CFH-independent risk factors in age-related macular degeneration

年龄相关性黄斑变性的独立于 CFH 的危险因素

• 批准号: 7241832
• 负责人: JOSEPHINE HOH
• 金额: $ 21.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241832
• 关键词: CFH; independent; risk; factors; age

DESCRIPTION (provided by applicant): 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 CFH402 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.

描述（由申请人提供）：我们最近发现，使用全基因组关联作图方法对96例病例和50例对照进行研究，在10个不同的高加索人群中显示了补体因子H变体CFH Y402 H与AMD之间的强关联。在这10个队列中，病例和对照组之间的频率惊人地一致：它们表明对照组更有可能但不完全是YY（42% vs. 18%），病例更有可能是HH（35% vs. 13%）。估计的遗传风险并不能解释导致这种疾病的整个风险状况。因此，可以合理地假设，在AMD的发展中，存在独立或协同作用的其他遗传和/或环境因素。我们想在这里解决的问题是：是什么危险因素促使18%的人携带两个非危险CFH等位基因的拷贝患上AMD，是什么保护了13%的人携带两个危险等位基因患上AMD？为了解决这些问题，我们确定了携带CFH 402变体的两个组氨酸（H）或两个酪氨酸（Y）拷贝的纯合子AMD/对照个体。纯合CFH402个体的DNA样品将使用全基因组SNP微阵列平台以源自HapMap数据的317，000个标签SNP的分辨率进行基因分型。将开发统计学和生物信息学方法/算法，并对所得基因型和表型数据进行分析，具体目标有三个：1.发现不携带补体因子H疾病风险等位基因的AMD患者的遗传/环境风险因素及其相互作用，即，AMD与CFH 402 YY; 2.为了发现不存在AMD但携带两个CFH风险等位基因拷贝的个体中的保护因素，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。