Two-Stage Genome-Wide Association Study in Systemic Sclerosis

描述(由申请人提供)：本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，普遍存在易感基因，特别是SSc易感基因；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和DNA库中现有的998例病例。具体目标是：1)建立3,000名系统性硬化症(SSC)患者和6,000名对照的病例对照样本，年龄、性别和种族的频率匹配；2)通过使用两阶段设计进行全基因组关联分析来确定候选基因区域；3)估计与已识别的显著SNPs相关的疾病风险；4)通过定义SSC表型的自身抗体亚群来分析数据；5)(探索性)对最密切相关的基因进行精细的图谱研究；以及6)为科学界提供数据和样本。我们和其他人的初步数据表明，特定的基因多态和HLAII类等位基因与基于自身抗体表达的SSC亚型的相关性比与SSC作为单一疾病实体的相关性更强。我们的方法是一个两阶段的研究，最初利用Illumina人类Hap550K基因分型芯片，使超过550,000个来自HapMap项目的标记SNP标记在1,500个病例上进行全基因组基因分型，然后在第一阶段对另外1,500个病例和对照中确定的大约15,000个最重要的SNP进行SNP基因分型。第一阶段和第二阶段3000名年龄、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(P.Gregersen，首席调查员)。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显著水平上检测OR 1.5-2的影响大小。我们提出了传统统计方法和新方法的结合作为分析策略。 与公共卫生相关。硬皮病(系统性硬化症)是一种自身免疫性疾病，其特征是皮肤和内部器官的纤维化和血管损伤，干扰了正常的功能。病因尚不清楚，但有一个遗传因素，只有那些拥有正确基因集的人才有可能患上这种疾病。这项研究将对3,000例硬皮病患者和6,000名对照的DNA进行全基因组扫描，以找出病例中与对照不同的基因组区域；使用这种方法，我们希望了解哪些基因与硬皮病的易感性有关，哪些生物途径被用来导致这种疾病的器官损害。

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.