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Analysis of functional polymorphisms in apoptosis-related genes in primary open angle glaucoma.

ABSTRACT: PURPOSE:Glaucoma is a disease with high heritability in which the degradation of retinal ganglion cells occurs via apoptosis. Therefore, we investigated the role of four functional apoptosis-related gene variants (Akt1 rs1130233, Bax rs4645878, Fas rs223476, and FasL rs763110) in patients with primary open angle glaucoma. METHODS:334 patients with primary open angle glaucoma and 334 controls were recruited for this case-control study. The main outcome measures were genotype distribution and allelic frequencies determined with PCR. RESULTS:After adjustment for multiple testing, no significant difference in either the genotype distribution or the allelic frequencies of any investigated gene variant was found. CONCLUSIONS:Our findings indicate that the investigated gene polymorphisms are unlikely to be major risk factors for primary open angle glaucoma in Caucasian patients.

SUBMITTER: Lindner E

PROVIDER: S-EPMC4704768 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Analysis of functional polymorphisms in apoptosis-related genes in primary open angle glaucoma.

Lindner Ewald E Glatz Wilfried W Schwab Christoph C El-Shabrawi Yosuf Y Mossböck Georg G

Molecular vision 20151230

<h4>Purpose</h4>Glaucoma is a disease with high heritability in which the degradation of retinal ganglion cells occurs via apoptosis. Therefore, we investigated the role of four functional apoptosis-related gene variants (Akt1 rs1130233, Bax rs4645878, Fas rs223476, and FasL rs763110) in patients with primary open angle glaucoma.<h4>Methods</h4>334 patients with primary open angle glaucoma and 334 controls were recruited for this case-control study. The main outcome measures were genotype distri ...[more]

PMID: 26788026

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Single nucleotide polymorphisms of metabolic syndrome-related genes in primary open angle glaucoma.

Project description:AIM:To analyze single nucleotide polymorphisms (SNP) of primary open angle glaucoma- and metabolic syndrome-related genes in primary open angle glaucoma (POAG), in order to elucidate the roles of metabolic syndrome as a risk factor in POAG progress. METHODS:SNP genotypes and alleles of interleukin-6 (IL-6), IL-6 receptor (IL-6R), dopamine D(2) receptor (DRD(2)), beta-fibrinogen (FGB), peroxisome proliferator-activated receptor-?2 (PPARG), transforming growth factor-?1 (TGF-?1), E-selectin (E-Sel), apolipoprotein A-5 (APOA5), C-reactive protein (CRP), ectonueleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), hepatic lipase (LIPC), adiponectin (ADIPOQ), paraoxonase 1 (PON1) and serine protease inhibitor E (SERPINE1) genes in POAG (n=37) and normal control (n=100) groups were measured with ABI Prism 7900HT Fluorescence Quantitative PCR and TaqMan SNP Genotyping fluorescence probe kit. RESULTS:Genotypes and allele frequencies of IL-6R, IL-6, FGB, CRP, ENPP1, LIPC, ADIPOQ, PON1, and SERPINE1 in total POAG group were significantly different compared to the control group. CONCLUSION:Metabolic syndrome as a risk factor for POAG may be associated with genotypes and allele frequencies of the related genes. The corresponding gene expression and function can affect POAG progress, including roles of SERPINE1 in extracellular matrix, ENPP1 in insulin inhibition, IL-6 in endogenous neuroprotection, IL-6, IL-6R and E-Sel in autoimmune response, LIPC and FGB in blood hyperviscosity syndrome, ADIPOQ in NOS/NO production, PON1 in vascular endothelial protection.

| S-EPMC3340651 | biostudies-literature

Primary open-angle glaucoma genes.

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

Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis.

Project description:BackgroundGlaucoma is the leading cause of irreversible blindness in the world. Recent evidence indicates a role for genetic susceptibility to primary open-angle glaucoma (POAG). The relation between myocilin polymorphisms and POAG susceptibility has been studied in different populations.MethodsA meta-analysis of 32 published genetic association case-control studies, which examined the relation between POAG and the R46X, R76K, Y347Y, T353I, and Q368X polymorphisms of the myocilin gene, was carried out.ResultsIn meta-analysis, significant associations were observed between POAG risk and two myocilin polymorphisms with summarized odds ratio of 4.68 (95%CI, 2.02-10.85) for Q368X and 2.17 (95% CI, 1.32-3.57) for T353I. Both Q368X and T353I were significantly associated with high-tension glaucoma, with summarized odds ratio of 4.26 (1.69, 10.73) and 2.26 (1.37-3.72). In Westerners, significant association was observed for Q368X mutation (odds ratio, 5.17; 95% CI, 2.16-12.40). However, in Asians it was for T353I (odds ratio, 2.17; 95% CI, 1.32-3.57).ConclusionsThere is strong evidence that myocilin polymorphisms are associated with POAG susceptibility, and the prevalence of myocilin mutations might be ethnicity-dependent in Caucasians for Q368X and in Asians for T353I.

| S-EPMC3460926 | biostudies-literature

Screening of candidate genes for primary open angle glaucoma.

Project description:PURPOSE: Primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness in the world. To make progress in understanding POAG, it is necessary to identify more POAG-causing genes. METHODS: Using haplotype analysis, we found that mutational region is located on chromosome 2 in two families. Furthermore, we screened 11 candidate genes on chromosome 2 by protein-protein interaction (PPI) analysis, including mutS homolog 6 (MSH6), mutS homolog 2 (MSH2), v-rel reticuloendotheliosis viral oncogene homolog (REL), endothelial PAS domain protein 1 (EPAS1), vaccinia related kinase 2 (VRK2), F-box protein 11 (FBXO11), EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1), reticulon 4 (RTN4), RAB1A, member RAS oncogene family (RAB1A), ARP2 actin-related protein 2 homolog (ACTR2), and calmodulin 2 (phosphorylase kinase, delta; CALM2). These 11 genes are all predicted to be related to trabecular meshwork changes and progressive loss of retinal ganglion cells in POAG patients. RESULTS: According to our study, FBXO11 and VRK2 may interact with tumor protein p53 to regulate mitochondrial membrane permeability, mitochondrial membrane organization, and apoptosis. MSH2 is responsible for repairing DNA mismatches and RTN4 is for neuronal regeneration. Therefore, they are supposed to play a negative role in cellular process in POAG. CALM2 may be involved in retinal ganglion cell death and oxidative damage to cell communication. CONCLUSIONS: The results demonstrate that the genes above may be associated with pathogenesis of POAG.

| S-EPMC3413431 | biostudies-literature

Patient-Reported Vision-Related Quality-of-Life Differences between Primary Angle-Closure Glaucoma and Primary Open-Angle Glaucoma.

Project description:PurposeTo investigate the different impacts on patient-reported vision-related quality of life (pVRQOL) outcomes in patients with primary angle-closure glaucoma(PACG) and primary open-angle glaucoma(POAG).MethodsProspective cross-sectional study. PACG and POAG patients who had a best-corrected visual acuity(BCVA) in the better eye equal to or better than 20/60, intraocular pressure controlled at or below 25 mmHg and reliable visual field test were invited to participate. The control group included patients with BCVA in the better eye equal to or better than 20/60 and who did not have major eye disease. A validated Taiwanese version of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25(T)) was performed to assess pVRQOL. The association between each domain of NEI VFQ-25(T) among 3 groups was determined using multivariable linear regression analysis.ResultsA total of 106 PACG, 186 POAG, and 95 controls were enrolled. In multivariable regression analysis of all three groups(PACG/POAG/controls), compared to POAG, PACG showed a weakly positive association with social functioning (R2 = 0.13, ? = 0.22, P = 0.04). PACG showed no significantly negative impact on pVRQOL compared to controls. Taking only glaucoma patients into consideration, PACG patients had a higher score on social functioning compared to POAG (R2 = 0.16, ? = 0.27, P = 0.01). The results of other domains of NEI VFQ-25(T) between the two groups did not differ significantly(p>0.05).ConclusionsIn patients with controlled disease, the impact of PACG and POAG on most domains of NEI VFQ-25(T) were similar, except for better social functioning in PACG compared to POAG.

| S-EPMC5045164 | biostudies-literature

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

Project description:AIMS:Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS:We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS:The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P?0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION:Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

| S-EPMC4058608 | biostudies-literature

Genes, pathways, and animal models in primary open-angle glaucoma.

Project description:Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

| S-EPMC4815694 | biostudies-literature

Association analysis of cigarette smoking with onset of primary open-angle glaucoma and glaucoma-related biometric parameters.

Project description:BACKGROUND: To date, studies on the role played by cigarette smoking in primary open-angle glaucoma (POAG) remains controversial. The current study evaluated cigarette smoking as a risk factor of POAG and its relationships with vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT) and intraocular pressure (IOP) in a Chinese cohort. METHODS: In a total of 248 unrelated individuals including 30 juvenile-onset POAG (JOAG), 92 adult-onset POAG (AOAG) and 126 sex-matched senile cataract controls, underwent comprehensive ophthalmic examination. Their smoking was obtained and documented by questionnaire. Association of cigarette smoking with POAG was performed using logistic regression controlled for age and sex. Effects of cigarette smoking on VCDR, IOP and CCT were analyzed with multiple linear regression. RESULTS: In either JOAG or AOAG, no association of cigarette smoking was found with disease onset (P = 0.692 and 0.925 respectively). In controls and JOAG, no significant effects of smoking were found on VCDR, IOP or CCT (all P > 0.05). Smoking was found to be correlated with decreased CCT in AOAG and combined POAG (JOAG?+?AOAG) (P = 0.009 and 0.003), but no association with VCDR or IOP was observed (P > 0.05). CONCLUSIONS: Although cigarette smoking was not found to be risk factor for onset of POAG, it was correlated with CCT in AOAG, and thus might still play a role in the disease course, especially for AOAG.

| S-EPMC3549870 | biostudies-other

Mitochondrial genome analysis of primary open angle glaucoma patients.

Project description:Primary open angle glaucoma (POAG) is a multi-factorial optic disc neuropathy characterized by accelerating damage of the retinal ganglion cells and atrophy of the optic nerve head. The vulnerability of the optic nerve damage leading to POAG has been postulated to result from oxidative stress and mitochondrial dysfunction. In this study, we investigated the possible involvement of the mitochondrial genomic variants in 101 patients and 71 controls by direct sequencing of the entire mitochondrial genome. The number of variable positions in the mtDNA with respect to the revised Cambridge Reference Sequence (rCRS), have been designated "Segregating Sites". The segregating sites present only in the patients or controls have been designated "Unique Segregating Sites (USS)". The population mutation rate (? = 4Ne?) as estimated by Watterson's ? (?w), considering only the USS, was significantly higher among the patients (p = 9.8 × 10(-15)) compared to controls. The difference in ?w and the number of USS were more pronounced when restricted to the coding region (p<1.31 × 10(-21) and p = 0.006607, respectively). Further analysis of the region revealed non-synonymous variations were significantly higher in Complex I among the patients (p = 0.0053). Similar trends were retained when USS was considered only within complex I (frequency 0.49 vs 0.31 with p<0.0001 and mutation rate p-value <1.49×10(-43)) and ND5 within its gene cluster (frequency 0.47 vs 0.23 with p<0.0001 and mutation rate p-value <4.42×10(-47)). ND5 is involved in the proton pumping mechanism. Incidentally, glaucomatous trabecular meshwork cells have been reported to be more sensitive to inhibition of complex I activity. Thus mutations in ND5, expected to inhibit complex I activity, could lead to generation of oxidative stress and favor glaucomatous condition.

| S-EPMC3733777 | biostudies-literature

Association of Interleukin-1 gene clusters polymorphisms with primary open-angle glaucoma: a meta-analysis.

Project description:Previous studies have associated the Interleukin-1 (IL-1) gene clusters polymorphisms with the risk of primary open-angle glaucoma (POAG). However, the results were not consistent. Here, we performed a meta-analysis to evaluate the role of IL-1 gene clusters polymorphisms in POAG susceptibility.PubMed, EMBASE and Cochrane Library (up to July 15, 2017) were searched by two independent investigators. All case-control studies investigating the association between single-nucleotide polymorphisms (SNPs) of IL-1 gene clusters and POAG risk were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for quantifying the strength of association that has been involved in at least two studies.Five studies on IL-1? rs16944 (c. -511C?>?T) (1053 cases and 986 controls), 4 studies on IL-1? rs1800587 (c. -889C?>?T) (822 cases and 714 controls), and 4 studies on IL-1? rs1143634 (c. +3953C?>?T) (798 cases and 730 controls) were included. The results suggest that all three SNPs were not associated with POAG risk. Stratification analyses indicated that the rs1143634 has a suggestive associated with high tension glaucoma (HTG) under dominant (P?=?0.03), heterozygote (P?=?0.04) and allelic models (P?=?0.02), however, the weak association was nullified after Bonferroni adjustments for multiple tests.Based on current meta-analysis, we indicated that there is lack of association between the three SNPs of IL-1 and POAG. However, this conclusion should be interpreted with caution and further well designed studies with large sample-size are required to validate the conclusion as low statistical powers.

| S-EPMC5704439 | biostudies-literature

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