Two-Stage Genome-Wide Association Study in Systemic Sclerosis

描述（由申请人提供）：该项目的总体目标是确定影响系统性硬化症（SSc）易感性的基因。我们的假设是，有易感基因一般会导致自身免疫，尤其是SSc；SSc的每一种独特的自身抗体亚型都有自己的一组不同的或不完全重叠的易感基因。为了获得足够的样本量，我们建议使用10个硬皮病中心来登记SSc病例，以补充硬皮病家族登记处和DNA库中的998例现有病例。具体目的是：1)建立3000例系统性硬化症（SSc）患者和6000例对照的病例对照样本，频率与年龄、性别和种族匹配；2)采用两阶段设计进行全基因组关联分析，确定候选基因区域；3)估计与已确定的显著snp相关的疾病风险；4)通过定义SSc表型的自身抗体亚群分析数据；5)（探索性）对相关性最强的基因进行精细的定位研究；6)为科学界提供数据和标本。我们和其他人的初步数据表明，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亚型的相关性比与SSc作为单一疾病实体的相关性更强。我们的方法是一项两阶段的研究，最初使用Illumina Human Hap550K基因分型BeadChip，可以对1500例病例进行来自HapMap项目的超过550,000个标记SNP标记的全基因组基因分型，然后对1500例其他病例和对照进行第一阶段鉴定的约15,000个最重要的SNP基因分型。在第一阶段和第二阶段，3000名年龄、性别和种族匹配的对照者的数据将从NYCP纵向队列研究（P. Gregersen，首席研究员）中获得。功率计算表明，在对两个阶段的病例进行联合分析时，我们将有足够的功率在10-4显著性水平上检测OR 1.5-2的效应量。我们建议将传统的统计方法与分析策略等新方法相结合。

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.