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2.
PLoS One ; 14(8): e0220143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31415580

RESUMO

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

3.
Acta Ophthalmol ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386803

RESUMO

PURPOSE: To assess the association between clinical and perinatal characteristics and subfoveal choroidal thickness in 9-year-old children. METHODS: The study included data from the population-based Generation R cohort, whose participants underwent cycloplegic refractometry, ocular biometry, height, weight and subfoveal choroidal thickness measurements using a swept-source optical coherence tomography (SS-OCT) instrument. Birth parameters were obtained using medical records. Statistical analyses were performed using multivariate regression models adjusted for age, ethnicity and sex. RESULTS: A total of 1018 children (52.5% girls, 47.5% boys) with a mean age of 9.9 ± 0.3 years and a mean cycloplegic spherical equivalent refraction of 0.80 ± 1.1 D in boys and 0.81 ± 1.4 in girls were eligible for analysis. The subfoveal choroid was 17 µm thicker in girls (298 ± 60.6 µm) than in boys (281 ± 55.0 µm; p < 0.001), a difference of 9.1 µm persisting after adjustment for age, ethnicity and axial length (p = 0.017). Subfoveal choroidal thickness decreased with increasing ocular axial length (-16.2 µm/mm, 95% CI -21.2 to -12.4, p < 0.001) and with increasing myopic refraction (-10.0 µm/D, 95% CI 6.8-13.1; p < 0.001, adjusted for age, ethnicity, axial length and sex) while it increased with increasing body height (1.3 µm/cm, 95% CI 0.8 to 1.9, p < 0.001). Additionally, choroidal thickness increased with increasing birthweight (13.0 µm/kg; 95% CI 0.006-0.020; p < 0.001) and increasing size for gestational age (8.2 µm/kg; 95% CI 4.6-11.8; p < 0.001). Smoking up until the time that pregnancy became known was associated with a thinner choroid (p = 0.016). There was no detectable effect of alcohol consumption. The distributions of axial length, refraction and choroidal thickness were narrower than in older populations. CONCLUSION: The subfoveal choroid was thicker in girls than in boys, and higher body height, higher birthweight and larger size for gestational age were associated with a thicker subfoveal choroid. The implications of these findings for myopia development need further evaluation in longitudinal studies.

4.
Invest Ophthalmol Vis Sci ; 60(8): 3142-3149, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323684

RESUMO

Purpose: To determine genetic correlations between common myopia and primary open-angle glaucoma (POAG). Methods: We tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method. Results: We did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup-disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10-3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10-9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = -0.12, P = 1.8 × 10-3), supporting the findings of the PRS approach. Conclusions: Using two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

5.
Ophthalmic Physiol Opt ; 39(4): 245-252, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31236981

RESUMO

PURPOSE: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. METHODS: 5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. RESULTS: Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9-9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (ß 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. CONCLUSIONS: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height.

6.
Invest Ophthalmol Vis Sci ; 60(6): 2049-2063, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074760

RESUMO

Purpose: To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations. Methods: Multiethnic cohort study (N = 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N = 27; cone-rod dystrophy [CRD], N = 1; and macular dystrophy, N = 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299+5_1299+8del variant in macular dystrophy patients. Results: We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was -0.84 ± 0.44 ln(deg2) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs = 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was -57 ± 17 µm per year (P < 0.01) (n = 14) or -3.69% ± 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299+5_1299+8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant. Conclusions: We report on EYS-associated macular dystrophy, extending the spectrum of EYS-associated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.


Assuntos
Proteínas do Olho/genética , Degeneração Macular/genética , Mutação , RNA Mensageiro/genética , Retina/patologia , Retinite Pigmentosa/genética , Acuidade Visual , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Homozigoto , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/metabolismo , Retina/fisiopatologia , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/metabolismo , Tomografia de Coerência Óptica , Adulto Jovem
7.
Eur J Epidemiol ; 34(8): 777-784, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30945054

RESUMO

Myopia is a refractive error of the eye caused by a complex interplay between nature and nurture. The aim of this study was to investigate whether environmental risk factors can influence the genetic effect in children developing myopia. A total of 3422 children participating in the birth-cohort study Generation R underwent an extensive eye examination at 9 years with measurements of refractive error and axial length corneal radius ratio (AL/CR). Environmental risk factors were evaluated using a questionnaire, and environmental risk scores (ERS) were calculated using backward regression analyses. Genetic risk scores (GRS) were calculated based on all currently known risk variants for myopia. Gene-environment interaction (G×E) was investigated using linear and logistic regression analyses. The predictive value of G×E and parental myopia was estimated using receiver operating characteristic curves. Myopia prevalence was 12%. Both GRS (P < 0.01) and ERS (P < 0.01) were significantly associated with myopia and AL/CR, as was G×E interaction (P < 0.01 for myopia; P = 0.07 for AL/CR). The predictive value of parental myopia was 0.67 (95% CI 0.65-0.70), similar to the values of GRS (0.67; 95% CI 0.64-0.70; P = 0.98) and ERS (0.69; 95% CI 0.66-0.72; P = 0.98). Adding G×E interaction significantly improved the predictive value to 0.73 (95% CI 0.70-0.75; P < 0.01). This study provides evidence that nature and nurture are equally important for myopia and AL/CR; however, the combination has the strongest influence. Since myopia genes are common in the population, adjustment of lifestyle should be a major focus in the prevention of myopia.


Assuntos
Exposição Ambiental , Interação Gene-Ambiente , Predisposição Genética para Doença , Miopia/genética , Adulto , Comprimento Axial do Olho , Criança , Estudos de Coortes , Feminino , Humanos , Estilo de Vida , Masculino , Miopia/diagnóstico , Miopia/epidemiologia , Vigilância da População , Valor Preditivo dos Testes , Gravidez , Prevalência , Estudos Prospectivos , Fatores de Risco , Acuidade Visual
8.
Invest Ophthalmol Vis Sci ; 60(4): 1192-1203, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30913292

RESUMO

Purpose: To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies. Methods: In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years. Results: Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14-56) in the patients with arMD/arCRD, 26.2 years (range 18-40) in adRP, and 8.8 years (range 5-12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRP and arRP patients were frameshift and/or nonsense variants located far from the C-terminus. Conclusions: Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.


Assuntos
Códon sem Sentido , Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Mutação da Fase de Leitura , Degeneração Macular/genética , Retinite Pigmentosa/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/fisiopatologia , Análise Mutacional de DNA , Eletrorretinografia , Éxons , Feminino , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto Jovem
9.
Invest Ophthalmol Vis Sci ; 60(3): M89-M105, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30817828

RESUMO

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.


Assuntos
Predisposição Genética para Doença , Miopia/genética , Interação Gene-Ambiente , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Internacionalidade , Fatores de Risco
10.
Invest Ophthalmol Vis Sci ; 60(3): M1-M19, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30817825

RESUMO

With the growing prevalence of myopia, already at epidemic levels in some countries, there is an urgent need for new management approaches. However, with the increasing number of research publications on the topic of myopia control, there is also a clear necessity for agreement and guidance on key issues, including on how myopia should be defined and how interventions, validated by well-conducted clinical trials, should be appropriately and ethically applied. The International Myopia Institute (IMI) reports the critical review and synthesis of the research evidence to date, from animal models, genetics, clinical studies, and randomized controlled trials, by more than 85 multidisciplinary experts in the field, as the basis for the recommendations contained therein. As background to the need for myopia control, the risk factors for myopia onset and progression are reviewed. The seven generated reports are summarized: (1) Defining and Classifying Myopia, (2) Experimental Models of Emmetropization and Myopia, (3) Myopia Genetics, (4) Interventions for Myopia Onset and Progression, (5) Clinical Myopia Control Trials and Instrumentation, (6) Industry Guidelines and Ethical Considerations for Myopia Control, and (7) Clinical Myopia Management Guidelines.


Assuntos
Miopia/prevenção & controle , Transtornos da Visão/prevenção & controle , Animais , Progressão da Doença , Humanos , Internacionalidade , Miopia/classificação , Miopia/epidemiologia , Prevalência , Fatores de Risco
11.
Genet Med ; 21(8): 1751-1760, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30643219

RESUMO

PURPOSE: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. METHODS: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. RESULTS: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. CONCLUSION: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

14.
Am J Ophthalmol ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30312575

RESUMO

PURPOSE: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. DESIGN: Prospective population-based cohort study. METHODS: 4202 participants from the Rotterdam Study aged 55+ years, free of AMD at baseline, were included and followed up for 9.1±5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox-proportional hazards models, and adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. RESULTS: A total of 754 persons developed incident AMD. Intake of the recommended amounts of vegetables (≥200gr/day), fruit (2x/day), and fish (2x/week) was 30.6%, 54.9% and 12.5%, respectively. In particular the intake of fish (2x/week) decreased the risk of incident AMD; hazard ratio (HR) 0.76 [95% Confidence Interval (CI) 0.60-0.97]). Intake of the recommended amounts of all three food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (HR 0.58 [95%CI 0.36-0.93]). Younger age, higher income, and nonsmoking were associated with this food pattern, but risk lowering effects remained significant after additional adjustment for these factors. CONCLUSION: A diet of 200 grams of vegetables/day, 2x fruit/day, and 2x fish/week is associated with a significantly reduced risk of AMD.

15.
Hum Genet ; 137(10): 847-862, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30317457

RESUMO

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/genética , Tiorredoxina Redutase 2/genética , Proteínas de Transporte Vesicular/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Ophthalmology ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30315903

RESUMO

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. DESIGN: Pooled analysis of cross-sectional data. PARTICIPANTS: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. METHODS: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. MAIN OUTCOME MEASURES: AMD features and stage; lipid measurements. RESULTS: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10-7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10-6 and P = 1.6 × 10-4). CONCLUSIONS: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.

17.
Acta Ophthalmol ; 2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30242982

RESUMO

PURPOSE: The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. METHODS: A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. RESULTS: Definitions and classifications are proposed for the structure assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. CONCLUSION: The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies.

18.
Invest Ophthalmol Vis Sci ; 59(11): 4384-4391, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30193310

RESUMO

Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

19.
Eur J Epidemiol ; 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30182323

RESUMO

A potential mechanism by which smoking affects ischemic stroke is through wider venules, but this mediating role of wider venules has never been quantified. Here, we aimed to estimate to what extent the effect of smoking on ischemic stroke is possibly mediated by the venules via the recently developed four-way effect decomposition. This study was part of a population-based study including 9109 stroke-free persons participated in the study in 1990, 2004, or 2006 (mean age: 63.7 years; 58% women). Smoking behavior (smoking versus non-smoking) was identified by interview. Retinal venular calibers were measured semi-automatically on retinal photographs. Incident strokes were assessed until January 2016. A regression-based approach was used with venular calibers as mediator to decompose the total effect of smoking compared to non-smoking into four components: controlled direct effect (neither mediation nor interaction), pure indirect effect (mediation only), reference interaction effect (interaction only) and mediated interaction effect (both mediation and interaction). During a mean follow-up of 12.5 years, 665 persons suffered an ischemic stroke. Smoking increased the risk of developing ischemic stroke compared to non-smoking with an excess risk of 0.41 (95% confidence interval 0.10; 0.67). With retinal venules as a potential mediator, the excess relative risk could be decomposed into 77% controlled direct effect, 4% mediation only, 4% interaction only, and 15% mediated interaction. To conclude, in the pathophysiology of ischemic stroke, the effect of smoking on ischemic stroke may partly explained by changes in the venules, where there is both pure mediation and mediated interaction.

20.
Acta Ophthalmol ; 96(5): 459-464, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30188024

RESUMO

PURPOSE: To investigate risk factors for the development and progression of diabetic retinopathy (DR) and long-term visual outcomes in Dutch patients with type 1 diabetes mellitus (T1DM). METHODS: Cumulative incidences were calculated for DR, vision-threatening DR (VTDR), defined as (pre)proliferative DR and diabetic macular oedema, and best-corrected visual acuity (BCVA) <0.5 and <0.3 at the most recent eye examination. The following factors were assessed: duration of diabetes, age of onset of T1DM, gender, mean HbA1c, HbA1c variability (defined as coefficient of variation of five separate HbA1c measurements), mean arterial blood pressure, body mass index, albuminuria and lipid profile. We used multivariable Cox regression models to identify factors associated with DR development and progression to VTDR. RESULTS: We found 25-year cumulative incidences of 63% for DR, 21% for VTDR, 2% for BCVA <0.5, and 1% for BCVA <0.3. Mean HbA1c (HR 1.023, p < 0.001), HbA1c variability (HR 1.054, p < 0.001), age of onset of T1DM (HR 1.024, p < 0.001), HDL cholesterol (HR 0.502, p = 0.002) and total cholesterol (HR 1.210, p = 0.029) showed an independent association with faster development of any form of DR. The mean HbA1c (HR 1.023, p < 0.001) and the presence of albuminuria (HR 2.940, p = 0.028) were associated with faster progression to VTDR. CONCLUSION: These data show relatively low cumulative incidences of DR, VTDR and visual impairment. Higher mean HbA1c, HbA1c variability, age of onset of T1DM and total cholesterol were independently associated with the risk of DR development, and a protective association was found for HDL cholesterol in subjects with T1DM. Mean HbA1c and presence of albuminuria were associated with progression of DR.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/epidemiologia , Retina/diagnóstico por imagem , Medição de Risco , Adolescente , Adulto , Idade de Início , Idoso , Criança , Diabetes Mellitus Tipo 1/epidemiologia , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Tomografia de Coerência Óptica , Adulto Jovem
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