Admixture Mapping of Sarcoidosis Genes in African American

非洲裔美国人结节病基因的混合图谱

• 批准号: 7866560
• 负责人: Benjamin A. Rybicki
• 金额: $ 76.06万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866560
• 关键词: Admixture; Affect; African; African American; Antigens; Area; Berylliosis; Candidate Disease Gene; Chronic; Clinical; Clinical Data; Crohn' s disease; DNA; Data; Development; Diagnosis; Disease; Disease Outcome; Disease susceptibility; Environmental Exposure; Epidemiology; Etiology; European; Family; Family Study; Family member; Funding; Genes; Genetic Predisposition to Disease; Genome; Genome Scan; Genomics; Genotype; German population; Granulomatous; Haplotypes; Inflammatory; Leprosy; Link; Linkage Disequilibrium; Maps; Measures; Methods; Morbidity - disease rate; Organ; Pathogenesis; Pathway interactions; Patients; Play; Population; Positioning Attribute; Predisposition; Preventive; Probability; Research; Resources; Risk; Role; Sampling; Sampling Studies; Sarcoidosis; Scanning; Staging; Susceptibility Gene; Symptoms; T cell response; Testing; Therapeutic; Tuberculosis; United States; Variant; Visual impairment; base; case control; combat; density; epidemiologic data; follow-up; gene environment interaction; genome wide association study; interest; mortality; novel; public health relevance; respiratory

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.

描述（由申请方提供）：结节病是一种多器官肉芽肿性炎性疾病，可能是由对空气传播抗原的过度T细胞反应引起的。结节病的遗传易感性早已被假定，在德国和非洲裔美国人受影响的同胞对样本中进行的独立基因组扫描表明涉及多个基因。非裔美国人更常见和严重的结节病，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。最近对整个基因组的祖先信息标记的表征现在使得扫描基因组以寻找与非洲裔美国人群体的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研究小组，我们已经积累了1,302例非裔美国人结节病病例的DMA样本。这些病例中的许多人参加了以前NIH资助的三项研究之一，两项家庭研究和一项病例对照研究，除了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，这些非裔美国人将作为对照样本。利用这些样本，我们提出了一个混合物连锁不平衡（MALD）研究，以确定与非洲血统的结节病基因的映射。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起源基因。我们计划首先使用一组1，536个SNP标记筛选基因组，这些标记在整个基因组中均匀间隔约1.9 cM，具有高度信息化的欧洲-非洲血统差异。在第二阶段，我们将三倍密度基因型祖先信息标记，以增加统计结果的信心和完善的立场。然后，我们将在最有趣的地区进行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，我们将对具有最高可能性的区域进行测序。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激发因子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发现不容易通过连锁检测的适度影响的基因，并且在某些情况下实际上可能比传统的病例对照关联方法更具统计学意义。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洲裔美国人。虽然直接归因于结节病的死亡率较低，但发病率很高，这种疾病的慢性患者通常具有使人衰弱的呼吸道症状、视觉障碍和对其他受影响器官的永久性损伤。通过鉴定增加非裔美国人结节病风险的基因，我们可以制定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。新的结节病基因的鉴定也可能间接有助于对抗其他肉芽肿性疾病，如克罗恩病，结核病，铍病和麻风病。