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

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

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

The role of methyl-CpG binding domain protein 2 (MBD2) in an ApoE-deficient mouse model of age-related macular degeneration (AMD) was investigated. Eight-week-old Mbd2/ApoE double deficient (Mbd2(-/-) ApoE(-/-)) mice (n=12, 24 eyes, experimental group) and MBD2 (wt) ApoE(-/-) mice (n=12, 24 eyes, control group) were fed on Western-type diet for 4 months. The mice were sacrificed, and total serum cholesterol levels were analyzed and Bruch's membrane (BM) of the eyes was removed for ultrastructural observation by transmission electron microscopy. Moreover, intercellular adhesion molecule 1 (ICAM-1) immunoreactivities were evaluated by fluorescence microscopy in sections of the eyes in both groups for further understanding the function mechanism of MBD2. There was no significant difference in the total serum cholesterol levels between control group and experimental group (P>0.05). Transmission electron microscopy revealed that AMD-like lesions, various vacuoles accumulated on BM, notable outer collagenous layer deposits and dilated basal infoldings of retinal pigment epithelium (RPE) were seen in both groups, and the BM in control group was significantly thickened as compared with experimental group (P<0.05). Fluorescence micrographs exhibited the expression of ICAM-1 in choroid was higher in control group than in experimental group. We are led to conclude that MBD2 gene knockout may lead to accumulation of more deposits on the BM and influence the pathogenesis of AMD via triggering endothelial activation and inflammatory response in choroid, improving microcirculation, and reducing lipid deposition so as to inhibit the development of AMD-like lesions. Our study helps to provide a new therapeutic approach for the clinical treatment of AMD.
Animals ; Apolipoproteins E ; genetics ; metabolism ; Bruch Membrane ; metabolism ; ultrastructure ; Cholesterol ; blood ; Choroid ; metabolism ; ultrastructure ; DNA-Binding Proteins ; genetics ; metabolism ; Intercellular Adhesion Molecule-1 ; metabolism ; Macular Degeneration ; blood ; genetics ; metabolism ; Male ; Mice ; Mice, Knockout ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Retinal Pigment Epithelium ; metabolism ; ultrastructure

Aptamers are capable of binding a wide range of biomolecular targets with high affinity and specificity. It has been widely developed for diagnostic and therapeutic purposes. Because of unique three dimensional structures and cell-membrane penetration, aptamers inhibit virus infection not only through binding specific target, such as the viral envelope, genomic site, enzyme, or other viral components, but also can be connected to each other or with siRNA jointly achieve antiviral activity. Taking human immunodeficiency virus and hepatitis C virus as examples, this paper reviewed the effects and mechanisms of aptamers on disturbing viral infection and replication steps. It may provide an insight to the development of aptamer-based new antiviral drugs.
Antiviral Agents ; pharmacology ; Aptamers, Nucleotide ; pharmacology ; therapeutic use ; Genome, Viral ; drug effects ; HIV ; drug effects ; HIV Reverse Transcriptase ; metabolism ; Hepacivirus ; drug effects ; genetics ; Humans ; Macular Degeneration ; drug therapy ; Neoplasms ; drug therapy ; Oligodeoxyribonucleotides ; therapeutic use ; RNA, Small Interfering ; pharmacology ; SELEX Aptamer Technique ; Viral Envelope Proteins ; metabolism ; Virus Replication ; drug 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

PURPOSE: The purpose of this study was to determine the pharmacogenetic effects of complement factor H (CFH) Y402H, LOC387715 and high-temperature requirement factor A1 (HTRA1) genotypes on the treatment of exudative age-related macular degeneration (AMD) by intravitreal bevacizumab injection in a Korean population. METHODS: Seventy-five patients diagnosed with exudative AMD were treated with intravitreal bevacizumab (2.5 mg) monotherapy. All patients received three initial intravitreal bevacizumab injections every four weeks and were then treated "as needed" based on clinical findings, optical coherence tomography and fluorescein angiography during the 12 month follow-up period after the third injection. RESULTS: The difference in visual acuity improvement among the three genotypes of LOC387715 were statistically significant at six months post-treatment (logarithm of the minimum angle of resolution; TT, 0.346; GT, 0.264; GG, 0.188; p = 0.037). Among the LOC387715 genotypes, the number of additional injections was lower in patients who had the risk T allele (GG, 2.143; GT, 2.000; TT, 1.575; p = 0.064). There was no significant difference between visual acuity and central macular thickness change in the CFH Y402H polymorphism group during the 12 month follow-up period. However, the TC group of CFH Y402H required more additional bevacizumab injections than the TT group (TT, 1.517; TC, 3.363; p = 0.020). CONCLUSIONS: This study demonstrated that different LOC387715/HTRA1 genotypes resulted in different bevacizumab treatment responses on exudative AMD. Patients with the risk allele had an improved treatment response and less need for additional injections. However, patients with the CFH Y402H risk allele needed more additional injections of bevacizumab in order to improve visual acuity. This study illustrates how pharmacogenetic factors may help determine treatment modality and dosing. This could ultimately provide basic data for 'personalized medicine' in AMD.
Aged ; Alleles ; Angiogenesis Inhibitors/administration & dosage/therapeutic use ; Antibodies, Monoclonal, Humanized/*administration & dosage/therapeutic use ; DNA/*genetics ; Female ; Follow-Up Studies ; Genotype ; Humans ; Intravitreal Injections ; Macular Degeneration/drug therapy/epidemiology/*genetics ; Male ; Pharmacogenetics/*methods ; *Polymorphism, Genetic ; Retrospective Studies ; Serine Endopeptidases/*genetics/metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Visual Acuity

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

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

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