Two-Stage Genome-Wide Association Study in Systemic Sclerosis

系统性硬化症的两阶段全基因组关联研究

基本信息

批准号：
7930526
负责人：
Maureen Maureen Mayes
金额：
$ 88.15万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2008-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7930526
关键词：
Accounting Address Affect African American Age Alleles American Antibodies Area Autoantibodies Autoimmune Diseases Autoimmunity Biological Blood Vessels Blood specimen Budgets Candidate Disease Gene Classification Clinical Cohort Studies Communities Cost Savings Cutaneous DNA Data Data Analyses Databases Diagnosis Diffuse Disease Enrollment Ensure Ethnic Origin European Family-Based Registry Fibrosis Frequencies Gender Genes Genetic Genetic Databases Genetic Polymorphism Genetic Variation Genome Genomics Genotype Goals Grant Guidelines Haplotypes Health Human Incidence Individual Intellectual Property Joints Learning Life Link Logistic Regressions Malignant Neoplasms Maps Medical History Methods New York Onset of illness Organ Overlapping Genes Pathway interactions Patients Phase Phenotype Plasma Population Predisposition Prevalence Price Principal Investigator Privacy Public Health RNA Polymerase III Rare Diseases Recruitment Activity Research Research Personnel Sample Size Sampling Scleroderma Serum Single Nucleotide Polymorphism Site Skin Specimen Staging Statistical Methods Stratification Susceptibility Gene Systemic Scleroderma Texas Trees United States National Institutes of Health Universities Woman base case control cost data sharing design disorder risk genetic analysis genetic risk factor genome wide association study high risk human subject human subject protection interest novel phase 2 study public health relevance repository scleroderma registry

项目摘要

DESCRIPTION (provided by applicant): The OVERALL GOAL of this project is to identify genes that influence susceptibility to systemic sclerosis (SSc). Our HYPOTHESES are that there are susceptibility genes that predispose to autoimmunity in general and to SSc in particular; and that each of the unique autoantibody subtypes of SSc has its own set of distinct or incompletely overlapping susceptibility genes. In order to obtain an adequate sample size, we propose to use a 10 scleroderma centers to enroll SSc cases to supplement the 998 current cases in the Scleroderma Family Registry and DNA Repository. The SPECIFIC AIMS are: 1) To establish a case-control sample of 3,000 systemic sclerosis (SSc) patients and 6,000 controls, frequency matched on age, gender, and ethnicity; 2) To identify candidate gene regions by performing a genome wide association analysis using a two-phase design; 3) To estimate disease risk associated with identified significant SNPs; 4) To analyze the data by autoantibody subsets which define the phenotypes of SSc; 5) (exploratory)To perform fine mapping studies of the most strongly associated genes; and 6) To make the data and specimens available for the scientific community. Our preliminary data and that of others indicate that particular gene polymorphisms and HLA class II alleles are more strongly associated with SSc subtypes based on autoantibody expression than with SSc as a single disease entity. Our METHOD OF APPROACH is a 2-phase study initially utilizing the Illumina Human Hap550K Genotyping BeadChip which enables whole-genome genotyping of over 550,000 tagged SNP markers from the HapMap Project on 1,500 cases, then directed SNP genotyping of approximately15,000 most significant SNPs identified in the first stage on 1,500 additional cases and controls. Data on 3,000 age-, gender-, and ethnicity-matched controls for the first and the second stage will be obtained from the NYCP, a longitudinal cohort study (P. Gregersen, Principal Investigator). POWER CALCULATIONS show that we will have adequate power to detect an effect size of OR 1.5-2 at the 10-4 significance level in joint analysis of cases from the two stages. We propose a combination of traditional statistical methods as well as novel methods as ANALYTICAL STRATEGY. PUBLIC HEALTH RELEVANCE. Scleroderma (systemic sclerosis) is an autoimmune disease characterized by fibrosis and blood vessel damage in the skin and in internal organs which interfere with normal function. The cause is unknown but there is a genetic component, such that only those individuals with the right set of genes are likely to develop this disease. This study will perform a genome-wide scan of DNA from 3,000 scleroderma cases and 6,000 controls in order to find areas of the genome that are different in the cases than in the controls; using this approach, we hope to learn what genes are responsible for susceptibility to scleroderma and which biological pathways are used to cause organ damage in this disease.

描述（由申请人提供）：该项目的总体目标是确定影响对系统性硬化症易感性（SSC）的基因。我们的假设是，有一些易感基因通常会自身免疫，尤其是SSC。 SSC的每个独特自身抗体亚型都有其自己的一组独特或不完全重叠的敏感性基因。为了获得足够的样本量，我们建议使用10个硬皮病中心招募SSC病例，以补充硬皮病家庭注册表和DNA存储库中的998例当前病例。具体目的是：1）建立3,000个系统性硬化症（SSC）患者和6,000例对照的病例对照样本，年龄，性别和种族匹配的频率； 2）通过使用两相设计进行基因组广泛的关联分析来识别候选基因区域； 3）估计与确定的大量SNP相关的疾病风险； 4）通过自身抗体子集分析定义SSC表型的数据； 5）（探索性）对最密切相关的基因进行精细的映射研究； 6）使数据和标本可用于科学界。我们的初步数据以及其他数据表明，基于自身抗体表达的特定基因多态性和HLA II类等位基因与SSC相比，与SSC作为单个疾病实体更强烈。我们的方法方法是一项2阶段研究，最初利用Illumina HAP550K基因分型珠雪花，可从HAPMAP项目中从1,500个病例的HAPMAP项目中进行超过550,000个标记的SNP标记的全基因组基因分型，然后在大约15,000个案例中指定了大约15,000个SNP基因分型，该基因分型在第一阶段中确定了大约1,500份的SNP。第一阶段和第二阶段的3,000年龄，性别和种族匹配的对照的数据将从NYCP获得，这是一项纵向队列研究的NYCP（P. Gregersen，首席研究员P. Gregersen）。电源计算表明，在两个阶段的案例联合分析中，我们将有足够的功率在10-4显着性水平下检测效应大小或1.5-2。我们提出了传统统计方法以及新方法作为分析策略的组合。公共卫生相关性。硬皮病（全身性硬化症）是一种自身免疫性疾病，其特征是皮肤和内脏中的纤维化和血管损伤，这些疾病会干扰正常功能。原因是未知的，但是有一个遗传成分，因此只有那些具有正确基因的个体可能会发展出这种疾病。这项研究将对3,000例硬皮病病例和6,000例对照的DNA进行全基因组扫描，以找到与对照组相比的基因组区域。使用这种方法，我们希望了解哪些基因对硬皮病的易感性负责，以及哪些生物途径用于在该疾病中造成器官损害。