Ethnic specific association of the CAV1/CAV2 locus with primary open-angle glaucoma.
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ABSTRACT:
SUBMITTER: Rong SS
PROVIDER: S-EPMC4906515 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Ethnic specific association of the CAV1/CAV2 locus with primary open-angle glaucoma.
Rong Shi Song SS Chen Li Jia LJ Leung Christopher K S CK Matsushita Kenji K Jia Liyun L Miki Atsuya A Chiang Sylvia W Y SW Tam Pancy O S PO Hashida Noriyasu N Young Alvin L AL Tsujikawa Motokazu M Zhang Mingzhi M Wang Ningli N Nishida Kohji K Pang Chi Pui CP
Scientific reports 20160614
A single-nucleotide polymorphism (SNP) rs4236601 at the CAV1/CAV2 locus is associated with primary open-angle glaucoma (POAG). Rs4236601 is common in Caucasians but rare in East Asians. Here we conducted a haplotype-tagging SNP analysis followed by replication in a total of 848 POAG cases and 1574 controls drawn from 3 cities in China and 1 city in Japan. Two SNPs, rs4236601 (odds ratio [OR] = 6.25; P = 0.0086) and a tagging-SNP rs3801994 (OR = 1.32; P = 0.042), were associated with POAG in the ...[more]
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Project description:We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10?¹?). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
| S-EPMC3222888 | biostudies-literature
Project description:PurposeThe CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further.DesignCase-control study.ParticipantsWe analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls).MethodsWe studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7 × 10(-4) was used to account for multiple comparisons.Main outcome measuresOverall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss.ResultsWe found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61 × 10(-7)). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59 × 10(-5)). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07 × 10(-4)), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men.ConclusionsCAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.
| S-EPMC3937766 | biostudies-literature
Project description:Primary open-angle glaucoma (POAG) is a genetically complex common disease characterized by progressive optic nerve degeneration that results in irreversible blindness. Recently, a genome-wide association study (GWAS) for POAG in an Icelandic population identified significant associations with single nucleotide polymorphisms (SNPs) between the CAV1 and CAV2 genes on chromosome 7q31. In this study, we confirm that the identified SNPs are associated with POAG in our Caucasian US population and that specific haplotypes located in the CAV1/CAV2 intergenic region are associated with the disease. We also present data suggesting that associations with several CAV1/CAV2 SNPs are significant mostly in women.
| S-EPMC3209825 | biostudies-literature
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| S-EPMC4525636 | biostudies-literature
Project description:A substantial fraction of glaucoma has a genetic basis. About 5% of primary open angle glaucoma (POAG) is currently attributed to single-gene or Mendelian forms of glaucoma (ie glaucoma caused by mutations in myocilin or optineurin). Mutations in these genes have a high likelihood of leading to glaucoma and are rarely seen in normal subjects. Other cases of POAG have a more complex genetic basis and are caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. These factors are more frequently detected in patients with POAG, but are also commonly observed in normal subjects. Additional genes that may be important in glaucoma pathogenesis have been investigated using quantitative traits approaches. Such studies have begun to identify genes that control the magnitude of important quantitative features of glaucoma that may also be important risk factors for POAG, such as central corneal thickness. Each of these different approaches to study glaucoma genetics is providing new insights into the pathogenesis of POAG.
| S-EPMC3171270 | biostudies-literature
Project description:INK4 locus at chromosome 9p21 has been reported to be associated with primary open angle glaucoma (POAG) and its subtypes along with the associated optic disc parameters across the populations of European, Japanese and African ancestries. The locus encodes three tumor suppressor genes namely CDKN2A, ARF, CDKN2B and a long non-coding RNA CDKN2B-AS1 (also known as ANRIL). Here, we report association study of 34 SNPs from INK4 locus with POAG in a population of Indo-European ancestry from the eastern part of India (350 patients and 354 controls). With 81% power to detect genetic association we observed only nominal association of rs1011970 (uncorrected p = 0.048) with POAG and rs10120688 (uncorrected p = 0.048) in patients without a high intra-ocular pressure (IOP<21?mm of Hg) compared to controls. This study, in contrast to the previous reports, suggests lack of significant genetic association of INK4 locus with POAG in East Indian population which needs to be replicated in larger studies in diverse world populations.
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Project description:BackgroundRecent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP) or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG). The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients.MethodsThe study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG) patients with intra ocular pressure (IOP) > 21 mmHg and 199 non-HTG patients (presenting IOP < 20 mmHg), and 301 healthy controls from eastern India. Genotypes were determined by polymerase chain reaction and restriction digestion for three single nucleotide polymorphisms (SNPs): IL1A (-889C/T; rs1800587), IL1B (-511C/T; rs16944) and IL1B (3953C/T; rs1143634). Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method.ResultsNo significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T) where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025) for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T) was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039). On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003) while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022) compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015) and expected to confer protection.ConclusionThe study suggests that the genomic region containing the IL1 gene cluster influences the POAG pathogenesis mostly in non-HTG patients in eastern India. A similar study in additional and larger cohorts of patients in other population groups is necessary to further substantiate the observation.
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Project description:The total RNA from control and POAG optic nerve lamina cribrosa region was isolated and subjected to analysis on U133A 2.0 affymetrix microarray chip. The results from these two analysis was compared to determine whether PAD II RNA level is altered. Purpose of the study. This study was done to determine which RNA transcripts undergo significant changes in the optic nerve between normal and cadaver primary open-angle glaucoma donors. Using donor tissues from NDRI we have performed proteomic analyses (which will be published shortly), we intend a comparison between the proteomic and RNA changes for select proteins in our study. Sample Collection and Preparation of Labeled Copy RNA; The total RNA from optic nerve was obtained using TRIZOL (Invitrogen Inc., Carlsbad, CA) with modification of recommended protocols. The optic nerve from donor eyes were carefully excised and minced into small pieces first using a scissor and then a scalpel. 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The volume of DEPC water used to elute the RNA from the Qiagen column was dictated by the nominal mass of the loaded RNA sample. Samples were eluted in 100ml of water, precipitated with 0.5 volume of 7.5M Ammonium Acetate and 2.5 volumes of 100% ethanol at -20oC for 1 hr and centrifuged for 10 min at room temperature. The pellet was drained and washed twice in 500µl of 70% ethanol. Supernatant was aspirated. The pellet was dried briefly (less than 1 min) in a speeedvac (Savant) and re-suspended in a small volume (~ 12â??15ml) of DEPC water. A small aliquot (2ml) of the sample was used for quantitation. Cleaned RNA samples were annotated as â??clnRNAâ?? and stored at -20oC. cDNA Synthesis; The protocol recommended by Affymetrix Inc. for cDNA synthesis was used at all times. The reaction was primed by annealing an oligo-dT primer coupled to a T7 RNA polymerase promoter to the RNA sample. Whenever possible, 8 mg of clnRNA were reverse transcribed using Superscript II reverse transcriptase in a 20ml reaction at 42oC for 1 hr. Second strand synthesis was carried out immediately in a total reaction volume of 150ml in the presence of E. coli DNA polymerase I, RNAse H and DNA ligase. The reaction mixture incubated for 2 hrs at 16oC and for a further 5 min in the presence of T4 DNA pol.. The reaction was terminated by the addition of EDTA. The sample was cleaned with a Qiagen cDNA clean-up column according to the manufacturers directions. The elution buffer volume was 14ml. The eluted samples were stored overnight at -20oC. In-Vitro Transcription (IVT) reaction; In a 0.5ml microfuge tube, complementary RNA (cRNA) was generated in an IVT reaction using a BioArray High Yield ENZO kit (Affymetrix). The 40ml reaction contained 10ml of cDNA sample and was incubated at 37oC in the heating block for 4-5hrs. Samples were mixed by flicking, pulse-centrifuged and returned to the incubator once every 40 minutes. Upon completion of the reaction, IVT samples were adjusted to a volume of 100ml with DEPC-treated water and cleaned using Qiagen RNA clean-up columns. Samples were eluted in 45ml of DEPC-treated water. A 2ml-aliquot was used for quantitation. Corrected concentrations of cRNA (minus the input clnRNA) were determined. A standard fragmentation reaction volume was 40ml in a 0.5 ml microfuge tube and used 20mg of overall IVT RNA in 1X fragmentation buffer (40mM Tris acetate, pH 8.1, 100mM KOAc, 30mM MgOAc). The reaction was incubated at 94oC for 35min in a heat block. After the 35 min incubation the fragmented samples were placed on ice. The standard hybridization cocktail volume was 300ml. 150ml of 2X hybridization buffer was added (final concentrations : 100mM MES, 1M [Na+], 20mM EDTA, 0.01% Tween 20) Herring sperm and acetylated BSA were added to a final concentration of 0.1 and 0.5mg/ml respectively. The amount of fragmentation reaction containing 15mg of cRNA was added to the cocktail and the remaining volume was made up with molecular biology grade water. A 15ml aliquot of a 20X mixture of in-vitro transcripts of bacterial genes BioB BioC BioD and cre as external controls (spikes) were added to the cocktail to give final concentrations of 1.5, 5, 25 and 100pM respectively. Control oligonucleotide (5ml) was added to a final concentration of 50pM. Array Hybridization; Sample Hyridization cocktails (300ml) were removed from storage at â??20oC and thawed in a 45oC temperature block. The samples were incubated at 45oC for 5 min, incubated at 45oC for 5 min and then centrifuged at 15,000g for 5 min. This study used commercially available Affymetrix HG U133A 2.0 arrays only. These are in situ synthesized, high density oligonucleotide arrays which can interrogate 22,777 gene entities. The part number is 900444 more detailed information may be found at www.affymetrix.com website. Meanwhile, the affymetrix chip arrays were taken from their storage at 4oC and allowed to come to room temperature. The chamber was filled with 1X hybridization buffer (final concentrations : 100mM MES, 1M [Na+], 20mM EDTA, 0.01% Tween 20). The chip was then preconditioned by incubation in the hybridization oven at 45oC for 10 min. The chip was removed and the chamber drained. Sample cocktails (200ml) were then introduced into the chamber of the chips. The ports were sealed with tough-spots stickers and placed in the hybridization oven and incubated at 45oC with rotation overnight. Next day (16hr later), the incubation was terminated and the chips removed from the oven. Samples were retrieved from the chips and stored again in a freezer at -20oC. The chips were filled with buffer A and placed in a module of Fluidics 400 wash station. The chips were subjected to the Affymetrix â??EuKws4 ver 2â?? programmed series of stringent post hybridization washes, staining and post-staining washes in accordance with Affy protocols. Upon completion of the wash series (approximately 2 hrs), the chips were removed from the Fluidics station. The chips were inspected. Chips were scanned using an Agilent Gene Array scanner 3000 driven by Affymetrix GCOS software. Generation of Expression Values; Microarray Suite, version 5 (Affymetrix), was used to generate *.cel files, and a computer program (Probe Profiler, ver. 1.3.11; Corimbia Inc., Berkeley, CA) developed specifically for the GeneChip system (Affymetrix) was used to convert intensity data into quantitative estimates of gene expression for each probe set. The software identifies informative probe pairs, and down-weights the signal contribution of probe pairs that are subject to differential cross-hybridization effects or that consistently produce no signal. The software also detects and corrects for saturation artifacts, outliers, and chip defects. A probability statistic was generated for each probe set. The probability is associated with the null hypothesis that the expression level of the probe set is equal to zero (background). Genes not significantly expressed above background in any of the samples (P > 0.05) were
2008-06-12 | E-GEOD-2387 | biostudies-arrayexpress
Project description:Long non-coding RNAs were associated with the development and progression of glaucoma. Our study aim to identify the potential genes in human trabecular meshwork related to primary open-angle glaucoma (POAG).
2019-09-28 | GSE138125 | GEO
Project description:This study aimed to investigate the molecular mechanism responsible for primary open-angle glaucoma (POAG) progression. We analyzed microRNAs (miRNAs) expression profiling in aqueous humor (AH) of both POAG patients and normal controls, using a microarray-based approach. Subsequently, differentially expressed miRNAs (DEmiRNAs) were identified using Bayes moderated t-test. Next, DEmiRNAs target genes were predicted based on miRNA databases, followed by GO analysis and pathway analysis using DAVID. Furthermore, OAG-related genes analysis for target genes was carried out using CTD database, respectively. Finally, verification of DEmiRNAs expression levels was performed by RT-qPCR. A total of 40 significant DEmiRNAs were identified between control and POAG groups, including 24 up-regulated miRNAs and 16 down-regulated miRNAs. Further, the target genes of hsa-miR-206, including BMP2, SMAD4, ID2, and TNF, were mainly enriched in transforming growth factor-β (TGF-β) signaling pathway. While, target genes of hsa-miR-184, hsa-miR-34c-5p, hsa-miR-7-2-3p and hsa-miR-20b-3p, including BCL2, EPHB2, VEGFA, COL4A1, APC, and TGFBR1, were enriched in eye development. Moreover, FNDC3B, CAV2 and VEGF, target genes of hsa-miR-206 or hsa-miR-34c-5p, were the OAG-related genes. Ultimately, RT-qPCR analysis confirmed that mRNA levels of hsa-miR-206, hsa-miR-7-2-3p, and hsa-miR-20b-3p were increased, while those of hsa-miR-184 and hsa-miR-34c-5p were decreased in POAG compared with normal groups (P < 0.05). Hsa-miR-206, hsa-miR-184, hsa-miR-34c-5p, hsa-miR-7-2-3p and hsa-miR-20b-3p might play a significant role in the pathogenesis of POAG and hsa-miR-206 might be associated with the development of POAG by regulating TGF-β signaling pathway. These results might provide insight toward a better understanding of the pathogenesis of POAG.
2015-08-04 | GSE71639 | GEO