Admixture Mapping of Sarcoidosis Genes in African American

结节病是一种多器官肉芽肿性炎症性疾病，很可能是由于T细胞夸大所致 对空气传播的抗原的反应。长期以来，结节病的遗传易感性一直被认为是 最近对德国和非裔美国人受影响的同胞对样本进行的独立基因组扫描表明 多个基因参与其中。非洲裔美国人更常见也更严重地受到 结节病，这意味着非洲血统的基因在疾病病因和 发病机制。最近对整个基因组的祖先信息标记的表征现在使它 在非裔美国人群体中扫描与祖先相关的疾病基因的基因组是可行的。作为一名 一个广泛研究非裔美国人结节病遗传易感性的研究小组， 我们已经积累了1,026例无关的非裔美国人结节病病例的DNA样本。许多. 这些病例参与了之前由NIH资助的三项研究中的一项、两项家庭研究和一项 病例对照，除了DNA样本外，还提供了丰富的临床和流行病学数据。从… ACCESS病例对照研究我们还有305名无关非洲人的DNA和流行病学数据 未患结节病的美国人将作为对照样本。使用这些样本，我们提出了一个 利用混合连锁不平衡(MALD)研究定位非洲结节病相关基因 血统。这项研究将涉及一项针对特定基因的多阶段全基因组扫描 易患结节病的非裔美国人的非洲血统和放射学特征 顽固性疾病。我们计划首先使用一组均匀分布的1536个SNP标记来筛选基因组 基因组全长约1.9 cM，具有高度信息量的欧洲-非洲血统 不同之处。在第二阶段，我们将三倍密度的基因祖先信息标记增加 统计数据对结果的信心，并完善仓位。然后我们将转到基于单倍型的目标 在最有趣的地区进行协会研究。一旦我们缩小了相关的 基因组区域到特定基因或特定基因内的区域，我们将对具有 存在因果变异的概率最高(S)。此外，为了更好地了解推定 我们确定的候选基因作用于结节病的致病途径，涉及环境刺激因素， 我们将利用从三个研究样本收集的可比较的环境数据来测试遗传环境 互动。我们提议的研究有可能发现影响不大的基因 很容易通过链接检测到，在某些情况下，实际上可能比 传统病例对照关联法。

Sarcoidosis, a multiorgan granulomatous inflammatory disease, likely results from an exaggerated T cell response to an airborne antigen. A genetic predisposition to sarcoidosis has long been posited, and recent independent genome scans in German and African-American affected sib pair samples suggest that multiple genes are involved. African-Americans are more commonly and severely affected by sarcoidosis, which imply that genes of African ancestry play a significant role in the disease etiology and pathogenesis. Recent characterization of ancestry informative markers across the genome now makes it feasible to scan the genome for disease genes linked to ancestry in African-American populations. As a research group that has extensively studied the genetic susceptibility of sarcoidosis in African Americans, we have accumulated DMA samples for 1,026 unrelated African American sarcoidosis cases. Many of these cases have participated in one of three previous NIH-funded studies, two family studies and one case-control, that provide a wealth of clinical and epidemiologic data in addition to a DNA sample. From the ACCESS case-control study we also have DNA and epidemiologic data on 305 unrelated African Americans without sarcoidosis who will serve as a control sample. Using these samples, we propose a mapping by admixture linkage disequilibrium (MALD) study to identify sarcoidosis genes linked to African ancestry. The study will involve a multi-staged genome-wide scan targeting specifically those genes of African origin in African Americans that predispose to sarcoidosis susceptibility and radiographically persistent disease. We plan to first screen the genome using a set of 1,536 SNP markers evenly spaced approximately 1.9 cM throughout the genome that are highly informative European - African ancestry differences. In the second stage, we will triple density genotype ancestry informative markers to increase statistical confidence in the results and refine the positions. We will then move to a targeted haplotypebased association study in the most interesting regions. Once we have narrowed the associated genomic areas to specific genes or areas within specific genes, we will sequence the areas that have the highest probability of harboring causal variant(s). In addition, to better understand how putative candidate genes we identify act in sarcoidosis causal pathways involving environmental inciting agents, we will utilize comparable environmental data collected across the three study samples to test for geneenvironment interaction. Our proposed study has the potential to uncover genes of modest effect not easily detectable by linkage and may in some instances actually be more statistically powerful than traditional case-control association methods.