Copy Number Variation in Chromosome 1 Candidates

给定基因拷贝数的变异，也称为拷贝数变异(CNV)或拷贝数 当频率超过1%时，多态(CNP)是一种可遗传的属性。特定目标的CNV 基因与癌症和炎症性肠病等复杂的表型有关。 的确，靶基因TLR7的CNV与BXSB小鼠的自身免疫表型有关， 而最近人类Fc受体基因座的数据表明，该区域的一种中性粒细胞特异性基因的CNV 在自身免疫性疾病中可能也很重要。我们现在有数据表明有多个 Fc受体区域的结构变异类型，包括不同程度的缺失和重复。 此外，由于紧邻FCGR3B的基因在病理生理上很重要，我们 假设激活和抑制FCR基因的完整谱系参与了这些结构 变化可能是最重要的。特别是，被大多数人认为是伪基因的FCGR2C编码了一个 在B细胞上表达的蛋白质，为经典的 FCGR2B介导的免疫复合物驱动的B细胞活性“刹车”。我们假设自然界和 这些CNV的频率在非洲裔美国人中是不同的，也许在西班牙裔美国人中也是如此 这些差异将有助于随着时间的推移疾病表型的严重程度 这两组人都是。在这个计划项目中，我们有独特的机会来定义结构 这一遗传和病理生理学重要区域在少数民族中的变异，以及与此相关 随着时间的推移，疾病易感性和疾病严重性都会发生变化。我们的具体目标是1)明确 经典Fc受体簇拷贝数变异的本质及其与系统性红斑狼疮的关系 定义祖先和拷贝数变异类型之间的关系，以及3)检查其他 拷贝数变异的“调理素/免疫复合体”途径中的基因以及这种变异与 系统性红斑狼疮总体风险。项目与总体PPG优先级的关系。拟议的研究计划将 研究CNV在Fc受体和其他途径基因中的重要性。该项目还将着眼于 遗传祖先标记和CNV之间的相互作用对SLE易感性和严重程度的影响。这项研究 计划将(1)与项目2和3合作，以确定区域目标，(2)利用遗传专家的专门知识 流行病学和生物统计学是设计和分析CNV与区域目标相关的核心， 加强伙伴机构之间的合作，(3)促进有效的持续发展 风湿病研究计划，(4)加强对系统性红斑狼疮相关健康差距的研究 以及(5)为系统性红斑狼疮作为一种自身免疫表型的遗传病因提供了新的见解 在少数民族人口中不成比例地更加频繁和严重。

Variations in the copy number of a given gene, also known as copy number variation (CNV) or copy number polymorphisms (CNP), when the frequency exceeds 1%, is a heritable property. CNVs of specific target genes have been associated with complex phenotypes such as cancer and inflammatory bowel disease. Indeed, CNV of the target gene, TLR7, has been associated with the autoimmune phenotype in BXSB mice, and recent data in the human Fc receptor locus suggest that CNV of a neutrophil specific gene in this region may also be important in autoimmune diseases. We now have data that demonstrate that there are multiple types of structural variation in the Fc receptor region, both deletions of varying extents and duplications. Furthermore, since the genes immediately adjacent FCGR3B are pathophysiologically important, we hypothesize that the full repertoire of activating and inhibitory FcR genes involved in these structural variations may be most important. In particular, FCGR2C, thought by most to be a pseudogene, encodes a protein expressed on B cells and provides a counterbalancing signal to the classical concept of the FCGR2B-mediated "brake" on immune complex driven B cell activity. We hypothesize that the nature and frequency of these CNVs will be distinct in African Americans, and perhaps Hispanics, compared to Caucasians and that these differences will contribute to the severity of the disease phenotype over time in both of these groups. In this Program Project, we have the unique opportunity to define the structural variations of this genetically and pathophysiologically important region, in ethnic minorities, and to relate this variation to both disease susceptibility and disease severity over time. Our Specific Aims are 1) To define the nature of copy number variation in the classical Fc receptor cluster and its relationship to SLE, 2) To define the relationship between ancestry and the types of copy number variants and 3) To examine other genes in the "opsonin / immune complex" pathway for copy number variation and relate this variation to overall SLE risk. Relationship of Project with Overall PPG Priorities. The proposed research plan will examine the importance of CNV in Fc receptors and other pathway genes. The project will also look at interactions between genetic ancestry markers and CNV for SLE susceptibility and severity. This research plan will (1) work with Projects 2 and 3 to identify regional AIMs, (2) draw on the expertise of the Genetic Epidemiology and Biostatistics Cores in the design and analysis of CNV in relation to regional AIMs, increase collaboration between partner institutions, (3) foster the continued development of an effective Rheumatic Diseases Research Program, (4) enhance research efforts toward SLE-related health disparities and (5) provide novel insight to the genetic etiology of SLE as an autoimmune phenotype that is disproportionately more frequent and severe among ethnic minority populations.