Familial aggregation of age-related macular degeneration in the Utah population

We examined familial aggregation and risk of age-related macular degeneration in the Utah population using a population-based case-control study. Over one million unique patient records were searched within the University of Utah Health Sciences Center and the Utah Population Database (UPDB), identifying 4764 patients with AMD. Specialized kinship analysis software was used to test for familial aggregation of disease, estimate the magnitude of familial risks, and identify families at high risk for disease. The population-attributable risk (PAR) for AMD was calculated to be 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases. There were 16 extended large families with AMD identified for potential use in genetic studies. Each family had five or more living affected members. The familial aggregation of AMD shown in this study exemplifies the merit of the UPDB and supports recent research demonstrating significant genetic contribution to disease development and progression.     

Age-related accumulation of 3-nitrotyrosine and nitro-A2E in human Bruch's membrane

Age-related macular degeneration (AMD) is a disease leading to severe visual loss and legal blindness in the elderly population. The pathophysiology of AMD is complex and may include genetic predispositions, accumulation of lipofuscin and drusen, local inflammation and neovascularization. Recently four independent research groups have identified a commonly inherited variant (Y402H) of the complement factor H gene in the genome from different groups of AMD patients. The Y402H variant of CFH significantly increases the risk of AMD and links the genetics of the disease with inflammation. During inflammation there is activation of inducible nitric oxide synthase and release of nitric oxide, which in principal could lead to non-enzymatic nitration within extracellular deposits and/or intrinsic extracellular matrix protein components of human Bruch's membrane. We have identified two biomarkers for non-enzymatic nitration in aged human Bruch's membrane, indicative of inflammation, that include 3-nitrotyrosine identified in Bruch's membrane preparations and nitrated A2E from the lipid soluble extract of the Bruch's membrane preparation. Approximately 30-40 times more A2E is observed in samples of the organic soluble extract of lipofuscin compared to the extract of Bruch's membrane. It is of interest to note that although A2E is a major constituent of RPE lipofuscin, nitrated A2E could not be detected in RPE extracts. We show here that nitro-A2E is a specific biomarker of nitrosative stress in Bruch's membrane and its concentration correlates directly with tissue age.     

老年黄斑变性的分子遗传学研究进展

老年黄斑变性(AMD)在西方发达国家是老年人视力损害的主要原因，在我国其发病率也有上升的趋势。AMD是一种复杂的疾病，虽然其发病机制尚不明确，但一些环境危险因素已得到证实。近来一些研究表明其可能在AMD的发病中起着重要的作用。ABCR、VMD2、TIMP3、ApoE、DHRD作为候补基因已开展研究，但研究结果尚存在争议。当前ABCR基因—Stargardt病的致病基因，成为研究的热点。的分子遗传学研究对于确定AMD的发病机制有重要作用。虽然遗传因素对于AMD的确切作用目前尚不明确，但AMD对老年黄斑变性的分子遗传研究进展进行综述。     

The genetics of age‐related macular degeneration

Aim: To review the genetics of age‐related macular degeneration (AMD). The pathogenesis of AMD, the leading cause of severe visual disability and blindness in our community, remains unknown. However, AMD is regarded as a genetic disease where family history of AMD is a significant risk factor for the disease. Understanding the genetic factors associated with AMD offers the greatest chance for understanding the underlying disease processes. Methods: Through a review of the literature and the use of original research findings, the current knowledge of the genetics of AMD is explored. Conclusion: AMD is increasing in prevalence and remains a major challenge for eye heath providers. Finding the genes that are associated with AMD offers the greatest chance for the development of preventative strategies and treatments.     

年龄相关性黄斑变性发病危险因素研究进展

年龄相关性黄斑变性（age-related macular degeneration,AMD）是一种主要的全球性致盲眼病之一。AMD是一种多因素的疾病,主要的危险因素包括年龄,吸烟,白内障手术史,环境因素,营养因素,遗传标志,包括基因调节补体,脂质,血管生成和细胞外基质的途径。除了治疗外,AMD的流行病学,危险因素和遗传学研究已有重大进展。本文将AMD发病的危险因素作简要综述。     

North Carolina macular dystrophy (MCDR1)

The macular degenerations comprise a heterogeneous group of diseases, generally reported in small families. Single, large family studies of North Carolina macular dystrophy have aided in defining the spectrum of the phenotype of this disorder and its relationship to other macular degenerations. North Carolina macular dystrophy has many phenotypic similarities to age-related macular degeneration with the glaring exception of the early age of onset of North Carolina macular dystrophy. The authors initially reported mapping this disease by linkage to the long arm of chromosome 6. They now report additional data on a total of 247 individuals in the original North Carolina macular dystrophy family whom we ascertained for clinical and molecular genetic studies. Standard clinical ophthalmic examination revealed that 96 of these individuals were affected. Molecular genetic studies increased the LOD score to 23 and refined the genomic localization of the disease-causing gene to 6q14-q16.2.     

年龄相关性黄斑变性流行病学研究进展

年龄相关性黄斑变性( age-related macular degeneration, AMD)是一种与年龄相关的致盲性退行性眼底病变,全球约有3000万老年黄斑变性患者,每年约有50万人因此致盲。随着我国经济发展及人口老龄化的加剧, AMD在我国发病率呈逐年上升的趋势,现已跃居我国第三大致盲原因。目前,AMD的发病机制尚不完全明确,可能与氧化应激,炎症免疫反应, VEGF形成及遗传调控密切相关。临床上主要有光动力疗法、药物治疗、放射治疗、激光光凝、黄斑下手术、经瞳孔温热治疗、中医药治疗以及玻璃体腔注射VEGF拮抗剂如雷珠单抗、康柏西普等方法。本文主要就AMD有关的流行病学因素做一系统阐述,并重点就遗传调控方面取得的进展进行综述。     

Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review

Malattia leventinese (ML) or Doyne honeycomb retinal dystrophy (DHRD) was the first clinically and histopathologically described Mendelian maculopathy. The gene responsible for ML/DHRD, EFEMP1(fibulin-3/S1-5/FBNL) encodes a member of the fibulin family, a newly recognized family of extracellular matrix proteins. EFEMP1mutations have not been found in age-related macular degeneration (AMD) patients despite the close phenotypic similarities between ML/DHRD and AMD. This non-correlating genotype/phenotype relationship between inherited and age-related conditions is typical for common age-related diseases. Biochemical pathways delineated in other diseases indicate that the gene associated with the inherited condition is nonetheless critical in age-related forms. This review summarizes current knowledge relating to ML/DHRD and EFEMP1, with discussion of why EFEMP1 mutations are absent in AMD and how EFEMP1 may be involved in the pathogenesis of ML/DHRD and AMD.     

Molecular mechanisms of retinal pigment epithelium damage and development of age‐related macular degeneration

Age‐related macular degeneration (AMD) is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE) and Bruch’s membrane, as well as alterations in choroidal capillaries. AMD pathogenesis is strongly associated with chronic oxidative stress and inflammation that ultimately lead to protein damage, aggregation and degeneration of RPE. Specific degenerative findings for AMD are accumulation of intracellular lysosomal lipofuscin and extracellular drusens. In this review, we discuss thoroughly RPE‐derived mechanisms in AMD pathology.     

年龄相关性黄斑变性相关危险因素的研究进展

年龄相关性黄斑变性(AMD)是全球主要的致盲性眼部疾病之一,但是其发病机制尚未完全明确。国内外研究学者普遍认为,个体因素、环境因素、全身因素及遗传因素为其主要的致病危险因素,如年龄、性别、种族、吸烟及全身相关疾病等。目前,全球对AMD流行病学相关危险因素的研究均有较大进展,故本文就AMD发病相关危险因素进行综述。