Functional Genomic Determinants of B cell Homeostasis and Susceptibility to SLE

这项试点和可行性研究的总体目标是促进对遗传易感性的了解。 系统性红斑狼疮通过选择候选基因及其生物学效应的独立和联合作用。这个 假说是编码BLyS，BAFF-R，BCMA， TACI和APRIL与增强的B细胞存活率相关，与SLE的存在相关，在 这些患者，肾脏受累。为了解决这一假设，(1)基因-疾病表型和(2) B细胞稳态和SLE发病机制的基因型-免疫表型关系将是 特色化的。因为系统性红斑狼疮的自然病史是复杂的，同时涉及到多变的临床。 多器官系统的表现，其结果的概括性可能是有限的。使用候选人 基因方法，我们打算利用一个独特的机会来探索现有的功能基因组学 大量、种族多样、特征良好的系统性红斑狼疮人群，并利用最近在 人类基因组重测序和肿瘤坏死因子/肿瘤坏死因子受体超家族在系统性红斑狼疮发病机制中的生物学可行性。 基于预测阶段、排列测试和Logistic或线性回归的单倍型分析将 用于利用病例对照、仅病例和横断面方法的频率差异。 免疫表型将使用流式细胞术进行。系统性红斑狼疮的广泛特征 来自现有明确研究人群的表型和相关风险因素 利用表位识别免疫反应剂核心的专业知识的功能基因组学方法， 分析和制备流式细胞术核心、综合临床研究中心和 调查小组将协助进行严格的评估。这些方法结合起来提供了最好的机会 快速开发B细胞稳态和系统性红斑狼疮的靶向关系并产生初步数据 有必要研究功能基因组学，将其作为针对可能受益的高危人群的工具 来自个体化的临床管理或治疗干预。这位候选人是一位新的无党派人士 没有现任或过去NIH外部研究支持的调查员，他们将翻译他们的演示 在分子流行病学和免疫遗传学方面的专门知识，以了解共同的途径 参与系统性红斑狼疮B细胞自身反应性和稳态的重要基因的激活。

The overall goal of this pilot and feasibility study is to facilitate the understanding of genetic susceptibility to SLE through the independent and joint effects of select candidate genes and their biological effects. The hypothesis is that functional variation in TNFfTNFR superfamily genes that encode BLyS, BAFF-R, BCMA, TACI and APRIL, associated with enhanced B cell survival, correlate with the presence of SLE and among these patients, renal involvement. To address this hypothesis, (1) genotype-disease phenotype and (2) genotype-immunophenotype relationships of B cell homeostasis and SLE pathogenesis will be characterized. Because the natural history of SLE is complex involving concurrent protean clinical manifestations of multiple organ systems, the generalizability of findings can be limiting. Using a candidate gene approach, we intend to capitalize on a unique opportunity to explore functional genomics in an existing large, ethnically diverse, well-characterized population of SLE and to take advantage of recent advances in human genome resequencing and biologic plausibility of the TNF/TNFR superfamily in SLE pathogenesis. Haplotype analyses based on predicted phase, permutation testing and logistic or linear regression will be used to exploit differences in frequencies using case-control, case-only and cross-sectional approaches. Immunophenotyping will be conducted using flow cytometry. The extensive characterization of the SLE phenotype and related risk factors from an existing well-defined study population coupled with a candidate functional genomics approach that exploits the expertise of the Epitope Recognition Immunoreagent Core, the Analytic and Preparative Flow Cytometry Core, the General Clinical Research Center and the investigative team will facilitate a rigorous evaluation. Together these approaches offer the best opportunity to rapidly exploit targeted relationships of B cell homeostasis and SLE and to generate preliminary data necessary to investigate functional genomics as a tool for targeting high-risk populations who may benefit from individualized clinical management or therapeutic intervention. The candidate is a new independent investigator without current or past extramural NIH research support who will translate their demonstrated expertise in molecular epidemiology and immunogenetics to the understanding of common pathways involved in the activation of genes important for B cell autoreactivity and homeostasis in SLE.