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

• 批准号: 8318559
• 负责人: Maureen Maureen Mayes
• 金额: $ 56.12万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318559
• 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 risk factor; genome wide association study; high risk; human subject; human subject protection; interest; novel; phase 2 study; public health relevance; repository; scleroderma registry

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）：本项目的总体目标是鉴定影响系统性硬化症（SSc）易感性的基因。我们的假设是，存在易感基因，这些易感基因通常易患自身免疫，特别是易患SSc;并且SSc的每种独特的自身抗体亚型都有自己的一组不同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个硬皮病中心招募SSc病例，以补充硬皮病家族登记和DNA库中的998例现有病例。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，在年龄、性别和种族上进行频率匹配; 2）通过使用两阶段设计进行全基因组关联分析来鉴定候选基因区域; 3）估计与鉴定的显著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）对最强相关基因进行精细定位研究;以及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，特定的基因多态性和HLA II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作为一个单一的疾病实体的相关性更强。我们的方法是一个2阶段的研究，首先利用Illumina人类Hap 550 K基因分型微珠芯片，它可以对来自HapMap项目的1,500例病例的超过550，000个标记的SNP标记进行全基因组基因分型，然后对第一阶段在1,500例额外病例和对照中鉴定的大约15，000个最重要的SNP进行定向SNP基因分型。第一阶段和第二阶段的3，000名年龄、性别和种族匹配对照的数据将从NYCP获得，NYCP是一项纵向队列研究（P. Gregersen，主要研究者）。把握度计算表明，我们将有足够的把握度在10-4显著性水平下检测两个阶段病例的联合分析中OR 1.5-2的效应量。我们提出了一个传统的统计方法以及分析策略的新方法相结合。 公共卫生相关性。硬皮病（系统性硬化症）是一种自身免疫性疾病，其特征是皮肤和内脏器官中的纤维化和血管损伤，干扰正常功能。病因不明，但有一个遗传因素，只有那些具有正确基因组的人才有可能患上这种疾病。这项研究将对来自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负责硬皮病的易感性，以及哪些生物学途径用于引起这种疾病的器官损伤。

项目成果

Association of the HLA-DRB1 with scleroderma in Chinese population.

中国人群HLA-DRB1与硬皮病的关联

• DOI: 10.1371/journal.pone.0106939
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: He D;Wang J;Yi L;Guo X;Guo S;Guo G;Tu W;Wu W;Yang L;Xiao R;Li Y;Chu H;Lai S;Jin L;Zou H;Reveille JD;Assassi S;Mayes MD;Zhou X
• 通讯作者: Zhou X

The genetics of scleroderma: looking into the postgenomic era.

• DOI: 10.1097/bor.0b013e328358575b
• 发表时间: 2012-11
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Mayes MD

Monospecific anti-Ro52/TRIM21 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects: evidence of an association with interstitial lung disease and worse survival.

由 1574 名系统性硬化症受试者组成的三国队列中的单特异性抗 Ro52/TRIM21 抗体：与间质性肺疾病和较差生存率相关的证据。

• 发表时间: 2015
• 期刊: Clinical and experimental rheumatology
• 影响因子: 3.7
• 作者: Wodkowski,Michael;Hudson,Marie;Proudman,Susanna;Walker,Jennifer;Stevens,Wendy;Nikpour,Mandana;Assassi,Shervin;Mayes,MaureenD;Wang,Mianbo;Baron,Murray;Fritzler,MarvinJ;CanadianSclerodermaResearchGroup(CSRG);AustralianScleroder
• 通讯作者: AustralianScleroder

Clinical correlates of monospecific anti-PM75 and anti-PM100 antibodies in a tri-nation cohort of 1574 systemic sclerosis subjects.

由 1574 名系统性硬化症受试者组成的三国队列中单特异性抗 PM75 和抗 PM100 抗体的临床相关性。

• DOI: 10.3109/08916934.2015.1077231
• 发表时间: 2015
• 期刊: Autoimmunity
• 影响因子: 3.5
• 作者: Wodkowski,Michael;Hudson,Marie;Proudman,Susanna;Walker,Jennifer;Stevens,Wendy;Nikpour,Mandana;Assassi,Shervin;Mayes,MaureenD;Tatibouet,Solène;Wang,Mianbo;CanadianSclerodermaResearchGroup(CSRG);AustralianSclerodermaInterestGrou
• 通讯作者: AustralianSclerodermaInterestGrou

Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population.

• DOI: 10.1371/journal.pone.0087363
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang J;Guo X;Yi L;Guo G;Tu W;Wu W;Yang L;Xiao R;Li Y;Chu H;He D;Jin L;Mayes MD;Zou H;Zhou X
• 通讯作者: Zhou X