Admixture Mapping of Sarcoidosis Genes in African American

非洲裔美国人结节病基因的混合图谱

基本信息

批准号：
8079699
负责人：
Benjamin A. Rybicki
金额：
$ 69.07万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079699
关键词：
Admixture Affect African African American Antigens Area Berylliosis Candidate Disease Gene Chronic Clinical Data Crohn&apos s disease DNA Data Development Diagnosis Disease Disease Outcome Disease susceptibility Environmental Exposure Etiology European Family Family Study Family member Funding Genes Genetic Predisposition to Disease Genome Genome Scan Genomics Genotype German population Granulomatous Haplotypes Health 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 United States National Institutes of Health Variant Visual impairment base case control combat density epidemiologic data follow-up gene environment interaction genome wide association study interest mortality novel respiratory

项目摘要

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（由申请人提供）：结节病，一种多器官颗粒炎性疾病，可能是由于对空气中抗原的T细胞反应而产生的。长期以来对结节病的遗传易感性一直存在，并且在德国和非裔美国人影响的SIB对样品中进行独立的基因组扫描表明涉及多个基因。非裔美国人更常见，严重受结节病的影响，这意味着非洲血统基因在疾病的病因学和发病机理中起着重要作用。现在，整个基因组中的祖先信息标记的最新表征使得扫描与非裔美国人人群中与祖先有关的疾病基因的基因组可行。作为一个研究小组，已经广泛研究了非裔美国人结节病的遗传敏感性，我们积累了1,302例非裔美国人结节病病例的DMA样品。这些病例中的许多案例都参加了以前的三项NIH资助研究之一，两项家庭研究和一项病例对照，除了DNA样本外，还提供了大量临床和流行病学数据。从这三项研究中，我们还拥有695名没有结节病的非裔美国人的DNA和流行病学数据，这些美国将作为对照样本。使用这些样品，我们提出了通过混合连锁不平衡（MALD）研究的映射，以鉴定与非洲血统相关的结节病基因。该研究将涉及多个分期基因组的扫描，该扫描针对非洲裔美国人的非洲起源基因，这些基因易于结节病的敏感性和射线照相持续性疾病。我们计划使用一组1,536个SNP标记在整个基因组中均匀间隔约1.9 cm，这是欧洲高度信息 - 非洲血统的差异。在第二阶段，我们将三重密度基因型祖先信息标记物增加对结果的统计信心并完善位置。然后，我们将在最有趣的地区进行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内的特定基因或区域，我们将对具有因果变异的可能性最高的区域进行测序。此外，为了更好地了解我们在涉及环境煽动剂的结节病因果途径中识别的假定候选基因如何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效应基因，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学上更强大。公共卫生相关性。结节病是一种肉芽肿的多器官疾病，对美国的非裔美国人产生了不成比例的影响。虽然死亡率直接归因于结节病很低，但由于这种疾病的慢性遭受的慢性遭受呼吸症状，视觉障碍和对其他受影响器官的永久损害，发病率很大。通过鉴定出增加非裔美国人种群中结节病风险的基因，我们可以设计有针对性的预防和治疗措施，从而有助于减少结节病发病率的种族差异。新型结节病基因的鉴定也可能间接受益于与其他肉芽肿性疾病作斗争的努力，例如克罗恩病，结核病，嗜存性和麻风病。