Admixture Mapping of Sarcoidosis Genes in African American

描述（由申请人提供）：结节病是一种多器官肉芽肿性炎症性疾病，可能是由T细胞对空气中抗原的过度反应引起的。长期以来，人们一直认为结节病的遗传易感性是存在的，对德国和非裔美国人患病兄弟姐妹样本的独立基因组扫描表明，多基因参与其中。非裔美国人更常见和严重受到结节病的影响，这意味着非洲血统的基因在疾病的病因和发病机制中起着重要作用。最近对基因组中祖先信息标记的表征使得扫描非裔美国人基因组中与祖先相关的疾病基因成为可能。作为一个广泛研究非裔美国人结节病遗传易感性的课题组，我们已经积累了1302例非裔美国人结节病的DMA样本。这些病例中的许多人都参加了此前由美国国立卫生研究院资助的三项研究中的一项，两项家庭研究和一项病例对照研究，这些研究除了提供DNA样本外，还提供了丰富的临床和流行病学数据。从这三项研究中，我们还获得了695名非裔美国人的DNA和流行病学数据，他们没有结节病，将作为对照样本。利用这些样本，我们提出了一项通过混合连锁不平衡（MALD）研究来确定与非洲血统相关的结节病基因的定位。该研究将涉及多阶段全基因组扫描，专门针对非洲裔美国人中易患结节病易感性和放射学持续性疾病的非洲血统基因。我们计划首先使用一组1536个SNP标记来筛选基因组，这些标记在整个基因组中均匀分布约1.9 cM，这些标记具有高度信息性的欧洲-非洲血统差异。在第二阶段，我们将增加三倍密度基因型祖先信息标记，以提高结果的统计置信度并完善位置。然后，我们将在最有趣的区域进行针对性的基于单倍型的关联研究。一旦我们将相关的基因组区域缩小到特定基因或特定基因内的区域，我们将对最有可能隐藏因果变异的区域进行排序。此外，为了更好地了解我们确定的候选基因如何在涉及环境刺激物的结节病因果通路中起作用，我们将利用在三个研究样本中收集的可比环境数据来测试基因-环境相互作用。我们提出的研究有可能揭示不容易通过连锁检测到的适度影响的基因，并且在某些情况下可能比传统的病例对照关联方法在统计上更强大。公共卫生相关性。结节病是一种肉芽肿性多器官疾病，在美国不成比例地影响非裔美国人。虽然结节病直接导致的死亡率很低，但这种疾病的慢性患者的发病率很高，通常有使人衰弱的呼吸系统症状、视力障碍和对其他受影响器官的永久性损伤。通过识别非裔美国人群中增加结节病风险的基因，我们可以设计出有针对性的预防和治疗措施，帮助减少结节病发病率的种族差异。鉴定新的结节病基因也可能间接地有利于对抗其他肉芽肿疾病，如克罗恩病、肺结核、青铜病和麻风病。

DESCRIPTION (provided by applicant): Sarcoidosis, a multi-organ 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 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 1,302 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 these three studies, we also have DNA and epidemiologic data on 695 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 haplotype-based 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 gene-environment 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. PUBLIC HEALTH RELEVANCE. Sarcoidosis is a granulomatous multi-organ disease that disproportionately affects African Americans in the United States. While mortality directly attributable to sarcoidosis is low, morbidity is significant with chronic suffers of this disease often having debilitating respiratory symptoms, visual impairments and permanent damage to other affected organs. By identifying genes that increase risk of sarcoidosis in African-American populations, we can potentially devise targeted preventive and therapeutic measures that can help reduce the racial disparity in sarcoidosis morbidity. Identification of novel sarcoidosis genes may also indirectly benefit efforts to combat other granulomatous disorders such as Crohn's disease, tuberculosis, berylliosis and leprosy.