CFH-independent risk factors in age-related macular degeneration

描述（由申请人提供）：我们最近发现，通过对96例病例和50例对照的全基因组关联作图方法，补体因子H、CFH Y402H变异和AMD之间的强关联已在10个不同的高加索人群中得到证实。在这10个队列中，病例和对照组之间的频率惊人地一致：他们表明对照组更有可能但不完全是YY(42%对18%)，病例更有可能是HH（35%对13%）。估计的遗传风险并不能解释导致该疾病的全部风险。因此，有理由假设在AMD的发展中有额外的遗传和/或环境因素独立或协同作用。我们想要解决的问题是：是什么风险因素导致18%的人携带两个非风险CFH等位基因副本患上AMD，是什么保护那些携带两个风险等位基因的13%的人不患AMD？为了解决这些问题，我们在AREDS中发现纯合AMD/对照个体，他们携带CFH 402变体的两个组氨酸(H)拷贝或两个酪氨酸(Y)拷贝。纯合子CFH402个体的DNA样本将使用全基因组SNP微阵列平台进行基因分型，该平台的分辨率为317,000个来自HapMap数据的标签SNP。将开发统计和生物信息学方法/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。不携带补体因子H疾病风险等位基因的AMD患者（即CFH 402 YY型AMD）的遗传/环境危险因素及其相互作用；2. 发现没有AMD但携带两个CFH风险等位基因拷贝的个体的保护因素，即非AMD伴CFH 402 HH；3. 发现两拷贝CFH 402风险等位基因的AMD患者的上位性遗传变异，即AMD合并CFH 402 HH。

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.