RESUMO
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Assuntos
Estudo de Associação Genômica Ampla , Degeneração Macular/genética , Predisposição Genética para Doença , Humanos , MutaçãoRESUMO
Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: PADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.
Assuntos
Proteínas do Olho/genética , Estudos de Associação Genética , Degeneração Macular/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Apoptose , Estudos de Casos e Controles , Diferenciação Celular , DNA Complementar/genética , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Masculino , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Risco , Análise de Sequência de DNA , Deleção de Sequência , Caracteres SexuaisRESUMO
PURPOSE: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. METHODS: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. RESULTS: Five affected patients from four families were identified. Mean age was 16 years (range, 6-42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. CONCLUSION: Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy-associated dominant mutations.
Assuntos
Canais de Cloreto/genética , Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Mutação , Doenças Retinianas/genética , Adulto , Bestrofinas , Criança , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/fisiopatologia , Angiofluoresceinografia , Genes Recessivos , Humanos , Reação em Cadeia da Polimerase , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.
Assuntos
Estudos de Associação Genética , Variação Genética , Degeneração Macular/genética , Proteínas dos Microfilamentos/genética , Adulto , Idoso , Sequência de Aminoácidos , Lâmina Basilar da Corioide/metabolismo , Análise Mutacional de DNA , Exoma , Matriz Extracelular/metabolismo , Fibrilina-2 , Fibrilinas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Degeneração Macular/diagnóstico , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Linhagem , Conformação Proteica , Estabilidade Proteica , Retina/metabolismo , Retina/patologia , Alinhamento de SequênciaRESUMO
Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47-0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.
Assuntos
Corticosteroides/farmacologia , Antígenos CD/genética , Caderinas/genética , Coriorretinopatia Serosa Central/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Adolescente , Adulto , Idoso , Alelos , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Coriorretinopatia Serosa Central/metabolismo , Corioide/efeitos dos fármacos , Corioide/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Junções Intercelulares/ultraestrutura , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transporte Proteico , Adulto JovemRESUMO
PURPOSE: To document longitudinal fundus autofluorescence (FAF) and electroretinogram (ERG) findings in a family with cone-rod dystrophy (CRD) caused by a novel missense mutation (D100G) in the GUCA1A gene. METHODS: Observational case series. RESULTS: Three family members 26-49 years old underwent complete clinical examinations. In all patients, funduscopic findings showed intraretinal pigment migration, loss of neurosensory retinal pigment epithelium, and macular atrophy. FAF imaging revealed the presence of a progressive hyperautofluorescent ring around a hypoautofluorescent center corresponding to macular atrophy. Full-field ERGs showed a more severe loss of cone than rod function in each patient. Thirty-hertz flicker responses fell far below normal limits. Longitudinal FAF and ERG findings in one patient suggested progressive CRD. Two more advanced patients exhibited reduced rod response consistent with disease stage. Direct sequencing of the GUCA1A gene revealed a new missense mutation, p.Asp100Gly (D100G), in each patient. CONCLUSION: Patients with autosomal dominant CRD caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG characteristics and subsequent genetic testing.
Assuntos
Proteínas Ativadoras de Guanilato Ciclase/genética , Mutação de Sentido Incorreto , Retinose Pigmentar/genética , Adulto , Idoso , Progressão da Doença , Eletrorretinografia , Éxons/genética , Feminino , Fundo de Olho , Humanos , Íntrons/genética , Masculino , Linhagem , Células Fotorreceptoras de Vertebrados/patologia , Reação em Cadeia da Polimerase , Retinose Pigmentar/diagnóstico , Acuidade Visual/fisiologiaRESUMO
Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
Assuntos
Biomarcadores/metabolismo , Loci Gênicos/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Fatores de RiscoRESUMO
PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.
Assuntos
Neovascularização de Coroide/genética , Atrofia Geográfica/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Serina Endopeptidases/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Fatores de Risco , IrmãosRESUMO
PURPOSE: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology. METHODS: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Würzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. RESULTS: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. CONCLUSIONS: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists.
Assuntos
Proteínas do Olho/genética , Transportador de Glucose Tipo 1/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , População Branca , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Alemanha/epidemiologia , Haplótipos , Heterozigoto , Homozigoto , Humanos , Desequilíbrio de Ligação , Degeneração Macular/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fenótipo , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD). METHODS: Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage. RESULTS: In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ(2) = 8.8; P = .003; odds ratio, 0.46 [95% confidence interval, 0.28-0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ(2) = 4.0; P = .045; odds ratio, 1.73 [95% confidence interval, 1.04-2.90]). Homozygosity for 402H was particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD (P < .001). Retinal macular disease also was associated with hypertension among male patients. CONCLUSIONS: The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD. CLINICAL RELEVANCE: Reticular macular disease may be genetically distinct from the rest of AMD.
Assuntos
Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Idoso , Idoso de 80 Anos ou mais , Fator H do Complemento/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Degeneração Macular/diagnóstico , Masculino , Microscopia Confocal , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Tomografia de Coerência ÓpticaRESUMO
Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
Assuntos
Colágeno Tipo X/genética , Variação Genética , Estudo de Associação Genômica Ampla , Degeneração Macular/genética , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinases/genética , Fator A de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
PURPOSE: To investigate the association of the rs2301995 haplotype-tagging single nucleotide polymorphism (htSNP) in the elastin gene (ELN) with polypoidal choroidal vasculopathy (PCV) in European-American patients. METHODS: Association analysis of allele and genotype frequencies, determined by TaqMan assays, was performed for the rs2301995 haplotype-tagging single nucleotide polymorphism (htSNP) in the ELN locus in fifty-six patients with PCV, 368 patients with advanced age-related macular degeneration (AMD) and 368 age- and ethnically-matched unaffected controls. RESULTS: The ELN rs2301995 SNP was not statistically significantly associated with the PCV phenotype (P = 0.9). The frequency of the minor allele of the rs2301995 SNP was practically identical in the PCV, AMD and control groups (6.3% vs. 5.4% vs. 7.1%). CONCLUSION: The PCV phenotype in European-American patients is not associated with rs2301995 SNP in the ELN locus.
Assuntos
Doenças da Coroide/genética , Corioide/irrigação sanguínea , Elastina/genética , Doenças Vasculares Periféricas/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Idoso , Genótipo , Humanos , Degeneração Macular/genéticaRESUMO
PURPOSE: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. METHODS: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. RESULTS: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. CONCLUSIONS: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel.
Assuntos
Macula Lutea/patologia , Telangiectasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Transporte Biológico , Segregação de Cromossomos/genética , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Ligação Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Pigmentos da Retina/metabolismoRESUMO
BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. METHODOLOGY/PRINCIPAL FINDINGS: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (Pâ=â0.018). CONCLUSIONS/SIGNIFICANCE: Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.
Assuntos
DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Degeneração Macular/patologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose , Estudos Prospectivos , Fatores de RiscoRESUMO
PURPOSE: To investigate the frequency of variants in 3 major age-related macular degeneration (AMD)-associated loci in patients of European-American descent with polypoidal choroidal vasculopathy (PCV). DESIGN: Cross-sectional, case-control association study. PARTICIPANTS: Fifty-five patients with PCV, 368 patients with advanced AMD, and 368 age-matched and ethnically matched unaffected controls of European-American descent. METHODS: Association analysis of allele and genotype frequencies, determined by TaqMan assays, was performed for the following haplotype-tagging single nucleotide polymorphisms (htSNPs): risk alleles in the complement factor H (CFH) gene (Y402H and IVS14) in the ARMS2/HTRA1 locus on 10q26 (A69S) and protective alleles in CFH (IVS1 and IVS6) and in the complement factor B/complement component C2 (CFB/C2) locus (IVS10 and H9L). MAIN OUTCOME MEASURES: Allele and genotype frequencies of the htSNPs in the CFH, CFB/C2, and ARMS2/HTRA1 loci. RESULTS: Four AMD-associated haplotype-tagging alleles (rs547154, rs1061170, rs1410996, rs10490924) in the 3 major loci, CFH, CFB/C2, and ARMS2/HTRA1, also were statistically significantly associated with the PCV phenotype (P<0.05). Three other alleles from the same loci (rs4151667, rs529825, rs3766404) showed a trend toward association (P<0.2) but did not reach statistical significance, possibly because of the combined effects of a relatively small sample size and low minor allele frequency in the screened populations. CONCLUSIONS: The PCV phenotype in Caucasian patients is associated with the major alleles/genotypes in the AMD-associated loci, suggesting that PCV and AMD are genetically similar in the tested loci.
Assuntos
Doenças da Coroide/genética , Corioide/irrigação sanguínea , Proteínas do Sistema Complemento/genética , Degeneração Macular/genética , Doenças Vasculares Periféricas/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Idoso , Estudos de Casos e Controles , Doenças da Coroide/diagnóstico , Complemento C2/genética , Fator B do Complemento/genética , Fator H do Complemento/genética , Estudos Transversais , Feminino , Angiofluoresceinografia , Perfilação da Expressão Gênica , Frequência do Gene , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Verde de Indocianina , Degeneração Macular/diagnóstico , Masculino , Doenças Vasculares Periféricas/diagnóstico , Reação em Cadeia da Polimerase , Serina Endopeptidases/genética , População Branca/genéticaRESUMO
Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.
Assuntos
Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Lipase/genética , Lipase/fisiologia , Degeneração Macular/genética , Alelos , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , Dessaturase de Ácido Graxo Delta-5 , Genótipo , Humanos , Lipídeos/química , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Risco , Inibidor Tecidual de Metaloproteinase-3/antagonistas & inibidoresRESUMO
OBJECTIVE: To investigate the association between variants in the complement component 5 (C5) gene and age-related macular degeneration (AMD). DESIGN: Separate and combined data from 3 large AMD case-control studies and a prospective population-based study (The Rotterdam Study). PARTICIPANTS: A total of 2599 AMD cases and 3458 ethnically matched controls. METHODS: Fifteen single nucleotide polymorphisms (SNPs) spanning the C5 gene were initially genotyped in 375 cases and 199 controls from The Netherlands (The Amsterdam/Rotterdam-Netherlands [AMRO-NL] study population). Replication testing of selected SNPs was performed in the Rotterdam Study (NL) and study populations from Southampton, United Kingdom (UK), and New York, United States (US). MAIN OUTCOME MEASURES: Early and late stages of prevalent and incident AMD, graded according to (a modification of) the international grading and classification system of AMD. RESULTS: Significant allelic or genotypic associations between 8 C5 SNPs and AMD were found in the AMRO-NL study and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, age, and gender. None of these findings could be confirmed consistently in 3 replication populations. CONCLUSIONS: Although the complement pathway, including C5, plays a crucial role in AMD, and the C5 protein is present in drusen, no consistent significant associations between C5 SNPs and AMD were found in any of these studies. The implications for genetic screening of AMD are discussed.
Assuntos
Complemento C5/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Estudos ProspectivosRESUMO
NR2E3, a photoreceptor-specific nuclear receptor (PNR), represses cone-specific genes and activates several rod-specific genes. In humans, mutations in NR2E3 have been associated with the recessively-inherited enhanced short-wavelength sensitive S-cone syndrome (ESCS) and, recently, with autosomal dominant (ad) retinitis pigmentosa (RP) (adRP). In the present work, we describe two additional families affected by adRP that carry a heterozygous c.166G>A (p.G56R) mutation in the NR2E3 gene. Functional analysis determined the dominant negative activity of the p.G56R mutant protein as the molecular mechanism of adRP. Interestingly, in one pedigree, the most common causal variant for ESCS (p.R311Q) cosegregated with the adRP-linked p.G56R mutation, and the compound heterozygotes exhibited an ESCS-like phenotype, which in 1 of the 2 cases was strikingly "milder" than the patients carrying the p.G56R mutation alone. Impaired repression of cone-specific genes by the corepressors atrophin-1 (dentatorubral-pallidoluysian atrophy [DRPLA] gene product) and atrophin-2 (arginine-glutamic acid dipeptide repeat [RERE] protein) appeared to be a molecular mechanism mediating the beneficial effect of the p.R311Q mutation. Finally, the functional dominance of the p.R311Q variant to the p.G56R mutation is discussed.
Assuntos
Mutação , Receptores Citoplasmáticos e Nucleares/genética , Degeneração Retiniana/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Animais , Linhagem Celular , Ensaio de Desvio de Mobilidade Eletroforética , Saúde da Família , Feminino , Genes Dominantes , Genes Recessivos , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Receptores Nucleares Órfãos , Linhagem , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/metabolismo , Degeneração Retiniana/patologia , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To analyze the frequency of major age-related macular degeneration (AMD)-associated alleles in patients with multifocal choroiditis (MFC). METHODS: A cohort of 48 patients with MFC was compared with previously characterized cohorts of patients with advanced AMD (368 samples) and matched unaffected controls (368 samples). Allele and genotype frequencies of single nucleotide polymorphisms for the following AMD-associated alleles were evaluated: risk alleles in complement factor H (CFH) gene (Y402H and IVS14) and LOC387715/HTRA1 gene on 10q26 (A69S) and protective alleles in CFH (IVS1, IVS6, and delCFHR1-3) and complement factor B loci (H9L and R32Q). RESULTS: Frequencies of all major AMD-associated alleles in the CFH locus indicate a strong, statistically significant association of CFH gene single nucleotide polymorphisms and MFC. However, the same analysis for the single nucleotide polymorphisms in complement factor B and 10q26 loci matched the results in the control group. CONCLUSIONS: Like AMD, the MFC phenotype is strongly associated with the major alleles/haplotypes in the CFH locus. Clinical Relevance We report compelling evidence of a strong association between CFH polymorphisms and MFC, which contributes to the understanding of MFC pathogenesis and suggests new potential therapeutic targets.
Assuntos
Alelos , Corioidite/genética , Degeneração Macular/genética , Idoso , Fator B do Complemento/genética , Fator H do Complemento/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Proteínas/genéticaRESUMO
PURPOSE: To investigate the prevalence of sequence variants in the ATM gene and to determine the frequency of major age-related macular degeneration (AMD)-associated variants in CFH, CFB, and 10q26 loci in patients with idiopathic perifoveal telangiectasia (IPT). METHODS: Thirty patients with diagnoses of IPT underwent standard ophthalmologic evaluation that included visual acuity testing, fundus photography, and fluorescein angiography. DNA was screened for variations in the ATM gene by a combination of denaturing high-performance liquid chromatography and direct sequencing. Major AMD-associated alleles in CFH, CFB, and 10q loci were screened by PCR-restriction fragment-length polymorphism. RESULTS: Nineteen female and 11 male patients (average age, 59 years) with a median visual acuity of 20/50 were evaluated. Six patients were of Asian-Indian origin, one was Hispanic, and 23 were of European-American ancestry. Nine of 30 (30%) patients had diabetes mellitus, 18 of 30 (60%) patients had hypertension, and 12 of 30 (40%) patients had a history of smoking. Screening of the ATM gene revealed a null allele in 2 of 23 (8.7%) patients of European ancestry, previously disease-associated missense alleles in 4 of 23 (17.4%) patients, and common missense alleles in 7 of 23 (30.4%) patients. No variants were identified in the ATM gene in patients of Asian or Hispanic origin. Frequencies of major AMD-associated alleles in CFH, CFB, and 10q loci in the IPT cohort were similar to those in the ethnically matched general population. CONCLUSIONS: At least 26%, and maybe up to 57%, of IPT patients of European-American descent carried possibly disease-associated ATM alleles. Vascular risk factors such as hypertension, diabetes, and smoking may be associated with the pathogenesis of the disease.