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理解， SLE通过独立和联合作用筛选候选基因及其生物学效应。的 假设是编码BLyS、BAFF-R、BCMA 与B细胞存活增强相关的TACI和APRIL与SLE的存在相关， 这些患者肾脏受累为了解决这一假设，（1）基因型-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 表征了由于SLE的自然病程复杂，涉及并发的多种临床表现， 多器官系统的表现，结果的普遍性可能是有限的。使用候选 基因的方法，我们打算利用一个独特的机会，探索功能基因组学在现有的 大的，种族多样的，特征良好的SLE人群，并利用最新进展， SLE发病机制中TNF/TNFR超家族的人类基因组重测序和生物学活性 基于预测相位、排列检验和逻辑或线性回归的单倍型分析将在 使用病例对照、仅病例和横断面方法来利用频率差异。 将使用流式细胞术进行免疫表型分析。SLE的广泛特征 来自现有明确定义的研究人群的表型和相关风险因素， 利用表位识别免疫试剂核心的专业知识的功能基因组学方法， 分析和简化流式细胞术核心，一般临床研究中心和 调查小组将协助进行严格的评估。这些方法共同提供了最佳机会 快速开发B细胞稳态和SLE的靶向关系，并生成初步数据， 有必要研究功能基因组学作为针对高危人群的工具， 个体化临床管理或治疗干预。这位候选人是一位新的无党派人士 没有当前或过去的院外NIH研究支持的研究者，他们将翻译他们的证明 在分子流行病学和免疫遗传学的专业知识，以了解共同的途径 参与SLE中对B细胞自身反应性和稳态重要的基因的活化。

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.