RESUMO
Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =â -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.
Assuntos
Câmara Anterior/patologia , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Fechado/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Câmara Anterior/metabolismo , Povo Asiático , Glaucoma de Ângulo Fechado/patologia , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Congenital hereditary endothelial dystrophy (CHED) is a heritable, bilateral corneal dystrophy characterized by corneal opacification and nystagmus. We describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive CHED. Mutations in SLC4A11, which encodes a membrane-bound sodium-borate cotransporter, cause loss of function of the protein either by blocking its membrane targeting or nonsense-mediated decay.
Assuntos
Proteínas de Transporte de Ânions/genética , Antiporters/genética , Distrofias Hereditárias da Córnea/genética , Mutação Puntual , Substituição de Aminoácidos , Proteínas de Transporte de Ânions/metabolismo , Antiporters/metabolismo , Boratos/metabolismo , Distrofias Hereditárias da Córnea/metabolismo , Feminino , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/metabolismo , Genes Recessivos , Humanos , MasculinoRESUMO
Glaucoma is a neurodegenerative disease, which results in characteristic visual field defects. Intraocular pressure (IOP) remains the main risk factor for this leading cause of blindness. Recent studies suggest that disturbances in neurovascular coupling (NVC) may be associated with glaucoma. The resultant imbalance between vascular perfusion and neuronal stimulation in the eye may precede retinal ganglion cell (RGC) loss and increase the susceptibility of the eye to raised IOP and glaucomatous degeneration. Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found abundantly in retinal glial and vascular tissues, with possible involvement in regulating the neurovascular coupling response. Mutations in Cav-1 have been identified as a major genetic risk factor for glaucoma. Therefore, we aim to evaluate the effects of Cav-1 depletion on neurovascular coupling, retinal vessel characteristics, RGC density and the positive scotopic threshold response (pSTR) in Cav-1 knockout (KO) versus wild type C57/Bl6 mice (WT). Following light flicker stimulation of the retina, Cav-1 KO mice showed a smaller increase in perfusion at the optic nerve head and peripapillary arteries, suggesting defective neurovascular coupling. Evaluation of the superficial capillary plexus in Cav-1 KO mice also revealed significant differences in vascular morphology with higher vessel density, junction density and decreased average vessel length. Cav-1 KO mice exhibited higher IOP and lower pSTR amplitude. However, there was no significant difference in RGC density between Cav-1 KO and wild type mice. These findings highlight the role of Cav-1 in regulating neurovascular coupling and IOP and suggest that the loss of Cav-1 may predispose to vascular dysfunction and decreased RGC signaling in the absence of structural loss. Current treatment for glaucoma relies heavily on IOP-lowering drugs, however, there is an immense potential for new therapeutic strategies that increase Cav-1 expression or augment its downstream signaling in order to avert vascular dysfunction and glaucomatous change.
RESUMO
The endothelial (posterior) corneal dystrophies, which result from primary endothelial dysfunction, include Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD) and congenital hereditary endothelial dystrophy (CHED). Mutations in SLC4A11 gene have been recently identified in patients with recessive CHED (CHED2). In this study, we show that heterozygous mutations in the SLC4A11 gene also cause late-onset FECD. Four heterozygous mutations [three missense mutations (E399K, G709E and T754M) and one deletion mutation (c.99-100delTC)] absent in ethnically matched controls were identified in a screen of 89 FECD patients. Missense mutations involved amino acid residues showing high interspecies conservation, indicating that mutations at these sites would be deleterious. Accordingly, immunoblot analysis, biochemical assay of cell surface localization and confocal immunolocalization showed that missense proteins encoded by the mutants were defective in localization to the cell surface. Our data suggests that SLC4A11 haploinsufficiency and gradual accumulation of the aberrant misfolded protein may play a role in FECD pathology and that reduced levels of SLC4A11 influence the long-term viability of the neural crest derived corneal endothelial cells.
Assuntos
Proteínas de Transporte de Ânions/genética , Antiporters/genética , Distrofia Endotelial de Fuchs/genética , Deleção de Genes , Mutação de Sentido Incorreto , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Substituição de Aminoácidos , Povo Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Sequência Conservada , Feminino , Mutação da Fase de Leitura , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/etiologia , Distrofia Endotelial de Fuchs/patologia , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Estatística como AssuntoRESUMO
PURPOSE: Because the endothelial (posterior) corneal dystrophies share common pathologic features and result from primary endothelial dysfunction, it is possible that a proportion of them could be clinical manifestations of different mutations of the same gene. The aim of our study was to determine whether mutations of the TCF8 gene, recently implicated in posterior polymorphous dystrophy, may also play a role in the development of the more common Fuchs endothelial corneal dystrophy (FECD). METHODS: Genomic DNA was extracted from leukocytes of peripheral blood, and the nine exons of the TCF8 gene were PCR amplified and subjected to bidirectional sequencing and analysis. Samples from 74 unrelated Chinese patients (55 women, 19 men) with a diagnosis of late-onset FECD and 93 age- and race-matched controls were studied. RESULTS: The affected probands ranged in age from 52 to 91 years (mean age, 65.1 years); 8 had familial FECD and 66 had sporadic FECD. The authors found two mutations in the coding region of the TCF8 gene: a novel missense mutation in one patient c.2087A>G in exon 7 (Asn696Ser) and a silent mutation in exon 2 c.192T>C (D64D). CONCLUSIONS: The identification of a novel missense mutation in only one of the patients implied that TCF8 does not play a significant role in the pathogenesis of FECD in this Chinese population.
Assuntos
Distrofia Endotelial de Fuchs/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Dedos de Zinco/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
PURPOSE: Polypoidal choroidal vasculopathy (PCV) is a major cause of serosanguinous maculopathy in Chinese patients with age-related macular degeneration (AMD). Variants in the CFH and HTRA1/LOC387715 genes are strongly associated with AMD in Caucasians and Chinese. Variants in the C2 and BF genes have been found to confer a significantly reduced risk of AMD. This study was undertaken to determine whether these associations occur in Chinese patients with PCV. METHODS: Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV and normal control subjects were recruited from the Singapore National Eye Centre. Five single-nucleotide polymorphisms (SNPs) in the CFH gene, two each within the C2 and BF genes and two variants located in the LOC387715 and HTRA1 genes, were screened in all patients and control subjects. RESULTS: Seventy-two patients with PCV and 93 normal control subjects were studied. A significant association was noted with CFH variants rs3753394 and rs800292 among the PCV cases (P = 0.0015 and P = 0.0045, respectively). Individuals homozygous for the TT genotype of rs3753394 had a significantly higher risk (P = 0.0076) of PCV (OR = 4.29; 95% CI: 1.47-12.50) than those carrying a single copy of the T allele (P = 0.3210; OR = 1.69; 95% CI: 0.60-4.78), after adjustment for such risk factors as age and sex. The genotype frequencies of rs11200638 and rs10490924 in HTRA1 and LOC387715, respectively, were also found to be significantly different between patients with PCV and normal control subjects (P = 0.00032 and P = 0.003, respectively). The AA genotype of rs11200638 and TT genotype of rs10490924 conferred a 4.9-fold (95% CI: 1.85-12.95) and 4.89-fold (95% CI: 1.85-12.90) increased risk of PCV, respectively, after adjustment for age and sex. The Y402H variant of CFH (rs1061170) and the BF and C2 variants were not significantly different in patients and normal control subjects. CONCLUSIONS: The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV in Chinese patients.
Assuntos
Doenças da Coroide/genética , Complemento C2/genética , Fator B do Complemento/genética , Doenças Vasculares Periféricas/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Corioide/irrigação sanguínea , Fator H do Complemento/genética , Feminino , Angiofluoresceinografia , Frequência do Gene , Genótipo , Haplótipos , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Desequilíbrio de Ligação , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Singapura/epidemiologiaRESUMO
PURPOSE: The genetic basis of primary angle closure glaucoma (PACG) has yet to be elucidated. Ocular characteristics related to PACG such as short hyperopic eyes with shallow anterior chambers suggest the involvement of genes that regulate ocular size. CHX10, a retinal homeobox gene associated with microphthalmia, and MFRP, the membrane-type frizzled-related protein gene underlying recessive nanophthalmos, represent good candidate genes for PACG due to the association with small eyes. To investigate the possible involvement of CHX10 and MFRP in PACG, we sequenced both genes in PACG patients with small ocular dimensions. METHODS: One hundred and eight Chinese patients with axial lengths measuring 22.50 mm or less were selected for analysis. Ninety-three age- and ethnically-matched control subjects were also screened. Genomic DNA was extracted from leukocytes of peripheral blood samples, and the exons of CHX10 and MFRP were amplified by polymerase chain reaction (PCR) and subjected to bidirectional sequencing and analysis. RESULTS: All study patients were Chinese with a mean age of 66.2+/-9.1 years (range 46-86). There were 77 females (71.3%). Forty-nine out of the one hundred and eight subjects had previous symptomatic PACG, and 59 had asymptomatic PACG. The mean axial length was 21.90+/-0.50 mm (range 19.98-22.50 mm). We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient. This variant was not found in 215 normal controls. Several CHX10 and MFRP polymorphisms were also identified. CONCLUSIONS: Our results do not support a significant role for CHX10 or MFRP mutations in PACG.
Assuntos
Povo Asiático/genética , Anormalidades do Olho/complicações , Anormalidades do Olho/genética , Glaucoma de Ângulo Fechado/complicações , Glaucoma de Ângulo Fechado/genética , Proteínas de Homeodomínio/genética , Proteínas de Membrana/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Sequência de Bases , China , Análise Mutacional de DNA , Demografia , Feminino , Proteínas de Homeodomínio/química , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , Fatores de Transcrição/químicaRESUMO
PURPOSE: A recent study identified the single nucleotide polymorphism (SNP) rs2664538 within the MMP-9 gene with risk for acute primary angle closure glaucoma (PACG). The aim of this study was to confirm this association in Singaporean Chinese subjects with both acute and chronic PACG. METHODS: This was an observational cross-sectional study. Genomic DNA was extracted from leukocytes of peripheral blood and genotypes were determined by polymerase chain reaction and direct sequencing. The association of the SNP with PACG was evaluated using chi tests. RESULTS: A total of 217 subjects with PACG (consisting of 85 acute and 132 chronic PACG), and 83 normal control Chinese subjects were studied. There was no significant difference in the rs2664538 SNP allele frequencies for acute or chronic PACG subjects compared with controls. CONCLUSIONS: This study did not find an association between the rs2664538 polymorphism within the MMP-9 gene and PACG in this sample of Chinese subjects.
Assuntos
Glaucoma de Ângulo Fechado/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/etnologia , Doença Crônica , Estudos Transversais , Feminino , Genótipo , Glaucoma de Ângulo Fechado/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Singapura/epidemiologiaRESUMO
Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is a severe and rare corneal disorder that presents at birth or shortly thereafter, characterized by corneal opacification and nystagmus. Recently the gene for CHED2 was identified and seven different mutations in the SLC4A11 gene were reported. Here, we report seven novel mutations and two previously identified mutations in families from India and the United Kingdom with recessive CHED. The novel changes include two nonsense (p.Trp240X; p.Gln800X) three missense (p.Glu143Lys; p.Cys386Arg; p.Arg755Trp) and two splice site mutations (c.2240+1G>A; c.2437-1G>A). Interestingly, the c.2398C>T (p.Gln800X) and c.2437-1G>A identified in two affected siblings represent the first compound heterozygous mutations in the SLC4A11 gene.
Assuntos
Proteínas de Transporte de Ânions/genética , Antiporters/genética , Doenças da Córnea/genética , Genes Recessivos , Mutação , Triagem de Portadores Genéticos , Humanos , Índia , Estados UnidosRESUMO
PURPOSE: A recent study identified single nucleotide polymorphisms (SNPs) within the IL-1 gene cluster at chromosomal locus 2q13 that were associated with reduced risk for primary open-angle glaucoma (POAG) in whites. The purpose of this study was to investigate the association between IL-1 SNPs and glaucoma in Chinese patients with either POAG or primary-angle closure glaucoma (PACG). METHODS: Patients with POAG with a mean IOP without treatment that was consistently <21 mm Hg on diurnal testing were classified as having normal-tension glaucoma (NTG) and those with higher IOP were classified as having high-tension glaucoma (HTG). Subjects with PACG had at least 180 degrees of angle closure on gonioscopy. Genotypes were determined by polymerase chain reaction and restriction digest enzymes at the following loci: IL1A (-889C/T), IL1B (+3953C/T), and IL1B (-511C/T). The association of individual SNPs with glaucoma was evaluated by using chi(2) testing. Haplotype analysis was performed with the PHASE program, with haplotype frequency estimated for combined cases and controls, assuming Hardy-Weinberg equilibrium (HWE) of haplotypes. RESULTS: Of the Chinese subjects studies, 194 had POAG (94 NTG and 100 HTG), 125 had PACG, and 79 were normal control subjects. There was no significant difference in IL-1 SNP or allele frequencies for in subjects with POAG or PACG compared with control subjects, or between NTG and HTG. None of the common haplotypes showed any significant difference between the HTG, NTG, PACG, and normal control subjects. CONCLUSIONS: This study did not find an association between IL-1 gene cluster polymorphisms and glaucoma in this sample of Chinese subjects.
Assuntos
Glaucoma de Ângulo Fechado/genética , Glaucoma de Ângulo Aberto/genética , Interleucina-1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Cromossomos Humanos Par 2/genética , Feminino , Genótipo , Haplótipos , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Família Multigênica , Hipertensão Ocular/genética , Reação em Cadeia da PolimeraseRESUMO
PURPOSE: Primary congenital glaucoma (PCG, OMIM 231300), the most common glaucoma in infancy, is caused by developmental defects in the anterior chamber angle. The 3 implicated genes are cytochrome P450 family I subfamily B polypeptide 1 (CYP1B1), latent transforming growth factor ß-binding protein 2 (LTBP2), and myocilin (MYOC). In this study, we sought to determine CYP1B1 and MYOC sequence variations in a Vietnamese cohort of index cases with PCG and their families. METHODS: Thirty Vietnamese subjects with PCG and 120 normal Vietnamese subjects were recruited. PCG was defined by the presence of at least 2 of the following clinical manifestations: increased corneal diameter (>10 mm at birth), corneal edema, Haab's striae, optic disc changes, and absence of other ocular or systemic diseases associated with childhood glaucoma. The coding exons, intron and exon boundaries, and untranslated regions of CYP1B1 and MYOC genes were PCR amplified and subjected to bidirectional sequencing in all subjects. RESULTS: We identified 2 homozygous and 3 heterozygous CYP1B1 sequence alterations in our study subjects. Among the 5 mutations identified, 2 (p.H279L and p.L283F) were novel mutations, whereas 3 (p.A121_S122insDRPAFA, p.L107V, and p.V320L) had been previously reported in PCG cases. None of these mutations was observed in any of the 120 controls. Haplotypes generated with 6 non-disease-causing intragenic single nucleotide polymorphisms detected in CYP1B1 indicated that the most common haplotype in Vietnamese population is similar to that found in Chinese and Japanese. The genotype-phenotype correlation showed no significant difference between mutation and no-mutation groups for quantitative clinical features (presenting intraocular pressure, corneal diameter, number of surgeries performed, the cup-to-disc ratio) as well as for qualitative factors (bilateral cases, phenotype severity, and the prognosis) (P>0.05). CONCLUSIONS: Five out of 30 families with PCG (16.7%) had disease attributable to CYP1B1 alterations suggesting that CYP1B1 is not the major gene causing PCG in Vietnamese unlike in the case of Arab or Romany patients. This percentage is similar to that detected in studies of Japanese and Chinese patients with sporadic PCG. PCG has proven to be an ocular disease of genetic heterogeneity, calling for further studies to identify novel genes causing this disease.
Assuntos
Povo Asiático/genética , Citocromo P-450 CYP1B1/genética , Proteínas do Citoesqueleto/genética , Proteínas do Olho/genética , Glicoproteínas/genética , Hidroftalmia/genética , Mutação , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Pressão Intraocular/fisiologia , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Tonometria Ocular , VietnãRESUMO
PURPOSE: Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS: Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS: Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS: This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Mutação , Degeneração Retiniana/genética , Adulto , Idoso , Sequência de Bases , Família 4 do Citocromo P450 , Análise Mutacional de DNA , Eletrorretinografia , Éxons/genética , Feminino , Angiofluoresceinografia , Efeito Fundador , Genes Recessivos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Degeneração Retiniana/diagnóstico , Deleção de Sequência , Singapura , Campos VisuaisRESUMO
PURPOSE: Mutations in the myocilin (MYOC) gene have been implicated in juvenile as well as late-onset primary open-angle glaucoma (POAG). Overall, MYOC mutations account for 3% to 5% of cases of POAG worldwide, making it the most significant gene identified so far in glaucoma. Although there are some similarities in the phenotype of POAG and in particular chronic primary angle-closure glaucoma (PACG), little is known about the role of MYOC in the causation of PACG. To address this, the MYOC gene was screened in a cohort of 106 patients with chronic PACG. METHODS: Genomic DNA was extracted from leukocytes of the peripheral blood and exons 1 to 3 of the MYOC gene were PCR amplified and subjected to bidirectional sequencing and analysis. RESULTS: One hundred six patients with chronic PACG of Chinese ethnicity were studied. Sequencing of the MYOC gene in these patients revealed eight sequence variants. Of these, one was a nonsense change, three were missense changes, two were synonymous codon changes, and two were changes in noncoding sequences. These included the Arg46Stop and Thr353Ile mutations, which have been reported in individuals with POAG. However, all the sequence alterations identified have been found in normal Chinese subjects. CONCLUSIONS: The results of this study do not support a role for MYOC mutations in the pathogenesis of chronic PACG in the Chinese.
Assuntos
Proteínas do Olho/genética , Glaucoma de Ângulo Fechado/genética , Glicoproteínas/genética , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/etnologia , Doença Crônica , Proteínas do Citoesqueleto , DNA/isolamento & purificação , Feminino , Glaucoma de Ângulo Fechado/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Biologia Molecular , Mutação , Reação em Cadeia da Polimerase , Singapura/epidemiologiaAssuntos
Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Adaptação Ocular/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Povo Asiático , Eletrorretinografia , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Linhagem , Células Fotorreceptoras de Vertebrados/fisiologia , Reação em Cadeia da Polimerase , Proteínas RGS/genética , Proteínas RGS/metabolismo , Transtornos da Visão/genética , Transtornos da Visão/fisiopatologiaRESUMO
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.
Assuntos
Proteínas de Transporte/genética , Colágeno Tipo XI/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Fechado/genética , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/genética , Estudos de Casos e Controles , Loci Gênicos , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Proteínas Repressoras/genéticaRESUMO
PURPOSE: The single nucleotide polymorphisms (SNPs) rs1048661, rs3825942, and rs2165241 within the LOXL1 gene were recently found to confer risk of pseudoexfoliation glaucoma (XFG) through pseudoexfoliation syndrome (XFS) in Caucasians. The purpose of this study was to test this association in Japanese subjects with XFS/XFG. METHODS: Japanese subjects with clinically diagnosed XFS/XFG and normal control subjects were recruited. Genomic DNA was extracted and the three SNPs of the LOXL1 gene were genotyped by bidirectional sequencing. The association of individual SNPs with XFG/XFS was evaluated by using chi(2) and the Fisher exact test. RESULTS: Two hundred nine Japanese patients (106 XFG and 103 XFS) and 172 control subjects were studied. Strong associations were observed for all three SNPs of LOXL1 for XFS (odds ratio [OR] = 13.56, P = 3.39 x 10(-28) for allele T of rs1048661; OR = 10.71, P = 1.49 x 10(-7) for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10(-4) for allele C of rs2165241) and XFG (OR = 25.21, P = 1.44 x 10(-34) for allele T of rs1048661; OR = 11.02, P = 1.40 x 10(-7) for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10(-6) for allele C of rs2165241). The risk-associated alleles of rs1048661 and rs2165241 differed between the Japanese and Caucasians, whereas allele G of rs3825942 was associated with disease in both populations. Conditional analysis indicated that rs3825942 was not independent but correlated highly with rs1048661. The at-risk haplotype T-G-C was present at an approximately two times higher rate (94.7% vs. 50.6%, P = 4.22 x 10(-43)) in cases than in control subjects and conferred a 2.9-fold (95% confidence interval [CI], 2.357-3.464) increased likelihood of XFS. CONCLUSIONS: Polymorphisms in the LOXL1 gene confer risk to XFS/XFG in the Japanese, but there are different risk-associated alleles and haplotypes in the Japanese.