Copy Number Variation in Chromosome 1 Candidates

给定基因的拷贝数变异，也称为拷贝数变异（CNV）或拷贝数变异。 当频率超过1%时，多态性（CNP）是可遗传的特性。特定靶标的CNV 基因与复杂的表型如癌症和炎症性肠病有关。 事实上，靶基因TLR 7的CNV与BXSB小鼠的自身免疫表型相关， 最近在人Fc受体基因座的数据表明，该区域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， Fc受体区的结构变异类型，包括不同程度的缺失和重复。 此外，由于紧邻FCGR 3B的基因在病理生理学上是重要的，我们 假设参与这些结构的激活和抑制性FcR基因的全部库 变化可能是最重要的。特别是，FCGR 2C，被大多数人认为是假基因，编码一种 在B细胞上表达的蛋白质，并提供了一个平衡信号的经典概念， FCGR 2B介导的对免疫复合物驱动的B细胞活性的“制动”。我们假设， 这些CNVs的频率在非洲裔美国人中是不同的，也许西班牙裔美国人，相比之下， 这些差异将随着时间的推移导致疾病表型的严重程度， 这两个群体。在这个项目中，我们有独特的机会来定义结构 在少数民族中，这一遗传和病理生理重要区域的变异，并将其与 随着时间的推移，疾病易感性和疾病严重程度的变化。我们的具体目标是：（1）定义 经典Fc受体簇中拷贝数变异的性质及其与SLE的关系，2） 定义祖先和拷贝数变异类型之间的关系，以及3）检查其他 基因在“调理素/免疫复合物”途径中的拷贝数变异，并将这种变异与 SLE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受体和其他通路基因中的重要性。该项目还将着眼于 遗传祖先标记和CNV对SLE易感性和严重性的相互作用。本研究 该计划将（1）与项目2和项目3合作，以确定区域目标实施方式，（2）利用遗传咨询委员会的专门知识， 流行病学和生物统计学核心，用于设计和分析与区域目标实施方案有关的CNV， 加强伙伴机构之间的合作，（3）促进持续发展有效的 风湿病研究计划，（4）加强对SLE相关健康差异的研究工作 和（5）提供了新的见解SLE的遗传病因学作为一种自身免疫表型， 在少数民族人口中，这种情况更加频繁和严重。

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.