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1.
Int J Epidemiol ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33211829

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear. METHODS: Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64-407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium. RESULTS: Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. CONCLUSION: These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.

2.
Clin Exp Ophthalmol ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058401

RESUMO

IMPORTANCE: Educating parents to recognize signs of eye disease and consult a healthcare professional is critical to timely diagnosis, intervention and outcomes. BACKGROUND: We evaluate the effectiveness of an eye-health information pamphlet on parents' level of concern and help-seeking intention should they hypothetically observe leukocoria or strabismus in their child. DESIGN: Double-blind, randomized controlled trial conducted at a metropolitan antenatal outpatient clinic. PARTICIPANTS: In total, 518 pregnant women were enrolled in the study. METHODS: After completing a study-specific, pre-test survey describing hypothetical clinical scenarios at baseline, participants were randomly assigned to receive a pamphlet on either paediatric eye health (intervention) or infant play (control). The post-test survey was sent by email 2 weeks after baseline. MAIN OUTCOME MEASURES: A change in the parents' level of concern if they observed leukocoria or strabismus and a change in their help-seeking intention if they hypothetically observed leukocoria or strabismus in their child. RESULTS: Of the 518 women, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] P = .005]) and were less likely to delay help-seeking (OR 0.560 [CI 0.382-0.817] P = .003). No change in the level of concern for strabismus was identified between the groups; however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] P = .016). CONCLUSION AND RELEVANCE: Providing parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed.

3.
Cells ; 9(9)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887382

RESUMO

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer's disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

4.
Angiogenesis ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32935224

RESUMO

Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Schematic diagram of the tunable system utilizing the DHFR(DD)-Flt23k approach to reduce VEGF secretion. a The schematic shows normal VEGF secretion. b Without the ligand TMP, the DHFR(DD)-Flt23k protein is destabilized and degraded by the proteasome. c In the presence of the ligand TMP, DHFR(DD)-Flt23k is stabilized and sequestered in the ER, thereby conditionally inhibiting VEGF. Green lines indicate the intracellular and extracellular distributions of VEGF. Blue lines indicate proteasomal degradation of the DHFR(DD)-Flt23k protein. Orange lines indicate the uptake of cell-permeable TMP. TMP, trimethoprim; VEGF, vascular endothelial growth factor; ER, endoplasmic reticulum.

5.
Nat Commun ; 11(1): 4871, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978399

RESUMO

Precision genome engineering has dramatically advanced with the development of CRISPR/Cas base editing systems that include cytosine base editors and adenine base editors (ABEs). Herein, we compare the editing profile of circularly permuted and domain-inlaid Cas9 base editors, and find that on-target editing is largely maintained following their intradomain insertion, but that structural permutation of the ABE can affect differing RNA off-target events. With this insight, structure-guided design was used to engineer an SaCas9 ABE variant (microABE I744) that has dramatically improved on-target editing efficiency and a reduced RNA-off target footprint compared to current N-terminal linked SaCas9 ABE variants. This represents one of the smallest AAV-deliverable Cas9-ABEs available, which has been optimized for robust on-target activity and RNA-fidelity based upon its stereochemistry.


Assuntos
Adenina/química , Sistemas CRISPR-Cas , Edição de Genes/métodos , Engenharia Genética/métodos , RNA/metabolismo , Proteína 9 Associada à CRISPR , Citosina , DNA , Exoma , Genoma , Células HEK293 , Humanos , Edição de RNA
6.
Ophthalmology ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32860813

RESUMO

PURPOSE: To describe the prevalence and systemic associations of keratoconus in young adults in Perth, Western Australia. DESIGN: Cross-sectional study. PARTICIPANTS: One thousand two hundred fifty-nine participants 20 years of age. METHODS: The Raine Study is a multigenerational, longitudinal cohort study based in Perth, Western Australia. This study represents a cross-sectional analysis of the birth cohort on returning for a 20-year follow-up. Participants underwent a detailed ophthalmic examination, including visual acuity assessment and Scheimpflug imaging using the Pentacam (Oculus, Wetzlar, Germany), and completed a health questionnaire. Keratoconus was defined as a Belin/Ambrόsio enhanced ectasia display score of 2.6 or more in either eye based on Pentacam imaging. MAIN OUTCOME MEASURES: Prevalence of keratoconus in this cohort. RESULTS: Of the 1259 participants, 50.8% were women and 85.7% were White. Fifteen participants had keratoconus in at least 1 eye, giving a prevalence of 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84. A significant difference was found in best-corrected visual acuity (0.01 logarithm of the minimum angle of resolution vs. -0.05 logarithm of the minimum angle of resolution; P = 0.007), cylinder (1.25 diopters [D] vs. 0.25 D cylinder; P < 0.001) and spherical equivalent (-1.42 D vs. -0.50 D sphere; P = 0.02) on objective refraction, mean keratometry of the steep meridian (45.19 D vs. 43.76 D; P < 0.001), and mean corneal thickness at the thinnest point (475 µm vs. 536 µm; P < 0.001) between those with and without keratoconus. Keratoconus was associated with regular cigarette smoking (38.5% vs. 14.6%; P = 0.04), but showed no association with gender, race, body mass index, use of spectacles or contact lenses, history of allergic eye disease, or pregnancy. CONCLUSIONS: The prevalence of keratoconus in this Australian population-based study of 20-year-old adults was 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84, which is one of the highest reported in the world. This has important implications for screening individuals at a younger age so that treatment can be initiated before disease progression.

7.
Mitochondrion ; 54: 113-121, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32687992

RESUMO

Leber hereditary optic neuropathy (LHON) is one of the most common primary mitochondrial diseases. It is caused by point mutations in mitochondrial DNA (mtDNA) genes and in some cases, it can result in irreversible vision loss, primarily in young men. It is currently unknown why LHON mutations affect only some carriers and whether bioenergetic compensation enables unaffected carriers to overcome mitochondrial impairment and preserve cellular function. Here, we conducted bioenergetic metabolic assays and RNA sequencing to address this question using male-only, age-matched, m.11778G > A lymphoblasts and primary fibroblasts from both unaffected carriers and affected individuals. Our work indicates that OXPHOS bioenergetic compensation in LHON peripheral cells does not explain disease phenotype. We show that complex I impairment is similar in cells from unaffected carrier and affected patients, despite a transcriptional downregulation of metabolic pathways including glycolysis in affected cells relative to carriers detected by RNA sequencing. Although we did not detect OXPHOS bioenergetic compensation in carrier cells under basal conditions, our results indicate that cells from affected patients suffer a growth impairment under metabolic challenge compared to carrier cells, which were unaffected by metabolic challenge. If recapitulated in retinal ganglion cells, decreased susceptibility to metabolic challenge in unaffected carriers may help preserve metabolic homeostasis in the face of the mitochondrial complex I bioenergetic defect.

8.
Ophthalmology ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32730956

RESUMO

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.

9.
Sci Rep ; 10(1): 12485, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719476

RESUMO

SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life.

10.
JAMA Ophthalmol ; 138(6): 671-678, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32352494

RESUMO

Importance: Rhegmatogenous retinal detachment is a potentially sight-threatening condition. The role of myopia or intraocular pressure (IOP) in retinal detachment remains unclear. Objective: To determine if myopia or IOP is associated with retinal detachment risk using genetic data. Design, Setting, and Participants: Observational analyses and 2-sample mendelian randomization were used to evaluate the associations between myopia, IOP, and retinal detachment risk in European descent participants from the UK Biobank (UKBB) cohort (n = 405 692). For retinal detachment, a genome-wide association study on 4257 cases and 39 181 controls in the UKBB was conducted. Genetic variants associated with mean spherical equivalent (MSE) refractive error (n = 95 827) and IOP (n = 101 939) were derived using independent participants from the retinal detachment genome-wide association study. Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from February 2019 to March 2020. Main Outcomes and Measures: The odds ratio (OR) of retinal detachment caused by per-unit increases in MSE refractive error (in diopters [D]) and IOP (in mm Hg). Results: Of the 405 692 participants in the UKBB cohort, the mean (SD) age was 56.87 (7.96) years, the mean (SD) MSE was -0.31 (2.65) D, the mean (SD) corneal-compensated IOP was 16.05 (3.49) mm Hg, and 4253 participants (1.0%) had retinal detachment. Genetic analyses of the 4257 cases and 39 181 controls identified 2 novel retinal detachment genes: COL22A1 (lead single-nucleotide variant rs11992725; P = 4.8 × 10-10) and FAT3 (lead single-nucleotide variant rs10765568; P = 1.2 × 10-15). Genetically assessed MSE refractive error was negatively associated with retinal detachment (per-unit [D] increase in MSE refractive error: OR, 0.72; 95% CI, 0.69-0.76; P = 3.8 × 10-44). For each 6-D decrease in MSE refractive error (representing the move of refractive error from emmetropia to high myopia), retinal detachment risk increased 7.2-fold (95% CI, 5.19-9.27). For per-unit (mm Hg) genetically assessed increase in IOP, the risk of retinal detachment increased by 8% (OR, 1.08; 95% CI, 1.03-1.14; P = .001). Conclusions and Relevance: This study provides genetic support for the assertion that myopia and IOP are associated with the risk of retinal detachment and that myopia prevention efforts may help prevent retinal detachment.

11.
J Glaucoma ; 29(7): 587-592, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32287148

RESUMO

PRECIS: Although mental or emotional stress may result raise in intraocular pressure (IOP) we found weak associations between endogenous stress markers concentrations and retinal nerve fiber layer (RNFL) thickness, thus limited evidence that stress affects retinal ganglion cells integrity. PURPOSE: Increased exposure to glucocorticoids is linked to elevated IOP, which is a risk factor for glaucoma. We explored the RNFL thickness for changes that may mimic preclinical glaucomatous changes, in relation to the hormonal stress response. MATERIALS AND METHODS: Young healthy adults (n=863) underwent a Trier Social Stress Test. Endogenous plasma adrenocorticotropic hormone (ACTH) and cortisol were measured for those who provided biological samples, and adrenal sensitivity was calculated. On the basis of cortisol levels before and after the Trier Social Stress Test, participants were categorized into one of 3 stress response types: anticipatory-responders, reactive-responders, and nonresponders. Participants underwent an eye examination that included spectral-domain optical coherence tomography to measure peripapillary RNFL thickness. RESULTS: Higher levels of ACTH were associated with thinner RNFL globally (P=0.009), and at the inferotemporal (P=0.015), superotemporal (P=0.044), and temporal sectors (P=0.046). Lower adrenal sensitivity was associated with thinner RNFL inferotemporally (P<0.001) and temporally (P=0.037). However, these effect sizes were small; for example, a 10 pg/mL increase in baseline ACTH was associated with only a 3 µm thinner RNFL. RNFL thickness was not associated with plasma cortisol levels and or significantly different between groups of acute stress response patterns. CONCLUSIONS: Although there was a link between ACTH or adrenal sensitivity and RNFL thickness, this association was weak and its clinical significance is unclear. Despite the close associations between levels of endogenous stress markers and IOP, we found limited evidence of a link to RNFL integrity.

12.
J Hum Genet ; 65(8): 657-665, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32277175

RESUMO

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.


Assuntos
Degeneração Macular/genética , Proteínas ADAM/genética , Proteínas da Fase Aguda/genética , Antígenos CD55/genética , Proteínas de Transporte/genética , Coenzima A Ligases/genética , Proteína de Ligação ao Complemento C4b/genética , Bases de Dados Genéticas , Proteínas do Olho/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Glicoproteínas de Membrana/genética , Subunidade p50 de NF-kappa B/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Repressoras/genética , Retina/metabolismo , Retina/patologia
13.
Nat Genet ; 52(4): 401-407, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231278

RESUMO

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.


Assuntos
Predisposição Genética para Doença/genética , Miopia/genética , Erros de Refração/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
14.
Commun Biol ; 3(1): 133, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193507

RESUMO

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

15.
Am J Ophthalmol ; 214: 40-51, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32112771

RESUMO

PURPOSE: To describe the choroidal thickness (ChT) in a large sample of young adults with the aim of establishing a normative ChT profile reference in this demographic cohort and explore its association with best-corrected visual acuity (BCVA). DESIGN: Cross-sectional study. METHODS: From a single center, 741 young adults (19-30 years of age, 49% male) were recruited to undergo a comprehensive ophthalmic examination, including BCVA measurement, post-cycloplegic autorefraction, ocular biometry, tonometry, and spectral-domain optical coherence tomography (SD-OCT) imaging. The enhanced depth imaging mode on the SD-OCT was used. The main outcome measure was the central macular ChT (0.5-mm radius around the fovea). The ChTs at the inner (between 0.5-mm and 1.5-mm radius) and outer macular rings (between 1.5-mm and 2.5-mm radius) were also measured. RESULTS: The median central macular ChT was 370 µm (interquartile range 312-406 µm). The choroid was thickest at the superior-inner, inferior-inner, and central macular regions (370-373 µm) and thinnest nasally at the outer macular region (median 256 µm). Decreased central macular ChT was associated with younger age, female sex, nonwhite ethnicities, and myopia (P ≤ .013). There was a significant association between better BCVA and increased central macular ChT (P < .001), after adjusting for age, sex, ethnicity, and ocular measures. His relationship was only apparent in eyes with central macular ChTs <300 µm (P = .019) and absent in eyes with ChTs >300 µm. CONCLUSIONS: The central ChT of young adults was 370 µm. There was a significant association between worse BCVA and thinner choroids below a threshold of 300 µm, raising the possibility that ChT could be predictive of visual function.


Assuntos
Corioide/anatomia & histologia , Acuidade Visual/fisiologia , Adulto , Biometria , Corioide/diagnóstico por imagem , Estudos de Coortes , Estudos Transversais , Grupos Étnicos , Feminino , Voluntários Saudáveis , Humanos , Pressão Intraocular/fisiologia , Masculino , Tamanho do Órgão , Valores de Referência , Refração Ocular/fisiologia , Fatores Sexuais , Tomografia de Coerência Óptica , Tonometria Ocular , Adulto Jovem
16.
J AAPOS ; 24(2): 74.e1-74.e7, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32151573

RESUMO

PURPOSE: To report the prevalence of amblyopia, strabismus, and anisometropia in a young adult population at a single center in Australia and to investigate the underlying prenatal and early-life risk factors. METHODS: Participants in the Raine Study have been followed from mid-gestation (n = 2,868 newborns) to young adulthood. At age 20 years, 1,344 participants had a comprehensive eye examination, including visual acuity and a detailed orthoptic assessment. Risk factors were determined from medical records and questionnaires completed by the mothers at 18 weeks' gestation. The main outcome measures were the proportions of participants with amblyopia, esotropia, exotropia, or anisometropia (defined as >1 D difference). RESULTS: Of the 1,125 white participants, 12 (1.1%) had amblyopia, 39 (3.5%) had strabismus, and 33 (2.9%) had anisometropia. In multivariable logistic regression, amblyopia was associated with a maternal history of pregnancy-induced hypertension (OR = 3.80; 95% CI, 1.19-12.13); esotropia, with lower gestational age (OR = 0.97; 95% CI, 0.95-0.97) and a heavier placenta (OR = 1.02; 95% CI, 1.00-1.04); exotropia, with a maternal history of previously treated hypertension (OR = 4.00; 95% CI, 1.06-15.03) and maternal use of recreational drugs during early pregnancy (OR = 3.61; 95% CI, 1.06-15.03); and anisometropia, with older maternal age (OR = 1.07; 95% CI, 1.01-1.14) and an abnormal umbilical cord (OR = 2.39; 95% CI, 1.04-5.47). CONCLUSIONS: The prevalence of amblyopia, strabismus, and anisometropia in this cohort was similar to that in other studies. Preterm birth and maternal health may have adverse effects on eye development.

17.
BMJ Open ; 10(3): e033440, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32217560

RESUMO

INTRODUCTION: Eye diseases and visual impairment more commonly affect elderly adults, thus, the majority of ophthalmic cohort studies have focused on older adults. Cohort studies on the ocular health of younger adults, on the other hand, have been few. The Raine Study is a longitudinal study that has been following a cohort since their birth in 1989-1991. As part of the 20-year follow-up of the Raine Study, participants underwent a comprehensive eye examination. As part of the 27- and 28-year follow-ups, eye assessments are being conducted and the data collected will be compared with those of the 20-year follow-up. This will provide an estimate of population incidence and updated prevalence of ocular conditions such as myopia and keratoconus, as well as longitudinal change in ocular parameters in young Australian adults. Additionally, the data will allow exploration of the environmental, health and genetic factors underlying inter-subject differential long-term ocular changes. METHODS AND ANALYSIS: Participants are being contacted via telephone, email and/or social media and invited to participate in the eye examination. At the 27-year follow-up, participants completed a follow-up eye screening, which assessed visual acuity, autorefraction, ocular biometry and ocular sun exposure. Currently, at the 28-year follow-up, a comprehensive eye examination is being conducted which, in addition to all the eye tests performed at the 27-year follow-up visit, includes tonometry, optical coherence tomography, funduscopy and anterior segment topography, among others. Outcome measures include the incidence of refractive error and pterygium, an updated prevalence of these conditions, and the 8-year change in ocular parameters. ETHICS AND DISSEMINATION: The Raine Study is registered in the Australian New Zealand Clinical Trials Registry. The Gen2 20-year, 27-year and 28-year follow-ups are approved by the Human Research Ethics Committee of the University of Western Australia. Findings resulting from the study will be published in health or medical journals and presented at conferences. TRIAL REGISTRATION NUMBER: ACTRN12617001599369; Active, not recruiting.

18.
Ophthalmology ; 127(7): 901-907, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32081492

RESUMO

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

19.
Ophthalmology ; 127(6): 758-766, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32085876

RESUMO

PURPOSE: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. PURPOSE: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. METHODS: Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. MAIN OUTCOME MEASURES: Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. RESULTS: We identified rare (allele frequency < 4×10-5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. CONCLUSIONS: Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment.

20.
Clin Exp Ophthalmol ; 48(4): 442-449, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031310

RESUMO

IMPORTANCE: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG. BACKGROUND: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up. DESIGN: Prospective, multicentre, matched case-control Australian study. PARTICIPANTS: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes. METHODS: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data. MAIN OUTCOME MEASURES: Change in IOP. RESULTS: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P < .001) with 59 eyes (34%) achieving at least 3 mmHg reduction. Compared to matched controls, the mean reduction in IOP was 1.75 mmHg (95% confidence interval 1.15-2.33 mmHg; P < .001). Higher preoperative IOP and being on fewer topical glaucoma medications preoperatively were strongly predictive of a larger IOP reduction in a multivariable model. Anterior chamber depth was not associated with IOP reduction. Eyes with preoperative IOP ≥24 mmHg had a mean IOP reduction of 4.03 mmHg with 81% experiencing at least 3 mmHg reduction. Sub-analysis of medication naïve and pseudoexfoliation patients showed similar results. CONCLUSIONS AND RELEVANCE: Cataract surgery has a confirmed effect in reducing IOP in a "real world" setting of early glaucoma patients.

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