RESUMO
Myopia, or nearsightedness, is the most common type of refractive error and is characterized by a mismatch between the optical power and ocular axial length. Light, and more specifically the spectral composition of light, has been known to influence myopic axial growth. In this pilot study, we exposed zebrafish to illuminations that vary in spectral composition and screened for changes in axial length. The illumination spectra included narrow band ultra-violet A (UVA) (peak wavelength 369 nm), violet (425 nm), cyan (483 nm), green/yellow (557 nm), and red (633 nm) light, as well as broad band white light (2700 K and 6500 K), dim white light and broad spectrum (day) light. We found that rearing zebrafish in cyan or red light leads to a reduction of the ocular axial length. The results of this pilot study may contribute to new perspectives on the role of light and lighting as an intervention strategy for myopia control.
Assuntos
Miopia , Erros de Refração , Animais , Peixe-Zebra , Projetos Piloto , Olho , Miopia/prevenção & controle , Refração Ocular , Comprimento Axial do OlhoRESUMO
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.
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Inibidor de Quinase Dependente de Ciclina p21/genética , Glaucoma de Ângulo Aberto/genética , Proteínas de Homeodomínio/genética , Doenças do Nervo Óptico/genética , Proteínas de Peixe-Zebra/genética , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/patologia , Humanos , Pressão Intraocular/genética , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Doenças do Nervo Óptico/patologia , Tonometria OcularRESUMO
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.
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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 VisualRESUMO
OBJECTIVE: The aim of this study is to demonstrate if routine assessment of patient index data 3 has a correlation with disease's activity as much as disease activity score 28, clinical disease activity index, and simplified disease activity index in Ecuadorian patients with rheumatoid arthritis seen in Unidad de Enfermedades Reumáticas y Autoinmunes [UNERA] from December 2016 to December 2017. METHODS: This is a retrospective study in 200 patients that fulfill the American College of Rheumatology 2010 criteria for diagnosis of rheumatoid arthritis. The patients were evaluated from December 2016 to December 2017. Descriptive analyses were carried out, also Pearson correlation was used, and, to give a better clinical significance, a chi-square test was conducted. Whenever assumptions of chi-square test were violated, a Fisher's exact test was reported. RESULTS: RAPID3 correlated best with DAS28 (r.83, p < 0.001), followed by CDAI (r.80, p < 0.001) and then SDAI (r.77, p < 0.001). CONCLUSION: RAPID3 is a questionnaire that only takes 10 seconds to calculate and correlates in a significant way with traditional clinical measures that require more time to perform, saving time in busy health facilities.
Assuntos
Artrite Reumatoide/epidemiologia , Índice de Gravidade de Doença , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/terapia , Equador/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
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
População Negra/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-IdadeRESUMO
Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10-61 ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.
Assuntos
Exoma/genética , Haplótipos/genética , Frequência do Gene/genética , Variação Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).
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Córnea/metabolismo , Córnea/patologia , Éxons , Variação Genética , Ceratocone/genética , Ceratocone/patologia , Proteínas Wnt/genética , Adulto , Idoso , Austrália/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Ceratocone/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco , Adulto JovemRESUMO
Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (ß = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (ß = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Glaucoma/genética , Glaucoma/fisiopatologia , Pressão Intraocular/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Idoso , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Glaucoma/epidemiologia , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismoRESUMO
PURPOSE: Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based). DESIGN: Cross-sectional, cohort study. PARTICIPANTS: For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189). METHODS: Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available). MAIN OUTCOME MEASURES: The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma. RESULTS: In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously. CONCLUSIONS: The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
Assuntos
Códon de Terminação/genética , Proteínas do Citoesqueleto/genética , Proteínas do Olho/genética , Glaucoma de Ângulo Aberto/genética , Glicoproteínas/genética , Mutação/genética , Penetrância , População Branca/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Transversais , Análise Mutacional de DNA , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/diagnóstico , Heterozigoto , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/diagnóstico , Hipertensão Ocular/genéticaRESUMO
Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
Assuntos
Estudo de Associação Genômica Ampla , Glaucoma/genética , Disco Óptico/patologia , Doenças do Nervo Óptico/genética , Locos de Características Quantitativas/genética , Povo Asiático/genética , Glaucoma/etnologia , Glaucoma/patologia , Humanos , Doenças do Nervo Óptico/etnologia , Doenças do Nervo Óptico/patologia , População Branca/genéticaRESUMO
Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10(-7), n = 11 473) and POAG (Pmeta = 6.09 × 10(-3), n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10(-3), n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
Assuntos
Diferenciação Celular/genética , Proteínas de Homeodomínio/genética , Degeneração Neural/genética , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Transativadores/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células , Mapeamento Cromossômico , Exoma , Olho/embriologia , Olho/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma de Ângulo Aberto/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Organogênese/genética , Fenótipo , Locos de Características Quantitativas , Transativadores/metabolismo , Adulto Jovem , Peixe-ZebraRESUMO
Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m2; 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.
Assuntos
Pressão Intraocular/fisiologia , Hipertensão Ocular/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Genome-wide association studies (GWAS) have dissected numerous genetic factors underlying refractive errors (RE) such as myopia. Despite significant insights into understanding the genetic architecture of RE, few studies have validated and explored the functional role of candidate genes within these loci. To functionally follow-up on GWAS and characterize the potential role of candidate genes on the development of RE, we prioritized nine genes (TJP2, PDE11A, SHISA6, LAMA2, LRRC4C, KCNQ5, GNB3, RBFOX1, and GRIA4) based on biological and statistical evidence; and used CRISPR/cas9 to generate knock-out zebrafish mutants. These mutant fish were screened for abnormalities in axial length by spectral-domain optical coherence tomography and refractive status by eccentric photorefraction at the juvenile (2 months) and adult (4 months) developmental stage. We found a significantly increased axial length and myopic shift in refractive status in three of our studied mutants, indicating a potential involvement of the human orthologs (LAMA2, LRRC4C, and KCNQ5) in myopia development. Further, in-situ hybridization studies showed that all three genes are expressed throughout the zebrafish retina. Our zebrafish models provide evidence of a functional role of these three genes in refractive error development and offer opportunities to elucidate pathways driving the retina-to-sclera signaling cascade that leads to myopia.
Assuntos
Miopia , Erros de Refração , Animais , Humanos , Estudo de Associação Genômica Ampla , Miopia/genética , Erros de Refração/genética , Retina , Peixe-Zebra/genéticaRESUMO
(1) Background: The impact of SARS-CoV-2 has been variable over the time course of the pandemic and in different populations. The aim was to analyze the impact of COVID-19 infection in a known population of hemodialysis (HD) patients and professionals in Spain at different times of the pandemic. (2) Methods: We conducted an observational, descriptive study with a follow-up from 3 March 2020 to 23 April 2022 (776 days), using in average of 414 professionals and 1381 patients from 18 HD units in Spain. The data from the positive PCR or the rapid antigen detection test (RADT) subject were analyzed and segmented into six periods (waves). (3) Results: Of 703 positive COVID-19 tests, 524 were HD patients (74.5%), and 179 were HD professionals (25.5%). Overall, 38% of staff and 43% of patients were affected. Differences were observed in regard to incidence (21% vs. 13%), mortality (3.5% vs. 0%), and symptomatology between the patients and professionals and throughout the pandemic. (4) Conclusions: COVID-19 severity varied during different pandemic waves, with a greater impact seen in the first wave. HD professionals and patients had similar infection rates, but patients had higher mortality rates. Community transmission was the primary route of infection.
RESUMO
Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.
Assuntos
Miopia , Erros de Refração , Humanos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Miopia/genética , Erros de Refração/genética , População Branca , População do Leste AsiáticoRESUMO
Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 (GJD2) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2(Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2(Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2(Cx36) in refractive error development.
Assuntos
Conexinas , Miopia , Erros de Refração , Conexinas/genética , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Humanos , Miopia/genética , Miopia/metabolismo , Erros de Refração/genética , Erros de Refração/metabolismo , Retina/metabolismo , Proteína delta-2 de Junções ComunicantesRESUMO
Purpose: To establish a set of assays that allow the in vivo screening of candidate genes for ocular diseases in zebrafish, with an emphasis on refractive error. Methods: Our pipeline includes the most relevant ocular screening measurements to assess (1) ocular biometry using spectral domain optical coherence tomography, (2) refractive status using an eccentric photorefractor, (3) intraocular pressure by tonometry, and (4) optokinetic response to study visual capability in zebrafish. To validate our pipeline and to demonstrate the potential of zebrafish as a valid animal model, we chose two well-characterized genes with an ocular phenotype (PRSS56 and FBN1) and generated two mutant zebrafish lines (prss56 and fbn1). Mutant fish were assessed at 2, 4, and 6 months after fertilization. Results: With the proposed phenotyping pipeline, we showed that ocular biometry, refractive status, intraocular pressure, and visual function can be studied in zebrafish. In the prss56 mutant, the pipeline revealed a dramatic decrease in axial length, mainly owing to a decreased vitreous chamber depth, whereas in the fbn1 mutant, ectopia lentis was the most distinctive ocular phenotype observed. Tonometry in both mutant lines showed an increase in intraocular pressure. Conclusions: The proposed pipeline was applied successfully in zebrafish and can be used for future genetic screenings of candidate genes. While validating our pipeline, we found a close resemblance between the ocular manifestations in the zebrafish mutants and patients harboring mutations in PRSS56 and FBN1. Our results support the validity of our pipeline and highlight the potential of zebrafish as an animal model for in vivo screening of candidate genes for ocular diseases.
Assuntos
Ectopia do Cristalino , Peixe-Zebra , Animais , Modelos Animais de Doenças , Ectopia do Cristalino/genética , Olho , Fibrilina-1/genética , Humanos , Fenótipo , Serina Proteases/genética , Peixe-Zebra/genéticaRESUMO
Myopia is the most common developmental disorder of juvenile eyes, and it has become an increasing cause of severe visual impairment. The GJD2 locus has been consistently associated with myopia in multiple independent genome-wide association studies. However, despite the strong genetic evidence, little is known about the functional role of GJD2 in refractive error development. Here, we find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish, cause changes in the biometry and refractive status of the eye. Our immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin and its depletion leads to hyperopia and electrophysiological changes in the retina. These findings support a role for Cx35.5 (gjd2a) in the regulation of ocular biometry. Cx35.1 (gjd2b) has previously been identified in the retina, however, we found an additional lenticular role. Lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. Our results provide functional evidence of a link between gjd2 and refractive error.
Assuntos
Conexinas/genética , Modelos Animais de Doenças , Proteínas do Olho/genética , Mutação , Erros de Refração/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Catarata/genética , Conexinas/metabolismo , Proteínas do Olho/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Miopia/genética , RNA-Seq/métodos , Retina/metabolismo , Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Análise de Célula Única/métodos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Glaucoma de Ângulo Aberto/genética , Povo Asiático , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , População BrancaRESUMO
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.