Admixture Mapping of Sarcoidosis Genes in African American

描述(申请人提供)：结节病，一种多器官肉芽肿性炎症性疾病，可能是由于T细胞对空气传播的抗原反应过度所致。长期以来，人们一直认为结节病的遗传易感性，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。非洲裔美国人受结节病的影响更为普遍和严重，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的作用。最近对整个基因组中祖先信息标记的表征使扫描基因组中与非裔美国人群体祖先有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研究小组，我们积累了1302例非裔美国人结节病的DMA样本。其中许多病例参与了之前由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研究，除了DNA样本外，这些研究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名没有结节病的非裔美国人的DNA和流行病学数据，他们将作为对照样本。利用这些样本，我们提出了一种通过混合连锁不平衡(MALD)研究来定位与非洲血统相关的结节病基因。这项研究将涉及多阶段全基因组扫描，特别是针对非洲裔美国人中那些容易患结节病、易感性和放射学持久性疾病的非洲基因。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平均间隔约1.9 cM，这些标记具有高度信息量的欧洲-非洲血统差异。在第二阶段，我们将三倍密度的基因祖先信息标记，以增加对结果的统计置信度，并细化位置。然后，我们将在最感兴趣的地区进行一项有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，我们将对具有最高概率的因果变异的区域进行排序(S)。此外，为了更好地了解我们确定的假定候选基因如何在涉及环境刺激因素的结节病致病途径中发挥作用，我们将利用从三个研究样本收集的可比环境数据来测试基因与环境的相互作用。我们建议的研究有可能发现不容易通过连锁检测到的适度影响的基因，在某些情况下，实际上可能比传统的病例对照关联方法在统计上更强大。与公共卫生相关。结节病是一种肉芽肿性多器官疾病，在美国对非裔美国人的影响不成比例。虽然直接可归因于结节病的死亡率很低，但发病率很高，这种疾病的慢性患者往往会出现令人衰弱的呼吸道症状、视力障碍和对其他受影响器官的永久性损害。通过识别增加非裔美国人结节病风险的基因，我们有可能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。识别新的结节病基因也可能间接有助于抗击其他肉芽肿性疾病的努力，如克罗恩病、结核病、铍病和麻风病。

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.