Nailfold Capillary Hemorrhages: Microvascular Risk Factors for Primary Open-Angle Glaucoma.
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ABSTRACT: Background
Primary open-angle glaucoma (POAG) is associated with systemic microvascular dysfunction including hemorrhages and other abnormalities of the nailfold capillary bed. This study aimed to verify the specificity of nailfold capillary hemorrhages and other abnormalities as risk factors for POAG.Methods
Nailfold video capillaroscopy was performed using a JH-1004 capillaroscope on the fourth and fifth digits of the nondominant hand in control (n?=?277), POAG (n?=?206), OHT (n?=?57), and SG (n?=?29) subjects. The number of hemorrhages, dilated capillaries >50?µm, and avascular zones ?200?µm were counted and adjusted to counts per 100 capillaries. Descriptive analyses as well as univariate- and multivariable-adjusted logistic regression were performed comparing all groups with controls and POAG with OHT and SG. Subanalyses were conducted in POAG patients examining the association between nailfold capillary outcomes and previous glaucoma surgery, successful IOP control, or disease severity.Results
All nailfold capillary outcomes were significantly increased in POAG, no outcomes were increased in SG, and only hemorrhages were mildly increased in OHT. Hemorrhages were significantly more frequent in POAG compared with both OHT (P < 0.0001) and SG (P=0.001). There were significant trends between higher numbers of hemorrhages and POAG compared with controls, OHT, and SG, with odds ratios of 18.3 (8.5-39.4), 9.1 (1.9-13.4), and 11.8 (1.7-7.3), respectively, for the presence of two or more hemorrhages per 100 capillaries. Hemorrhages were not significantly associated with previous glaucoma surgery, successful postoperative IOP control, or disease severity in POAG.Conclusions
These findings suggest that systemic microvascular dysfunction is frequent in POAG and occurs early in the disease process. The high specificity of nailfold hemorrhages makes them viable clinical risk factors for POAG.
SUBMITTER: Pfahler NM
PROVIDER: S-EPMC7301193 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Nailfold Capillary Hemorrhages: Microvascular Risk Factors for Primary Open-Angle Glaucoma.
Pfahler Nicholas M NM Barry Jordan L JL Bielskus Indre E IE Kakouri Agni A Giovingo Michael C MC Volpe Nicholas J NJ Knepper Paul A PA
Journal of ophthalmology 20200608
<h4>Background</h4>Primary open-angle glaucoma (POAG) is associated with systemic microvascular dysfunction including hemorrhages and other abnormalities of the nailfold capillary bed. This study aimed to verify the specificity of nailfold capillary hemorrhages and other abnormalities as risk factors for POAG.<h4>Methods</h4>Nailfold video capillaroscopy was performed using a JH-1004 capillaroscope on the fourth and fifth digits of the nondominant hand in control (<i>n</i> = 277), POAG (<i>n</i> ...[more]
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Project description:PurposeTo assess microvascular beds in the optic nerve head (ONH), peripapillary tissue, and the nailfold in patients with primary open-angle glaucoma (POAG) versus controls.MethodsPatients with POAG (n = 22) and controls (n = 12) underwent swept-source optical coherence tomography angiography of ophthalmic microvasculature and nailfold video capillaroscopy of the hand. The main outcomes were vessel density (VD) and blood flow of the ONH, the peripapillary and the nailfold microvasculatures.ResultsPatients with POAG were younger than controls (63.5 ± 9.4 vs. 69.9 ± 6.5 years, P = 0.03). Deep ONH VD and blood flow were lower in patients with POAG than controls (39.1% ± 3.5% vs. 43.8% ± 5.7%; 37.8% ± 5.3% vs. 46.0% ± 7.8%, respectively, P < 0.02 for both); similar results were observed with peripapillary VD (37.9 ± 2.6%, 43.4 ± 7.6%, respectively, P = 0.03). Nailfold capillary density and blood flow were lower in patients with POAG than controls (8.8 ± 1.0 vs. 9.8 ± 0.9 capillaries/mm; 19.9 ± 9.4 vs. 33.7 ± 9.8 pL/s, respectively; P < 0.009 for both). After adjusting for age and gender, deep ONH VD and blood flow, peripapillary VD, and nailfold capillary blood flow were lower in POAG than controls (β = -0.04, -0.07, -0.05, -13.19, respectively, P ≤ 0.046 for all). Among all participants, there were positive correlations between deep ONH and nailfold capillary blood flow (Pearson's correlation coefficient r = 0.42, P = 0.02), peripapillary and nailfold capillary density (r = 0.43, P = 0.03), and peripapillary and nailfold capillary blood flow (r = 0.49, P = 0.01).ConclusionsPatients with POAG demonstrated morphologic and hemodynamic alterations in both ophthalmic and nailfold microvascular beds compared to controls.Translational relevanceThe concomitant abnormalities in nailfold capillaries and relevant ocular vascular beds in POAG suggest that the microvasculature may be a target for POAG treatment.
| S-EPMC8196412 | biostudies-literature
Project description:PurposeTo analyze optic disc hemorrhages (DH) associated with primary open-angle glaucoma by quantifying their geometric profile and comparing their densitometry with hemorrhages from retinal vein occlusions (RVO) and retinal macroaneurysms (MA), which have venous and arterial sources of bleeding, respectively.DesignRetrospective cross-sectional study.MethodsSetting: Massachusetts Eye & Ear.PopulationFundus images of DH (n = 40), MA (n = 14), and RVO (n = 25) were identified. Patient clinical backgrounds and demographics were obtained.Main outcome measuresGrayscale pixel intensity units of hemorrhages and adjacent arteriole and venule over the same background tissue were measured. Densitometry differentials (arteriole or venule minus hemorrhage [ΔA and ΔV, respectively]) were calculated. The ratios of length (radial) to midpoint width for DH were calculated. Mean ΔA and ΔV between groups were compared with t tests. Multiple linear regression assessed the relation of retinal hemorrhage diagnosis to ΔA and ΔV and of DH shape to ΔA and ΔV.ResultsMean (± standard deviation) ΔA and ΔV for DH (6.9 ± 7.1 and -4.7 ± 8.0 pixel intensity units, respectively) and MA (5.3 ± 5.9 and -6.0 ± 4.6, respectively) were comparable (P ≥ .43). Mean ΔA (14.6 ± 7.7) and ΔV (6.4 ± 6.3) for RVO were significantly higher compared to DH and MA (P < .0001) and remained significant in multivariable analyses. A unit increase in DH length-to-width ratio was associated with 1.2 (0.5) and 1.3 (0.5) pixel intensity unit (standard error) decrease in ΔA and ΔV, respectively (P ≤ .014).ConclusionsDH have densitometry profiles comparable to MA and different from RVO, suggesting that DH in glaucoma have an arterial origin.
| S-EPMC6754625 | 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:PurposeTo evaluate the risk factors associated with recurrent disc hemorrhage (DH), defined for the present study as at least 3 occurrences of DH in primary open-angle glaucoma (POAG).MethodsA total of 178 POAG patients (89 eyes showing at least 3 occurrences of DH and 89 age-matched control eyes with a minimum of 10 years' follow-up without DH) were included in a retrospective, case-control study. Ocular factors were evaluated by a retrospective chart review, and systemic factors were evaluated by a telephone survey. Associations between factors and recurrent DH were investigated by logistic regression analysis. The Kaplan-Meier survival analysis and Cox proportional-hazards regression models were used to evaluate glaucoma progression and to identify the factors predictive of glaucoma progression.ResultsUnivariate regression analysis revealed the association of recurrent DH with low baseline intraocular pressure (IOP) [odds ratio (OR), 0.88; 95% confidential interval (CI), 0.80-0.98; P = 0.014], lower percentage reduction of IOP (OR, 0.96; 95% CI, 0.93-0.99; P = 0.020), cold extremities (OR, 2.80; 95% CI, 1.03-7.60; P = 0.043), prone or lateral decubitus sleeping position (OR, 2.14; 95% CI, 1.13-4.03; P = 0.019), and sleeping disorders (OR, 2.33; 95% CI, 1.05-5.15; P = 0.037). Multivariate regression analysis revealed that a lower percentage reduction in IOP (OR, 0.96; 95% CI, 0.93-1.00; P = 0.046) increased the risk of recurrent DH. The control group exhibited a greater cumulative probability of non-progression than the recurrent DH group (P = 0.01, by log-rank test). The Cox proportional-hazards regression model showed that recurrent DH was associated with glaucoma progression [hazard ratio (HR), 1.88; 95% CI; 1.66-3.05; P = 0.01.ConclusionsAmong the ocular and systemic factors, only lower-percentage reduction of IOP in POAG was associated with recurrent DH. DH recurrence is associated with glaucoma progression and may be dependent on IOP.
| S-EPMC6746379 | biostudies-literature
Project description:To investigate whether associations with the nitric oxide synthase gene (NOS3) variants and risk of primary open-angle glaucoma (POAG) depend on female reproductive factors.Two functional and two tagging single nucleotide polymorphisms (SNPs; T-786C: rs2070744, Glu298Asp: rs1799983, rs7830, and rs3918188) were evaluated in a nested case-control study from the Nurses' Health Study (women followed 1980 - 2002). Participants were aged ?40 years and Caucasian, who were followed biennially with update information on reproductive factors. We included 374 Nurses' Health Study (NHS) cases and 1,085 controls, matched on age and eye exam at the matched cases' diagnosis dates. Relative risks (RRs) were estimated using multivariable conditional logistic regression.Among women with age at menarche <13 years, compared with the CC homozygotes of the rs3918188 tagging SNP, the wild-type AA homozygotes were at significantly reduced risk of POAG (RR=0.31, 95% CI=0.16, 0.59); however, for women with age at menarche ?13 years, the SNP was not associated with POAG (p-interaction=0.0007). Among parous women with 3+ children, carriers of the minor variant (T) allele of the functional Glu298Asp SNP were at increased risk, while among parous women with 1-2 children, they were not (p-interaction=0.003). No significant interactions between NOS3 SNPs and oral contraceptive use in POAG were detected.These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis.
| S-EPMC3198482 | biostudies-literature
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. Prior to use tissue was washed with DEPC water and all solutions were prepared in DEPC water. The minced tissue was placed in a glass homogenizer with 1 ml TRIZOL per 100 mg of tissue and homogenized in a glass homogenizer DUALL 20 (Kimble Kontes Glass Co, Vineland, NJ) with 10 strokes cycles each at room temperature and after freezing with liquid nitrogen for 1 min for 40 cycles. This RNA was extracted with chloroform, isoamylalcohol and precipitated with sodium citrate/sodium chloride and isopropanol. The final air-dried RNA precipitate was suspended in DEPC water and stored in â??80oC prior to use. RNA was prepared for hybridization according to the GeneChip Expression Analysis Technical Manual (Affymetrix, Santa Clara, CA). The hybridization was performed at Gene Expression Array Core Facility at Case Western Reserve University (www.geacf.net). The RNA sample was cleaned using a column from a Qiagen RNeasy kit, (part # 74104 ) in accordance with the manufacturerâ??s instructions. 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:Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG.We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ?21 mm Hg) and high pressure glaucoma (HPG, IOP >21 mm Hg).In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples.POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population.
| S-EPMC3776712 | biostudies-literature
Project description:Glaucoma is a genetically heterogeneous disorder and is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons. Very few genes causing glaucoma were identified to this date. In this study, we screened 10 candidate genes of glaucoma between the D14S261 and D14S121 markers of chromosome 14q11, a critical region previously linked to primary open-angle glaucoma (POAG). Mutation analyses of two large cohorts of patients with POAG, normal tension glaucoma (NTG) and juvenile open-angle glaucoma (JOAG), and control subjects, found only association of non-synonymous heterozygous variants of the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) with POAG, NTG and JOAG. The 20 non-synonymous variants identified in RPGRIP1 were all distinct from variants causing photoreceptor dystrophies and were found throughout all but one domain (RPGR-interacting domain) of RPGRIP1. Among them, 14 missense variants clustered within or around the C2 domains of RPGRIP1. Yeast two-hybrid analyses of a subset of the missense mutations within the C2 domains of RPGRIP1 shows that five of them (p.R598Q, p.A635G, p.T806I, p.A837G and p.I838V) decrease the association of the C2 domains with nephrocystin-4 (NPHPH). When considering only these five confirmed C2-domain mutations, the association remains statistically significant (P=0.001). Altogether, the data support that heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma and that among other factors, physical impairment of the interaction of RPGRIP1with different proteins may contribute to the pathogenesis of forms of glaucoma.
| S-EPMC3060327 | biostudies-literature
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
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