CFH-independent risk factors in age-related macular degeneration

描述：参见说明。说明申请的广泛、长期目标和具体目标，并提及 该项目（即，与原子能机构的使命相关）。简要描述研究设计和实现这些目标的方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句话，用通俗的语言描述这项研究与公共卫生的相关性。如果申请得到资助， 这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空间 提供了 我们最近在96例病例和50例对照中使用全基因组关联作图方法发现， 补体因子H的变体CFHY 402 H和AMD之间的强关联已在10 不同的高加索人在这10个队列中，病例和对照组之间的频率为 惊人的一致性：他们表明对照组更有可能但不完全是YY（42%对18%） 病例更可能是HH（35%对13%）。估计的遗传风险并不能解释整个 疾病的风险特征。因此，有理由假设存在额外的遗传因素。 和/或环境因素在AMD的发展中独立或协同作用。的问题 我们想在这里解决的是：是什么风险因素驱动了这18%的两个副本的非风险 CFH等位基因与AMD相关，是什么保护了13%携带两个危险等位基因的人不患AMD？ 为了解决这些问题，我们确定了携带两种基因的纯合子AMD/对照个体。 CFH 402变体的组氨酸（H）的两个拷贝或酪氨酸（Y）的两个拷贝。纯合子DNA样本 CFH 402个体将使用全基因组SNP微阵列平台以 317，000个标签SNP来自HapMap数据。统计和生物信息学方法/算法将 开发，并将对所得的基因型和表型数据进行分析， 目的： 1.发现遗传/环境风险因素及其在AMD患者中的相互作用， 携带补体因子H的疾病风险等位基因，即，AMD与CFH 402 YY; 2.为了发现未出现AMD但携带两份AMD基因的个体中的保护因素， CFH风险等位基因，即，无AMD与CFH 402 HH; 3.为了发现AMD患者中具有两个CFH 402风险等位基因拷贝的上位性遗传变异，即， AMD CFH 402 HH。 履约地点（组织、城市、州） 耶鲁大学，康涅狄格州纽黑文

DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Our recent discovery, using a whole-genome association mapping approach on 96 cases and 50 controls, of strong association between a variant in complement factor H, CFH Y402H, and AMD has been shown in 10 different Caucasian populations. Across these 10 cohorts, frequencies between cases and controls are strikingly consistent: They show that controls are more likely but not exclusively to have YY (42% vs. 18%) and cases are more likely to be HH (35% vs. 13%). The estimated genetic risk does not explain the entire risk profile conferring the disease. Therefore, it is reasonable to assume that there are additional genetic and/or environmental factors acting independently or in concert in the development of AMD. The questions we would like to resolve here are: What are the risk factors that drive those 18% with two copies of non-risk CFH alleles to AMD, and what protects those 13% who carry two risk alleles from having AMD? To address these questions, we identified homozygous AMD/control individuals in AREDS who carried two copies of histidine (H) or two copies of tyrosine (Y) of the CFH 402 variant. DNA samples of homozygous CFH 402 individuals will be genotyped using a whole-genome SNP microarray platform at a resolution of 317,000 tag SNPs derived from the HapMap data. Statistical and bioinformatics methods/algorithms will be developed, and analyses will be performed on the resulting genotype and phenotype data with three specific aims: 1. To discover the genetic/environmental risk factors and their interactions in AMD patients who do not carry the disease risk allele of complement factor H, i.e., AMD with CFH 402 YY; 2. To discover the protective factors in individuals who do not present with AMD but carry two copies of the CFH risk alleles, i.e., None-AMD with CFH 402 HH; 3. To discover the epistatic genetic variant(s) in AMD patients with two copies of CFH 402 risk alleles, i.e., AMD with CFH 402 HH. PERFORMANCE SITE(S) (organization, city, state) Yale University, New Haven, CT