HLA Region Genetics and SLE in U.S. Black Women

美国黑人女性的 HLA 区域遗传学和 SLE

• 批准号: 7174822
• 负责人: Lynn Rosenberg
• 金额: $ 34.51万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174822
• 关键词: Address; Admixture; Affect; African American; Alleles; Autoimmune Diseases; Cells; Cheek structure; Chronic; Classification; Collection; Complement component C4a; Consensus; DNA; DNA amplification; Ensure; European; Follow-Up Studies; Funding; Gene Deletion; Gene Frequency; Gene-Modified; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Grant; HLA-DRB1; Health; Inflammatory; Lupus Erythematosus; Maps; Participant; Patients; Play; Population; Relative (related person); Research Design; Rest; Risk; Role; Sampling; Stratification; Surveys; Systemic Lupus Erythematosus; TNF gene; Technology; Variant; Woman; Women' s Health; base; case control; density; design; disorder risk; genetic association; innovation

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects African-American women. Numerous studies have shown that HLA-region genes play a key role in genetic susceptibility to SLE, but studies so far have not established which factors in the HLA region are important and how much of overall risk is explained by HLA. We propose to address these questions with a large and uniformly collected group of samples from the Black Women's Health Study (BWHS), the largest follow-up study of African-American women yet conducted. We will use cheek cell samples collected from 400 BWHS participants with SLE and 800 matched controls. Since the collection of cheek cell samples is already funded, the present grant will focus on (a) DNA extraction from the samples, (b) DNA amplification, (c) SNP haplotyping of the HLA region, (d) PCR-based genotyping for the C4A deletion allele for which there is particular evidence of association to SLE in order to control for its effect, and (e) genotyping a panel of SNPs to control for European admixture in African-Americans. We will exhaustively survey the HLA region for genetic associations with SLE; this will involve typing a high-density panel of SNPs over the region, which will provide excellent power to detect variants that confer 2-fold or greater increased risk for SLE. Among the specific genes that we will assess are TNF, IKBL, MICA, and HLA-DRB1, with adjustment for C4A gene deletion status. In addition, we will genotype a panel of SNPs across the genome to ensure that any associations with HLA alleles that we detect are real rather than due to population stratification (systematic differences in allele frequency between cases and controls due to differences in their population ancestry). This will also allow us to assess whether specific regions of the genome show unusually high or low levels of European ancestry in African-American SLE patients, thus allowing us to use an 'admixture mapping' approach to find sections of the genome containing genes that modify HLA-induced risk for SLE. The proposed study is population-based and not only uses an innovative and statistically high-powered design-which will exhaustively survey the HLA region for SLE risk, as well as search the rest of the genome for modifiers of that risk-but also focuses on African-American women, a population that is high-risk for SLE but medically and scientifically underserved.

描述（申请人提供）：系统性红斑狼疮（SLE）是一种慢性炎症性自身免疫性疾病，不成比例地影响非洲裔美国妇女。许多研究表明，HLA区域基因在SLE的遗传易感性中起着关键作用，但迄今为止的研究尚未确定HLA区域中的哪些因素是重要的，以及HLA在多大程度上解释了总体风险。我们建议解决这些问题，从黑人妇女健康研究（BWHS），最大的后续研究非洲裔美国妇女进行了大量的和统一收集的样本组。我们将使用从400名患有SLE的BWHS参与者和800名匹配的对照者收集的脸颊细胞样本。由于颊细胞样本的收集已经得到资助，目前的资助将集中在（a）样本的DNA提取，（B）DNA扩增，（c）HLA区域的SNP单倍型分型，（d）C4 A缺失等位基因的基于PCR的基因分型，其中有特别证据表明与SLE相关，以控制其影响，和（e）对一组SNP进行基因分型以控制非裔美国人中的欧洲混合物。我们将详尽地调查HLA区域与SLE的遗传关联;这将涉及在该区域分型高密度的SNP组，这将为检测导致SLE风险增加2倍或更高的变异提供极好的能力。我们将评估的特定基因包括TNF、IKBL、云母和HLA-DRB 1，并调整C4 A基因缺失状态。此外，我们将对一组SNP进行基因分型，以确保我们检测到的与HLA等位基因的任何关联是真实的，而不是由于人群分层（由于人群血统的差异，病例和对照之间等位基因频率的系统差异）。这也将使我们能够评估基因组的特定区域是否在非裔美国人SLE患者中显示出异常高或低的欧洲血统水平，从而使我们能够使用“混合作图”方法来找到含有改变HLA诱导的SLE风险的基因组部分。这项研究是以人群为基础的，不仅使用了一种创新的和统计学上的高功率设计-这将彻底调查HLA区域的SLE风险，以及搜索基因组的其余部分的风险修饰符-而且还关注非裔美国妇女，这是一个高风险的人群SLE，但医学和科学服务不足。