Genetic polymorphisms associated with endothelial function in nonarteritic anterior ischemic optic neuropathy.
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ABSTRACT: Purpose
To examine the relationship between nonarteritic anterior ischemic optic neuropathy (NAION) and genetic polymorphisms of enzymes influencing endothelial function.Methods
The subjects were 34 patients with NAION (mean age, 62.4 years old; 59% male) and 102 controls (mean age, 63.8 years old; 66% male). Genetic polymorphisms were investigated in three candidate genes associated with endothelial function: endothelin-1 (ET-1), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR). The genotype distributions in the patients with NAION were compared with those in the controls.Results
There were no significant differences in the genotype distributions of the ACE I/D and MTHFR C677T polymorphisms between the NAION and control groups (p=0.261 and p=0.354, respectively), whereas the genotype distribution of the G/T (Lys198Asn) polymorphism of the ET-1 gene varied significantly between the groups (p=0.009). After adjusting for covariates, individuals with the TT genotype of the Lys198Asn polymorphism were more likely to develop NAION compared with those with the GG genotype (odds ratio=4.43, 95% confidence interval 1.33-14.73, p=0.015).Conclusions
We found an increased prevalence of a G/T polymorphism of the ET-1 gene in patients with NAION. Our data suggest that this polymorphism may be an important risk factor in developing NAION in the Japanese population.
SUBMITTER: Sakai T
PROVIDER: S-EPMC3566895 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Genetic polymorphisms associated with endothelial function in nonarteritic anterior ischemic optic neuropathy.
Sakai Tsutomu T Shikishima Keigo K Matsushima Masato M Tsuneoka Hiroshi H
Molecular vision 20130201
<h4>Purpose</h4>To examine the relationship between nonarteritic anterior ischemic optic neuropathy (NAION) and genetic polymorphisms of enzymes influencing endothelial function.<h4>Methods</h4>The subjects were 34 patients with NAION (mean age, 62.4 years old; 59% male) and 102 controls (mean age, 63.8 years old; 66% male). Genetic polymorphisms were investigated in three candidate genes associated with endothelial function: endothelin-1 (ET-1), angiotensin-converting enzyme (ACE), and methylen ...[more]
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Project description:ImportanceSemaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D).ObjectiveTo investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network.Design, setting, and participantsThis was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non-GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals' risks during exposure and nonexposure periods for each drug. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model.ExposuresGLP-1RA and non-GLP-1RAs.Main outcomes and measuresNAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific.ResultsThe study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum's deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non-GLP-1RAs using the sensitive NAION definition-empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001).Conclusions and relevanceResults of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.
| S-EPMC11843465 | biostudies-literature
Project description:PurposeNonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION.MethodsWe conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors.ResultsIn acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1α and CXCL10 emerged as the strongest therapeutic targets.ConclusionsPost-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION.Translational relevanceWe identified blood molecular targets to improve NAION diagnosis and treatment.
| S-EPMC8288058 | biostudies-literature
Project description:ImportanceThe association between nonarteritic anterior ischemic optic neuropathy (NAION) and an increased risk of stroke has been a subject of debate. However, multinational studies on this topic are scarce.ObjectiveTo evaluate the short-term and long-term stroke risk after NAION compared with a matched control group.Design, setting, and participantsThis global, retrospective, population-based cohort study used aggregated electronic health records from January 1, 2004, through March 19, 2024, sourced from the Global Collaborative Network of TriNetX, which includes data from over 152 million patients across 17 countries. Patients in the study were followed up for a maximum duration of 10 years. Patients with NAION and age-related cataract were included in the analysis. Those with stroke before the diagnosis of NAION and age-related cataract were excluded. Propensity score matching was applied to balance age, sex, race, ethnicity, comorbidities, and medication use.ExposureInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code for NAION or age-related cataract.Main outcomes and measuresThe primary outcome was the relative risk (RR) of stroke (ICD-10 code I60-63) in the NAION cohort vs the matched controls. Multivariable logistic regression analyses were applied to identify potential clinical factors associated with stroke within the NAION cohort.ResultsA total of 89 811 patients were identified in both the NAION (mean [SD] age, 57.2 [18.5] years; 38 678 men [43.1%]) and control (mean [SD] age, 57.0 [17.9] years; 40 014 men [44.6%]) cohorts after matching. The NAION cohort demonstrated a significantly higher all-stroke risk at all time points: 1 month (RR, 5.04; 95% CI, 4.41-5.78), 3 months (RR, 3.79; 95% CI, 3.40-4.21), 1 year (RR, 2.50; 95% CI, 2.32-2.70), 5 years (RR, 1.54; 95% CI, 1.45-1.63), and 10 years (RR, 1.33; 95% CI, 1.23-1.43). Sensitivity analysis in patients without comorbidities similarly revealed a significantly increased all-stroke risk across all intervals: 1 month (RR, 7.55; 95% CI, 4.74-12.03), 3 months (RR, 6.70; 95% CI, 4.48-10.04), 1 year (RR, 3.96; 95% CI, 2.94-5.34), 5 years (RR, 2.85; 95% CI, 2.18-3.72), and 10 years (RR, 1.68; 95% CI, 1.25-2.26). Among all the clinical factors of interest, only hypertension was consistently associated with all subtypes of stroke following NAION.Conclusions and relevanceThis cohort study of patients with NAION found a significantly elevated risk of stroke compared with matched controls, independently of comorbidities. These findings underscore the importance of regular stroke workups following the onset of NAION.
| S-EPMC11558474 | biostudies-literature
Project description:Anterior ischemic optic neuropathy (AION) can be divided into nonarteritic (NAION) and arteritic (AAION) forms. NAION makes up ~85% of all cases of AION, and until recently was poorly understood. There is no treatment for NAION, and its initiating causes are poorly understood, in part because NAION is not lethal, making it difficult to obtain fresh, newly affected tissue for study. In-vivo electrophysiology and post-mortem studies reveal specific responses that are associated with NAION. New models of NAION have been developed which enable insights into the pathophysiological events surrounding this disease. These models include both rodent and primate species, and the power of a 'vertically integrated' multi-species approach can help in understanding the common cellular mechanisms and physiological responses to clinical NAION, and to identify potential approaches to treatment. The models utilize laser light to activate intravascular photoactive dye to induce capillary vascular thrombosis, while sparing the larger vessels. The observable optic nerve changes associated with rodent models of AION (rAION) and primate NAION (pNAION) are indistinguishable from that seen in clinical disease, including sectoral axonal involvement, and in-vivo electrophysiological data from these models are consistent with clinical data. Early post-infarct events reveal an unexpected inflammatory response, and changes in intraretinal gene expression for both stress response, while sparing outer retinal function, which occurs in AAION models. Histologically, the NAION models reveal an isolated loss of retinal ganglion cells by apoptosis. There are changes detectable by immunohistochemistry suggesting that other retinal cells mount a brisk response to retinal ganglion cell distress without themselves dying. The optic nerve ultimately shows axonal loss and scarring. Inflammation is a prominent early histological feature. This suggests that clinically, specific modulation of inflammation may be a useful approach to NAION treatment early in the course of the disease.
| S-EPMC3367439 | biostudies-literature
Project description:PurposeThe evaluation and management of Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) lacks standardized guidelines. This study aimed to investigate the real-world practices of neuro-ophthalmologists in the evaluation and management of typical NAION cases.MethodsA national survey, conducted between 2019 and 2021, involved all practicing neuro-ophthalmologists. A structured questionnaire assessed their approach to risk factor evaluation and treatment of NAION, with 19 questions about risk factors and six questions concerning treatment and prevention of fellow-eye involvement.ResultsThirty-six out of 37 neuro-ophthalmologists participated. Most physicians referred patients for evaluation of the following risk factors: obstructive sleep apnea (83.3%), diabetes mellitus (83.3%), hypertension (77.7%), dyslipidemia (72.2%), and optic disc drusen (38.8%). However, there was considerable variation in the choice of diagnostic tests recommended. Furthermore, nearly 47% recommended an embolism workup. Regarding treatment, the majority (91%) did not recommend routine treatment for NAION, although in 16.7%, high-dose corticosteroids were occasionally prescribed. Secondary prevention with aspirin (80.6%), smoking cessation advice (86.1%), and advising against erectile dysfunction medications for men (80.6%) were common recommendations.ConclusionWhile the risk factors associated with NAION are well-reported, there is a lack of uniformity on which tests should be ordered to evaluate these risk factors. Most neuro-ophthalmologists concur that routine treatment for NAION is not warranted, but not unanimously. Future studies to develop a consensus guideline for post-NAION work-up and management recommendations may assist in the detection and management of preventable risk factors.
| S-EPMC11458737 | biostudies-literature
Project description:IntroductionNonarteritic anterior ischemic optic neuropathy (NAION), painless loss of central and/or peripheral vision, is a multifactorial disease caused by insufficient blood flow through the posterior ciliary arteries to the optic nerve head. Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene, triggering hyperhomocysteinemia as a consequence of a decreased activity of the codified enzyme, have been considered to be among the risk factors of NAION.ObjectiveThe main aim was to study the association of the most common MTHFR genetic polymorphisms C677T and A1298C with NAION in a Spanish population.MethodsIn this case-control study, the association of the most common MTHFR polymorphisms was investigated in 94 unrelated native Spanish patients diagnosed with NAION and 204 healthy controls. Two single nucleotide polymorphisms located in the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131), were analyzed by DNA sequencing and TaqMan assays.ResultsThe allelic and genotypic frequencies of the MTHFR variants obtained in the NAION group were not significantly different when compared with the control group. A higher frequency of the C677T/A1298C genotype, codifying the nonmutated MTHFR form, was obtained in control subjects (11.27%) compared to NAION patients (4.26%), suggesting a protective effect of the wild-type protein, although this result was not conclusive considering the obtained confidence interval (CI) (95% CI: 0.13-1.06). Study of additional clinical factors including hypertension, diabetes mellitus, and dyslipidemia showed no association with a higher risk of NAION. Conversely, the clinical history of heart or cerebrovascular diseases was significantly higher in NAION patients compared to controls. Over the world, risk variants of the MTHFR gene are highly frequent, excluding African black populations, indicating a racial influence.ConclusionsThe MTHFR variants did not significantly increase the risk of suffering from NAION. However, considering that individuals with at least one of the risk variants have the MTHFR enzyme with decreased activity, it cannot be ruled out that these mutations are relevant for the development of NAION in a subgroup of the population with other specific characteristics. These may include high plasma levels of homocysteine along with nutritional deficiencies including low folate or vitamin B12 and the combination of systemic and local risk factors.
| S-EPMC7383253 | biostudies-literature
Project description:PurposeNonarteritic anterior ischemic optic neuropathy (NAION) has been associated with a thickened choroid at the optic nerve head (ONH). Here, we use computational modeling to better understand how choroidal expansion and choroidal geometry influence tissue deformation within the ONH relative to intraocular pressure (IOP) and intracranial pressure (ICP) effects.MethodsUsing a model of the posterior eye that included the sclera, peripapillary sclera, annular ring, pia mater, dura mater, neural tissues, Bruch's membrane, choroid, and lamina cribrosa, we examined how varying material properties of ocular tissues influenced ONH deformations under physiological and supra-physiological, or "pathological," conditions. We considered choroidal expansion (c. 35 µL of expansion), elevated IOP (30 mm Hg), and elevated ICP (20 mm Hg), and calculated peak strains in the ONH relative to a baseline condition representing an individual in the upright position.ResultsSupra-physiological choroidal expansion had the largest impact on strains in the prelaminar neural tissue. In addition, compared to a tapered choroid, a "blunt" choroid insertion at the ONH resulted in higher strains. Elevated IOP and ICP caused the highest strains within the lamina cribrosa and retrolaminar neural tissue, respectively.ConclusionsAcute choroidal expansion caused large deformations of the ONH and these deformations were impacted by choroid geometry. These results are consistent with the concept that compartment syndrome due to the choroid geometry and/or expansion at the ONH contributes to NAION. Prolonged deformations due to supra-physiological loading may induce a mechanobiological response or ischemia, highlighting the potential impact of choroidal expansion on biomechanical strains in the ONH.
| S-EPMC9055550 | biostudies-literature
Project description:PurposeTo compare the microvasculature of the optic nerve head (ONH) and peripapillary tissues in eyes with normal-tension glaucoma (NTG) and nonarteritic anterior ischemic optic neuropathy (NAION) using optical coherence tomography angiography (OCTA).MethodsThirty-eight eyes with treatment-naïve NTG, 38 eyes with NAION matched for retinal nerve fiber layer (RNFL) thickness in each superior and inferior quadrant, and 38 healthy eyes matched by age were included. ONH and peripapillary retinal microvasculature was evaluated in en face images obtained using OCTA. Vessel density (VD) was calculated as the percent area occupied by vessels in the measured region in each layer segmented into the prelaminar tissue (PLT), lamina cribrosa (LC), and peripapillary retina (PR).ResultsVDs in the PLT and LC were lower in NTG eyes than in both NAION and healthy eyes (P ≤ 0.008), and did not differ between the NAION and healthy eyes. VDs in the PR did not differ between the NTG and NAION eyes. In intersectoral comparisons, VDs in the PLT (P = 0.030) and LC (P = 0.028) were lower in the affected than in the unaffected sector of eyes with NTG, but the differences did not occur in eyes with NAION. VD in the PR was lower in the affected than in the unaffected sector in both NTG and NAION eyes (both P < 0.001).ConclusionsDespite similar degrees of RNFL loss and VD decreases in the PR, VDs in the ONH differed between eyes with NTG and NAION, indicating different mechanisms of vascular impairment and ONH damage in each condition.
| S-EPMC8374994 | biostudies-literature
Project description:Purpose. To describe a patient who developed bilateral, simultaneous nonarteritic anterior ischemic optic neuropathy (NAION) after ingestion of Sildenafil citrate (Viagra) for erectile dysfunction. Methods. Observational case report. Results. A 60-year-old diabetic man noted sudden decrease of vision in both eyes 16 hours after his third consecutive 50 mg daily Sildenafil ingestion. A diagnosis of bilateral NAION was made and he was treated for three days with methylprednisolone 1 g/d intravenously, followed by oral prednisone 75 mg/d. Final visual acuity was 20/50 right eye (OD) and 20/20 left eye (OS). He had preexisting diabetes. Conclusion. This is the first reported case of simultaneous bilateral NAION occurred in a diabetic patient early after Sildenafil intake. Patients with predisposing conditions such as diabetes have to be warned against the use of PDE inhibitors.
| S-EPMC3313560 | biostudies-literature
Project description:There is currently no accepted treatment for Nonarteritic Anterior Ischemic Optic Neuropathy (NAION). One new therapeutic approach involves decreasing optic nerve edema with intravitreal bevacizumab in order to resolve a proposed compartment syndrome.In this non-randomized controlled clinical trial, 1.25 mg intravitreal bevacizumab was compared with natural history. Patients were examined at baseline, 1, 3, and 6 months with a full neuro-ophthalmic exam, automated perimetry, and optic nerve optical coherence tomography (OCT) measurements. The primary outcome measure was change in mean deviation on Humphrey visual field testing. Secondary outcome measures were change in visual acuity and optic nerve OCT thickness. Incidence and type of complications were also recorded.Twenty-five patients were enrolled (17 treatment and 8 control). There was no significant effect of treatment on the primary outcome measure of mean deviation score (P=0.4). There was similarly no effect of group assignment on the secondary outcome measures of change in mean Early Treatment Diabetic Retinopathy Study letters (P=0.33) or nerve fiber layer thickness on OCT (P=0.11). In the bevacizumab group, there was one case of a corneal abrasion and two cases of recurrent NAION. No other complications were noted.We found no difference between bevacizumab and natural history for change in visual field, visual acuity, or optic nerve OCT thickness. Based on the current evidence we would not recommend the use of intravitreal bevacizumab to treat patients with the new onset of NAION.
| S-EPMC3626001 | biostudies-literature