Epigenetic modifications such as DNA methylation, histone post-translational modifications, non-coding RNA are reversible, heritable alterations which are induced by environmental stimuli. Major risk factors of diabetes and diabetic complications including hyperglycemia, oxidative stress and advanced glycation end products, can lead to abnormal epigenetic modifications in retinal vascular endothelial cells and retinal pigment epithelium cells. Epigenetic mechanisms are involved in the pathogenesis of macular edema and neovascularization of diabetic retinopathy (DR), as well as diabetic metabolic memory. The heritable nature of epigenetic marks also playsakey role in familial diabetes mellitus. Further elucidation of epigenetic mechanisms in DR can open the way for the discovery of novel therapeutic targets to prevent DR progression.
Objective To investigate the disease-causing gene of Stargardt disease. Method Fifteen patients with Stargardt disease were analyzed with 11 primers of the 11 exons of ABCR gene by using PCR-SSCP and DNA direct sequencing techniques. Results Three newly detected disease-causing mutations were found. Among those mutations, one is a frameshift mutation and others are single base transition. Conclusion This research confirmed that ABCR gene is associated with Stargardt disease, and 3 new mutations of ABCR gene were found. (Chin J Ocul Fundus Dis,2000,16:240-243)
Objective To analyze the relationship of human leukocyte antigen alleles (HLA-A/B, HLA-DRB/DQB) polymorphism and Eales disease, tuberculosis infection in a Han population in Zunyi city of China. Methods The subjects were analyzed by case control study, which consisted of three groups including Eales disease group (47 patients), pulmonary tuberculosis group (36 patients) and normal control group (100 healthy people). Thirty-nine patients in Eales disease group who had complete history were divided into 4 subgroups according to the history and tuberculin PPD test. Twelve patients with past or present pulmonary tuberculosis were in group A, 27 patients without pulmonary tuberculosis were in group B, 27 patients with positive PPD test were in group C, and 12 patients with negative PPD test were in group D. Fifty-nine alleles of HLA-A/B and HLA-DRB/DQB were analyzed by polymerase chain reaction with sequencespecific primers (PCR-SSP) in all subjects. Odds ratios between each group (OR) and 95% confidence interval (CI) were calculated; Frequency distribution of HLA-A02 gene were analyzed for the group A and the TB group. Results The frequency distribution of HLA-A02 （OR=9.719, OR95% CI:4.377-21.580,P=0.000）and HLA-B07 （OR=11.605, OR95% CI:2.397-56.191,P=0.001）alleles in Eales disease group were obviously higher than that in normal control group, but frequency distribution of HLA-A11（OR=0.495, OR95% CI:0.245-1.000,P=0.048）in Eales disease group was obviously lower than that in normal control group. There was no significant difference in frequency distribution of HLA-A02, HLA-A11 and HLA-B07 alleles between groups A and B, and between groups C and D (P＞0.05). The distribution frequency of HLA-A02, HLA-A24, HLA-B07 and HLA-DRB16 alleles among Eales disease group, pulmonary tuberculosis group and control group was statistically different (P＜0.05). The frequency distribution of HLA-A24 alleles in pulmonary tuberculosis group was lower than that in Eales disease group （chi;2=7.289,P=0.007）, but the frequency distribution of HLA-A02 alleles had no significant difference (OR=0.515,P=0.202) between two groups. Conclusions The alleles of HLA-A02 and HLA-B07 may be genetic predisposing genes of Eales disease, but HLA-A11 alleles may be protective gene in population of Han nationality from Zunyi city. The alleles of HLA-DRB16 and HLA-A02 may be genetic predisposing genes of pulmonay tuberculosis. The alleles of HLA-A02 may be a common susceptible gene for Eales disease and pulmonary tuberculosis. HLA-A11 and HLA-A24 alleles were protective genes of Eales disease and pulmonary tuberculosis respectively.
Epigenetics refers to the changes in gene expression level and function caused by non-genetic sequence changes. It can provide the time, location and mode of the genetic information for the execution of DNA sequences, including DNA methylation, histone modification, non-coding RNA and chromatin remodeling. Studies had shown that epigenetics plays an important role in the development of diabetic retinopathy (DR), and it had been found that epigenetic-related treatment regimens had a certain effect on the treatment of DR through animal experiments and in vitro experiments. It was benefit to regulate the development of diabetes and its complications by depth study of DNA methylation, histone modification, miRNA and metabolic memory. An understanding of changes in gene transcriptional mechanisms at the epigenetic level could help us to further study the prevention and control of diabetes and its complications, and to provide new ideas for treatment.
ObjectiveTo observe the transthyretin (TTR) gene mutation, protein and mRNA expression in patients with familial vitreous amyloidosis. MethodsSubjects were divided into three groups: (1) illness group: seven patients with familial vitreous amyloidosis. (2) No-illness group: 9 unaffected family members. (3) Control group: 9 healthy individuals in same area. Subjects' peripheral venous blood were collected and DNA were extracted, 4 exons of TTR gene were amplified by reverse transcription polymerase chain reaction(RT-PCR), the gene fragments were sequencing by the fluorescence labelling method. Serum TTR protein expression was detected by Western blot, and TTR mRNA in leukocyte was assayed by RT-PCR. Results4 exons of TTR gene of all samples were amplified, and DNA sequencing data showed that 7 patients and 3 subjects DNA from unaffected family members had mutated in the 3rd exon of 107th base, changing from G to C. Heterozygous mutation occurred in codon of the 83th amino acid in exon 3, namely, Gly83Arg, resulted in the change of GGC to CGC. The protein and mRNA expression of TTR was lower in illness group than no-illness group and control groups(P < 0.05). Compared with control group, TTR mRNA expression in unaffected family members groups was significant decreased(P < 0.05). ConclusionHeterozygous mutation occurred in codon of the 83th amino acid in exon 3, namely Gly83Arg, and suggested that Gly83Arg is connected with the change of TTR mRNA and protein expression.
Familial exudative vitreoretinopathy (FEVR) is a hereditary disease with high geneticheterogeneity, including autosomal dominant inheritance, autosomal recessive inheritance, snd X-linked recessive inheritance. So far, six genes have been found to be associated with FEVR: Wnt receptor fizzled protein (FZD4), Norrie disease (NDP), co-receptor low-densitylipoprotein receptor-related protein 5 (LRP5), and tetrasin 12 (TSPANI2), zinc finger protein408 (ZNF408), kinesin family member 11 (KIF11) gene. Among them, FZD4, NDP, LRPS, TSPANI2 and other four genes play an important role in the Norrin/Frizzled 4 signaling pathway. In retinal capillary endothelial cells, Norrin specifically controls the occurrence of ocular capillaries by activating the Norrin/Frizzled 4 signaling pathway. ZNF408 and KIF11 are newly discovered pathogenic genes related to FEVR in the past 5 years. ZNF408 encodes the transcription factor that plays an important role in retinal angiogenesis. KIF11 plays a role in eye development and maintenance of retinal morphology and function.
X-linked retinoschisis (XLRS) is a rare X-linked inherited retinal disorder, caused by mutations in retinoschisin 1 (RS1) gene. Three XLRS mice were established, providing ideal systems to study the mechanism and treatment methods for XLRS. RS1 gene mutations can induce abnormal secretion or adhesion function of RS1 protein. In the past year, phase I clinical trials for XLRS has begun in USA, using adeno associated virus (AAV, AAV8 or AAV2)-mediated gene delivery. With the rapid development of new generation of AAV vector that can transduce more retinal cells through intravitreous delivery, gene therapy for XLRS will have a brighter future.
ObjectiveTo summarize the current research status of the relationship between DNA methylation and liver regeneration.MethodThe related literatures at home and abroad were searched to review the studies on relationships between the methylation level of liver cells, regulation of gene expression, and methylation related proteins and liver regeneration.ResultsThe DNA methylation was an important epigenetic regulation method in vivo and its role in the liver regeneration had been paid more and more attentions in recent years. The existing studies had found the epigenetic phenomena during the liver regeneration such as the genomic hypomethylation, methylation changes of related proliferating genes and DNA methyltransferase and UHRF1 regulation of the liver regeneration.ConclusionsThere are many relationships between DNA methylation and liver regeneration. Regulation of liver regeneration from DNA methylation level is expected to become a reality in the near future.
ObjectiveTo review the research progress of pathogenesis and genetics of alcohol-induced osteonecrosis of the femoral head (AIONFH). MethodsThe relevant domestic and foreign literature in recent years was extensively reviewed. The pathogenesis, the relationship between gene polymorphism and susceptibility, the related factors of disease progression, and the potential therapeutic targets of AIONFH were summarized. ResultsAIONFH is a refractory orthopedic disease caused by excessive drinking, seriously affecting the daily life of patients due to its high disability rate. The pathogenesis of AIONFH includes lipid metabolism disorder, endothelial dysfunction, bone homeostasis imbalance, and et al. Gene polymorphism and non-coding RNA are also involved. The hematological and molecular changes involved in AIONFH may be used as early diagnostic markers and potential therapeutic targets of the disease. ConclusionThe pathogenesis of AIONFH has not been fully elucidated. Research based on genetics, including gene polymorphism and non-coding RNA, combined with next-generation sequencing technology, may provide directions for future research on the mechanism and discovery of potential therapeutic targets.
Objective To investigate the polymorphism of the vitamin D receptor gene (VDR)TaqⅠin relation to diabetic retinopathy. Method Fragment length discrepant allele specific PCR(FLDAS-PCR) were used to determine VDR genetypes in 158 patients with diabetic retinopathy and in 198 normal subjects. Results The frequency distribution of VDR genotypes in diabetic retinopathy patients was 106 (67.1%) in TT, 33(20.9%) in Tt, 19(12.0%) in tt; and in normal persons was 165 (83.3%) in TT, 23(11.6%) in Tt, 10 (5.1%) in tt. There was a significant difference between diabetic retinopathy patients and normal persons in distribution of VDR gene TaqⅠgenotypes(Plt;0.05). Conclusions There is some distribution alterations of VDR gene polymorphism in diabetic retinopathy patients. (Chin J Ocul Fundus Dis, 2006, 22: 94-96)