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: 7438792
• 负责人: Benjamin A. Rybicki
• 金额: $ 70.61万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438792
• 关键词: Admixture; Affect; African; African American; Antigens; Area; Candidate Disease Gene; Case-Control Studies; Chromosome Mapping; Clinical; 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; Inflammatory; Link; Linkage Disequilibrium; Maps; Methods; Pathogenesis; Pathway interactions; Patients; Play; Population; Positioning Attribute; Predisposition; Probability; Research; Resources; Risk; Role; Sampling; Sampling Studies; Sarcoidosis; Scanning; Staging; T-Lymphocyte; Testing; Variant; base; case control; density; follow-up; gene environment interaction; genome wide association study; interest; response

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.

结节病是一种多器官肉芽肿性炎性疾病，可能是由于过度的T细胞 对空气传播的抗原的反应结节病的遗传易感性早已被假定， 最近对德国和非洲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。非裔美国人更普遍和严重的影响， 结节病，这意味着非洲血统基因在疾病病因学中起重要作用， 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得 在非裔美国人群体中扫描与祖先有关的疾病基因是可行的。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， 我们已经收集了1,026例非裔美国人结节病的DMA样本。许多 这些病例参加了以前NIH资助的三项研究之一，两项家庭研究和一项 病例对照，提供了丰富的临床和流行病学数据，除了DNA样本。从 ACCESS病例对照研究中，我们也有305个无关非洲人的DNA和流行病学数据 没有结节病的美国人将作为对照样本。利用这些样本，我们提出了一个 通过混合连锁不平衡（MALD）研究定位，以确定与非洲人相关的结节病基因 祖先这项研究将涉及一个多阶段的全基因组扫描，专门针对那些基因， 非裔美国人中的非洲血统易患结节病， 持续性疾病。我们计划首先使用一组1，536个均匀分布的SNP标记筛选基因组 在整个基因组中大约1.9 cM，是高度信息化的欧洲-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，我们将转移到一个有针对性的单倍型为基础的 在最有趣的地区进行关联研究。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 具有因果变异的最高概率。此外，为了更好地理解 我们鉴定的候选基因在涉及环境激发剂的结节病致病途径中起作用， 我们将利用从三个研究样本中收集的可比较的环境数据来测试基因环境 互动我们提出的研究有可能发现影响不大的基因， 很容易通过连接检测到，在某些情况下，实际上可能比 传统的病例对照关联方法。

项目成果

Elevated 1, 25-dihydroxyvitamin D levels are associated with protracted treatment in sarcoidosis.

• DOI: 10.1016/j.rmed.2009.12.004
• 发表时间: 2010-04
• 期刊: Respiratory medicine
• 影响因子: 4.3
• 作者: Kavathia D;Buckley JD;Rao D;Rybicki B;Burke R
• 通讯作者: Burke R

Calcium and vitamin D in sarcoidosis: how to assess and manage.

• DOI: 10.1055/s-0030-1262215
• 发表时间: 2010-08
• 期刊: Seminars in respiratory and critical care medicine
• 影响因子: 3.2
• 作者: Burke RR;Rybicki BA;Rao DS
• 通讯作者: Rao DS

Extending admixture mapping to nuclear pedigrees: application to sarcoidosis.

• DOI: 10.1002/gepi.21710
• 发表时间: 2013-04
• 期刊: GENETIC EPIDEMIOLOGY
• 影响因子: 2.1
• 作者: McKeigue, Paul M.;Colombo, Marco;Agakov, Felix;Datta, Indrani;Levin, Albert;Favro, David;Gray-Montgomery, Courtney;Iannuzzi, Michael C.;Rybicki, Benjamin A.
• 通讯作者: Rybicki, Benjamin A.