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

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，对非裔美国女性的影响不成比例。大量研究表明，人类白细胞抗原区域基因在系统性红斑狼疮的遗传易感性中起着关键作用，但到目前为止，研究还没有确定人类白细胞抗原区域中哪些因素是重要的，以及人类白细胞抗原在多大程度上解释了总体风险。我们建议从黑人妇女健康研究(BWHS)中收集大量统一收集的样本来解决这些问题，这是迄今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名匹配的对照组收集的面颊细胞样本。由于脸颊细胞样本的采集已经获得资金，目前的赠款将集中在(A)从样本中提取DNA，(B)DNA扩增，(C)人类白细胞抗原区域的SNP单倍型，(D)基于聚合酶链式反应的C4a缺失等位基因的基因分型，其中有特别证据表明与系统性红斑狼疮有关，以控制其影响，以及(E)对一组SNPs进行基因分型，以控制非裔美国人中欧洲混血的情况。我们将详尽地调查人类白细胞抗原区域与系统性红斑狼疮的遗传关联；这将涉及到对该区域的高密度SNPs进行分型，这将提供极好的能力来检测导致SLE风险增加2倍或更多的变异。我们将评估的特定基因包括肿瘤坏死因子、IKBL、MICA和人类白细胞抗原DRB1，并对C4a基因缺失状态进行了调整。此外，我们将对基因组中的一组SNPs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其群体血统的差异而产生的系统性差异)。这也将使我们能够评估基因组的特定区域在非裔美国人SLE患者中显示出异常高或低水平的欧洲血统，从而使我们能够使用“混合图谱”方法来找到包含修改人类白细胞抗原诱导的SLE风险的基因的基因组部分。这项拟议的研究是以人群为基础的，不仅使用了一种创新的、在统计学上具有很高威力的设计--它将详尽地调查人类白细胞抗原区域的系统性红斑狼疮风险，并在基因组的其余部分搜索该风险的修饰因素--而且还将重点放在非裔美国女性身上，这一群体是系统性红斑狼疮的高危人群，但在医学和科学上得不到足够的服务。

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.