CFH-independent risk factors in age-related macular degeneration

说明：请参阅说明。说明应用程序的广泛、长期目标和具体目标，并提及与健康相关的 项目(即与该机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果应用程序得到资助，则此 原样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空格 但前提是。 我们最近的发现，使用全基因组关联图谱方法，在96例病例和50名对照中， 补体因子H的一个变异体CFH Y402H与AMD之间有很强的相关性，在10 不同的高加索人群。在这10个队列中，病例和对照之间的频率是 惊人的一致性：他们显示，控制组更有可能但不只是YY(42%对18%) 病例更有可能是HH(35%对13%)。估计的遗传风险不能解释整个 与这种疾病有关的风险概况。因此，可以合理地假设有额外的基因 和/或在AMD的发展中独立或协同作用的环境因素。这些问题 我们想在这里解决的问题是：驱动这18%的人拥有两份无风险的风险因素是什么 CFH是AMD的等位基因，是什么保护了这13%携带两个风险等位基因的人患上AMD？ 为了解决这些问题，我们确定了AREDS患者中携带两种基因的纯合子AMD/对照个体 CFH 402变异体的组氨酸(H)拷贝或两个酪氨酸(Y)拷贝。纯合子的DNA样本 CFH 402个体将使用全基因组SNP微阵列平台进行基因分型，分辨率为 从HapMap数据中衍生出317,000个标签SNP。统计和生物信息学方法/算法将是 将对产生的基因型和表型数据进行分析，其中包括三个特定的 目标： 1.发现非AMD患者的遗传/环境危险因素及其相互作用 携带补体因子H的疾病风险等位基因，即伴有CFH 402 YY的AMD； 2.发现没有AMD但携带两份拷贝的AMD的保护因素 CFH风险等位基因，即非AMD伴CFH 402 HH； 3.发现具有两个CFH402风险等位基因拷贝的AMD患者的上位性遗传变异(S)。 AMD，CFH 402 HH。 演出现场(S)(组织、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