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Genetic Epidemiology of Age-Related Macular Degeneration

年龄相关性黄斑变性的遗传流行病学

基本信息

批准号：
8146031
负责人：
DEBRA A SCHAUMBERG
金额：
$ 57.5万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8146031
关键词：
Address Age Age related macular degeneration Archives Biological Blindness Candidate Disease Gene Case-Control Studies Cell Line Clinic Cohort Studies Complement Complement Factor B Complement Factor H Complex DNA Data Databases Diet Dietary Factors Disease Association Elderly Environment Epidemiology Exposure to Fatty acid glycerol esters Foundations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Haplotypes Incidence Individual Intake Knowledge Life Style Light Link Measures Microarray Analysis Modeling Nested Case-Control Study Nonexudative age-related macular degeneration Obesity Odds Ratio Other Genetics Pathogenesis Plasma Population Population Attributable Risks Positioning Attribute Prevalence Preventive Prospective Studies Public Health RNA Research Research Design Resources Risk Risk Assessment Risk Factors Sample Size Serum Smoking Solutions Source Specimen Techniques Therapeutic Translations United States National Institutes of Health Validation Variant Vascular Endothelial Growth Factors Woman base case control cigarette smoking clinically relevant cohort cost effective data mining design disease-causing mutation epidemiology study gene discovery gene environment interaction genetic association genetic epidemiology genetic variant inflammatory marker interest lifestyle factors meetings men modifiable risk neovascular novel predictive modeling prospective sex

项目摘要

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD), the leading cause of incurable blindness among older adults in the US, is caused by interactions between underlying genetic susceptibility and lifestyle risk factors. However, our knowledge of the network of contributors to the pathogenesis of AMD remains incomplete, and treatment is inadequate. The proposed studies build upon a strong and growing foundation of research and invaluable existing resources to comprehensively study the genetic epidemiology of AMD. Through its use of archived DNA specimens from several large prospective cohort studies, this proposal represents a cost-effective, efficient, and informative approach to investigate the following specific aims: 1) determine the incidence rate ratio and attributable fraction for AMD in relation to common variants within a group of strong candidate genes including complement factor H, HTRA1/LOC387715, and others (candidates identified based on position, function, expression, etc.) using both single locus and haplotype analyses for AMD overall as well as for both dry and neovascular subtypes, 2) effectively utilize data derived from RNA microarray analysis of sibpairs extremely discordant for AMD to inform selection of candidate genes, 3) estimate the magnitude and significance of any gene-gene, or gene-environment interactions among these candidates and risk factors such as cigarette smoking, obesity, diet, and serum inflammatory markers. These aims will be accomplished through genotyping of >1300 confirmed incident AMD cases and >3000 controls in our high-tech core genotyping facility, along with direct sequencing when indicated for SNP discovery as well as to search for functional variants or disease-causing mutations if association analyses are significant. Unique strengths of this approach include the prospective design, large sample size, high-quality, high-throughput genotyping, integration with a study of extremely discordant sib-pairs, and state-of-the-art statistical analyses to provide precise estimates for effects of genes, gene-gene and gene-environment interactions. The proposed studies minimize bias through prospective assessment of exposures and AMD status, direct estimation of incidence rate ratios, novel candidate gene selection, and high statistical power. The long-term objective and clinical relevance of this research is to shed light on underlying biological mechanisms relevant to AMD, to suggest avenues for novel preventive or therapeutic approaches, and identify clinically useful risk assessments.

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是美国老年人无法治愈的失明的主要原因，是由潜在的遗传易感性和生活方式风险因素之间的相互作用引起的。然而，我们对AMD发病机制的网络贡献者的了解仍然不完整，治疗也不充分。拟议的研究建立在一个强大的和不断增长的研究基础和宝贵的现有资源，以全面研究AMD的遗传流行病学。通过使用来自几项大型前瞻性队列研究的存档DNA标本，该提案代表了一种具有成本效益，高效且信息丰富的方法来调查以下具体目标：1)确定AMD与一组强候选基因(包括补体因子H、HTRA1/LOC387715和其他（根据位置、功能、表达等确定的候选基因）中的常见变异相关的发病率比和归因分数，并对AMD总体以及干性和新生血管亚型进行单位点和单倍型分析；2)有效利用来自极度不一致的兄弟姐妹的RNA微阵列分析数据，为候选基因的选择提供信息；3)估计任何基因-基因或基因-环境相互作用在这些候选基因和危险因素（如吸烟、肥胖、饮食和血清炎症标志物）之间的程度和重要性。这些目标将通过在我们高科技的核心基因分型设施中对>1300例确诊的AMD病例和>3000例对照进行基因分型来实现，同时在需要发现SNP时进行直接测序，以及在相关性分析显著时搜索功能变异或致病突变。该方法的独特优势包括前瞻性设计，大样本量，高质量，高通量基因分型，与极度不一致的兄弟姐妹对的研究相结合，以及最先进的统计分析，以提供精确的估计基因，基因-基因和基因-环境相互作用的影响。拟议的研究通过前瞻性评估暴露和AMD状态、直接估计发病率比、新的候选基因选择和高统计能力来最大限度地减少偏倚。本研究的长期目标和临床意义是阐明与AMD相关的潜在生物学机制，为新的预防或治疗方法提供途径，并确定临床有用的风险评估。