Age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries. It is a genetically heterogeneous disorder. With the development of molecular biology and molecular genetics, multiple potentially causative genes have been identified. Current studies of susceptibility genes and genetic epidemiology of AMD are reviewed.
Blindness ; epidemiology ; genetics ; Chromosomes, Human ; genetics ; Genetic Predisposition to Disease ; Humans ; Macular Degeneration ; epidemiology ; genetics ; Molecular Epidemiology

INTRODUCTIONIn this paper, we report a novel VMD2 gene mutation in a Chinese family with Best vitelliform macular dystrophy.

MATERIALS AND METHODSOphthalmologic examination and optical coherence tomography (OCT) were performed in 2 members of this family. Mutational screening was performed by single-strand conformation polymorphism (SSCP) and direct sequencing of PCR-amplified DNA fragments, corresponding to the 11 exons of the gene.

RESULTSSequence analysis identified a previously unreported C to G change, predicting a Phe-113-Leu substitution. Both the proband and his sister harboured this novel mutation. Each had bilateral vitelliform lesions.

CONCLUSIONSA novel mutation in the VMD2 gene (C427G) was found in Chinese patients with Best vitelliform macular dystrophy.

Adult ; Bestrophins ; China ; Chloride Channels ; Eye Proteins ; genetics ; Female ; Humans ; Macular Degeneration ; genetics ; Male ; Mutation ; Pedigree

Cataract ; genetics ; Diabetic Retinopathy ; genetics ; Eye Diseases ; genetics ; therapy ; Genetic Therapy ; Glaucoma, Open-Angle ; genetics ; Humans ; Macular Degeneration ; genetics

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of vision loss worldwide. However, the mechanisms involved in the development and progression of AMD are poorly delineated. We aimed to explore the critical genes involved in the progression of AMD. METHODS: The differentially expressed genes (DEGs) in AMD retinal pigment epithelial (RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564, which were downloaded from the gene expression omnibus database. The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The hub genes were identified from these DEGs through protein-protein interaction network analyses. The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866. Following the identification of AMD-related key genes, the potential small molecule compounds targeting the key genes were predicted by PharmacoDB. Finally, a microRNA-gene interaction network was constructed. RESULTS: Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples. These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Among the top ten hub genes, HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in the senescent ARPE-19 cells. Additionally, the drugs targeting HSP90AA1, CHEK1, and PSMA4 were identified. We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE. CONCLUSIONS Based on our findings, HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD. Targeting HSP90AA1, CHEK1, PSMA4, PSMD4, and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.
DNA Replication ; Gene Expression Profiling ; Gene Ontology ; Humans ; Macular Degeneration/genetics* ; Proteasome Endopeptidase Complex

OBJECTIVEA R1210C mutation of complement factor H (CFH) gene has been associated with age-related macular degeneration (AMD) in Caucasian population. This study was to verify above association in Han Chinese population.

METHODSThe mutation was detected by direct sequencing in 258 patients with wet AMD and 426 matched controls.

RESULTSThe R1210C mutation has not been identified in either sample.

CONCLUSIONThe R1210C mutation in CFH gene is not associated with AMD in Han Chinese population.

Aged ; Aged, 80 and over ; Complement Factor H ; genetics ; Female ; Humans ; Macular Degeneration ; genetics ; Male ; Middle Aged ; Mutation

OBJECTIVE: To assess the association of 7 single nucleotide polymorphisms (SNPs) including rs13278062 (TNFRSF10A), rs3750846 (ARMS2-HTRA1), rs429358 (APOE), rs5817082 (CEPT), rs2043085 (LIPC), rs1626340 (TGFBR1), and rs8135665 (SLC16A8) identified through genome-wide association study (GWAS) with age-related macular degeneration (AMD) among ethnic Han Chinese from Sichuan, China. METHODS: A cohort of 576 AMD patients and 572 healthy controls were enrolled in a case-control study. The SNPs were genotyped by a Mass array MALDI-TOF System. On the premise that the genotype distribution of each SNP locus in both groups satisfied Hardy-Weinberg equilibrium, the genetic pattern was analyzed and the scores of allele and genotype frequencies ware compared. RESULTS: There was a significant association between TNFRSF10A rs13278062 and AMD under the heterozygous model (P = 0.000, OR = 1.529, 95%CI = 1.196-1.954) and the dominant model (P = 0.002, OR = 1.459, 95%CI = 1.154-1.865), suggesting that subjects carrying rs13278062GT and rs13278062TT + GT are more likely to develop the AMD, whereas no significant difference was observed for rs13278062 under other models. No association was detected with the other six SNPs and AMD under various genetic models. CONCLUSION This case-control association study has indicated that TNFRSF10A rs13278062 is associated with AMD under the heterozygous and dominant models, suggesting that the TNFRSF10A variant may be involved in the development of AMD among ethnic Han Chinese population.
Case-Control Studies ; Gene Frequency ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; High-Temperature Requirement A Serine Peptidase 1/genetics* ; Humans ; Macular Degeneration/genetics* ; Polymorphism, Single Nucleotide

No abstract available.
Adult ; Alleles ; Asian Continental Ancestry Group/*genetics ; Bardet-Biedl Syndrome/diagnosis/*genetics ; Base Sequence ; Blindness/pathology ; DNA/chemistry/metabolism ; Exons ; *Heterozygote ; Humans ; Macular Degeneration/diagnosis ; Male ; *Mutation ; Pedigree ; Phenotype ; Polymorphism, Single Nucleotide ; Proteins/*genetics ; Republic of Korea

PURPOSE: To characterize and report the phenotype of a Korean family with an early-onset autosomal dominant macular dystrophy resembling North Carolina macular dystrophy (NCMD). METHODS: Five members of a Korean family were examined clinically and underwent fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, full field electroretinogram (ERG), multifocal ERG, electro-oculography (EOG), a color vision test, and a visual field test. RESULTS: Visual acuity ranged from 20/200 to 20/20. Fundus findings demonstrated varying degrees of involvement ranging from drusen only to chorioretinal involvement. Central scotoma corresponded to retinal lesions in two patients. Full field ERG was normal but multifocal ERG showed decreased amplitude and delayed implicit time in the macular area. EOG was normal except in one patient. Color vision tests were also normal. CONCLUSIONS: The phenotype of this Korean family is consistent with NCMD. Linkage analysis is required to confirm the diagnosis.
Tomography, Optical Coherence ; Prevalence ; Phenotype ; Pedigree ; Middle Aged ; Male ; *Macular Degeneration/diagnosis/epidemiology/genetics ; Macula Lutea/*pathology ; Korea/epidemiology ; Humans ; Fundus Oculi ; Fluorescein Angiography ; Female ; Electroretinography ; Diagnosis, Differential ; Child ; Age of Onset ; Adult ; Adolescent

BACKGROUNDThe present study was undertaken to replicate the associations of representative polymorphisms in three genes (complement factor H (CFH), complement factor B (BF) and HtrA serine peptidase 1 (HTRA1)) with exudative age-related macular degeneration (AMD) in a Han Chinese population, and to test if the modifiable environmental factors affect AMD susceptibility associated with different type of genotype in these genes.

METHODSAn age, gender and ethnicity matched case-control study was conducted to genotype the representative single neucleotide polymorphisms (SNPs) loci including rs1061170 and rs1410996 in CFH, rs641153 and rs4151667 in BF and rs11200638 in HTRA1 gene in 144 exudative AMD patients and 126 normal controls using PCR-RFLP and direct resequencing. The demographic characteristics and behavioral risk factors were also recorded. Allelic and genotypic associations for individual SNP and joint associations with two loci were performed. The gene-gene and gene-environment interactions were analyzed using multivariate non-conditional Logistic regression analysis.

RESULTSThe C risk allele frequencies for CFH Y402H (rs1061170) in cases and controls were 12.5% and 5.4% respectively, which were much lower than those in Caucasians (P < 0.001). Compared with TT homozygous genotype, the CT heterozygous genotype was positively associated with AMD with odds ratio (OR) of 3.23 (1.36 - 5.07). However, the population attributable risk (PAR) of C allele was only 3.3% (1.4% - 4.3%). rs1410996 was also associated with AMD independent of Y402H. The ORs of exudative AMD for individuals carrying one copy risk allele and two copy risk alleles were 2.57 (1.21 - 5.45) and 4.76 (2.15 - 10.55) respectively, with correspondent PARs of 28.3% (2.0% - 40.5%) and 38.2% (21.8% - 45.4%). rs11200638 in HTRA1 was another susceptible locus for AMD and the risk homozygotes were significantly susceptible for exudutive AMD (OR = 3.98, 1.88 - 8.43) with PAR of 38.9% (24.3% - 45.8%). Education status and cigarette smoking were also related to exudative AMD. After controlling for environmental risk factors, CFH and HTRA1 SNPs were independently associated with exudative AMD, with OR of 3.50 (1.45 - 8.45) for CT genotype in Y402H, 3.34 (1.33 - 8.36) for GG genotype in rs1410996 and 3.85 (1.58 - 9.42) for AA genotype in rs11200638 respectively. The interaction analysis between gene and environmental factors showed that smoking synergistically increased susceptibility of AMD for heterozygotes of rs1410996, with OR(interaction) of 7.33 (P(interaction) = 0.029).

CONCLUSIONSIn a Han Chinese population, CFH and HTRA1 polymorphisms appear to be independently and possibly additively hereditary contributors to exudative AMD. Y402H polymorphism conferred a significant but relatively lower contribution in Chinese than in Caucasians with a low frequency of risk allele. The gene-environment interaction may be a best way to encourage those with a high genetic risk to prevent AMD by avoiding modifiable factors until there is effective treatment for AMD.

Aged ; Asian Continental Ancestry Group ; Complement Factor B ; genetics ; Complement Factor H ; genetics ; Female ; Gene Frequency ; genetics ; Genetic Predisposition to Disease ; genetics ; Genotype ; High-Temperature Requirement A Serine Peptidase 1 ; Humans ; Macular Degeneration ; genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; genetics ; Risk Factors ; Serine Endopeptidases ; genetics ; Smoking ; adverse effects

PURPOSE: To investigate whether the G6721T polymorphism (rs.7003908) of the non-homologous end-joining DNA repair XRCC7 gene contributes to the development of exudative age-related macular degeneration (ARMD). METHODS: The present case-control study consisted of 111 patients with exudative ARMD and 112 sex frequency-matched healthy controls that were randomly selected from unrelated volunteers in the same clinic. Genotypes were determined by the Restriction Fragment Length Polymorphism (PCR-RFLP) based method. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ARMD risk associated with polymorphism of XRCC7. In all analysis the GG genotype was considered to be the reference genotype. RESULTS: There was no significant association between genotypes of XRCC7 and susceptibility to ARMD. Considering the significant difference in age distribution between cases and controls, age was used as a covariate in further analysis. After ORs were adjusted for age, the same result was observed. In the next step we stratified our subjects into outdoor and indoor groups according to their job titles. The outdoor and indoor patients were occupationally exposed to sunlight and not exposed to sunlight, respectively. Our present study showed that among indoor subjects there was no association between XRCC7 polymorphism and susceptibility to ARMD. However, among outdoor subjects, the GT + TT genotypes compared to the GG genotype increased the risk of ARMD (OR, 3.13; 95% CI, 1.04-9.39; p = 0.042). CONCLUSIONS: Our study revealed that the T allele of the G6721T polymorphism of XRCC7 increased the risk of ARMD among outdoor subjects.
Aged ; DNA/*genetics ; DNA-Activated Protein Kinase/*genetics/metabolism ; *Environmental Exposure ; Exudates and Transudates ; Female ; Follow-Up Studies ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Macular Degeneration/*genetics/metabolism ; Male ; Middle Aged ; Nuclear Proteins/*genetics/metabolism ; Polymerase Chain Reaction ; *Polymorphism, Genetic ; Retrospective Studies ; Risk Factors