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: 7383863
• 负责人: Lynn Rosenberg
• 金额: $ 33.95万
• 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/7383863
• 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（由申请人提供）：系统性红斑狼疮 (SLE) 是一种慢性炎症性自身免疫性疾病，对非裔美国女性的影响尤为严重。大量研究表明，HLA 区域基因在 SLE 遗传易感性中发挥着关键作用，但迄今为止的研究尚未确定 HLA 区域中的哪些因素很重要，以及 HLA 可以解释多少总体风险。我们建议通过黑人女性健康研究 (BWHS) 中统一收集的大量样本来解决这些问题，该研究是迄今为止针对非裔美国女性进行的最大规模的后续研究。我们将使用从 400 名患有 SLE 的 BWHS 参与者和 800 名匹配对照中收集的颊细胞样本。由于脸颊细胞样本的收集已经获得资助，目前的资助将集中于 (a) 从样本中提取 DNA，(b) DNA 扩增，(c) HLA 区域的 SNP 单倍型分析，(d) 基于 PCR 的基因分型C4A 缺失等位基因，有与 SLE 相关的特定证据，以便控制其影响，以及 (e) 对一组 SNP 进行基因分型，以控制非裔美国人中的欧洲混血。我们将详尽调查 HLA 区域与 SLE 的遗传关联；这将涉及对该区域的高密度 SNP 面板进行分型，这将提供卓越的能力来检测导致 SLE 风险增加 2 倍或更大的变异。我们将评估的特定基因包括 TNF、IKBL、MICA 和 HLA-DRB1，并根据 C4A 基因缺失状态进行调整。此外，我们将对整个基因组中的一组 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都是真实的，而不是由于群体分层（病例和对照之间的等位基因频率因群体血统差异而存在系统性差异） 。这也将使我们能够评估非洲裔美国 SLE 患者基因组的特定区域是否表现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”方法来找到包含修饰基因的基因组部分。 HLA 诱发的 SLE 风险。拟议的研究以人群为基础，不仅采用了创新且统计上高效的设计（将详尽调查 HLA 区域的 SLE 风险，并搜索基因组的其余部分以寻找该风险的修饰因素），而且还重点关注非裔美国女性是罹患系统性红斑狼疮的高危人群，但医疗和科学服务却不足。