that LOXL1-AS1 promoted glucose metabolism, proliferation, migration and EMT of liver cancer cells by sponging miR-377-3p and modulating NFIB, which may provide a novel insight for the treatment of liver cancer.
| S-EPMC8258629 | biostudies-literature
Project description:Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.
| S-EPMC4614704 | biostudies-literature
Project description:To identify if recently described LOXL1 (lysyl oxidase-like 1) polymorphisms are associated with pseudoexfoliation glaucoma (XFG) in a United States (U.S.) Caucasian patient population.Individuals with XFG were identified using standard clinical examination techniques. TaqMan allelic discrimination assays were used to genotype 13 single nucleotide polymorphisms (SNPs) that tag LOXL1 in Caucasian individuals. The coding region of exon 1 that includes the previously associated SNP, rs1048661, was sequenced. Allele and genotype frequencies were compared between cases and unrelated controls.Fifty affected individuals and 235 control individuals were recruited into this study. We replicated the previously reported association of three SNPs (rs1048661, rs2165241, and rs3825942) in our independent XFG population (single SNP p-values were 0.001-0.02). The risk alleles at these three and several other intragenic SNPs are part of an extended XFG-associated LOXL1 haplotype with a frequency of 32.0% in XFG patients and 21.6% in controls.We have performed an analysis of LOXL1 and XFG in a United States patient population and have confirmed the strong association previously reported for Icelandic and Swedish samples. However, due to the high frequency of risk alleles in non-XFG individuals, this association should not form the basis of a diagnostic test for XFG. It is likely that additional genetic or environmental factors modulate the penetrance of LOXL1 susceptibility alleles.
| S-EPMC2255060 | biostudies-literature
Project description:PURPOSE: To investigate whether single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene are associated with pseudoexfoliation glaucoma (PEG) in the Saudi Arabian population. METHODS: The coding regions of LOXL1 were fully sequenced in 93 clinically diagnosed PEG patients and 101 healthy controls. Both groups were Saudi Arabs. Previously reported and newly identified SNPs were evaluated for possible association with PEG and their pathological consequences on the gene were assessed. RESULTS: The "G" allele frequencies of both rs1048661 and rs3825942 SNPs differed between PEG patients and control subjects from Saudi Arabia (p=0.0056 and p=0.000005, respectively). This significance remained after applying the Bonferroni correction. Two non-synonymous novel SNPs in LOXL1 were detected in the PEG patients and not in the controls. One of these SNPs was in exon 4 (g.25722 C>G; codon change D484E) of LOXL1 and was predicted to be non-pathological; the other was in exon 6 of LOXL1 (g.28084 T>G; codon change Y559D) and was predicted to be probably damaging. All alleles of SNPs (rs28706550, rs35203737, rs41429348, rs12906373, rs41435250, and rs13329473) were monoallelic in this population. No allele frequency difference for rs8818 and rs3522 SNP between patients and controls (p values were 0.126 and 0.994 respectively). CONCLUSIONS: Similar to almost all non-African populations tested thus far, the "G" allele of both rs1048661 and rs3825942 SNPs were associated with the risk of PEG in the Saudi Arab population.
| S-EPMC3008719 | biostudies-literature