Copy Number Variation in Chromosome 1 Candidates

1 号染色体候选者的拷贝数变异

• 批准号: 7870367
• 负责人: Robert P. Kimberly
• 金额: $ 26.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870367
• 关键词: 1q21; Affect; Affinity; African; African American; Alleles; Antigen-Antibody Complex; Asians; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological; Biostatistics Core; Blood Banks; Caucasians; Caucasoid Race; Cell Line; Cells; Chromosomes; Chromosomes, Human, Pair 1; Clinical Data; Collaborations; Complement Receptor; Complex; Consent; Copy Number Polymorphism; DNA; Data; Development; Disease susceptibility; Electrophoresis; End stage renal failure; Equilibrium; Ethnic Origin; European; FCGR2A gene; FCGR2B gene; FCGR2C gene; FCGR3A gene; FCGR3B gene; Family; Family member; Fc Receptor; Fostering; Frequencies; Gene Dosage; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Haplotypes; Hematology; Hispanics; Homologous Gene; Human; In Vitro; Individual; Inflammatory Bowel Diseases; Institution; Laboratories; Ligands; Literature; Malignant Neoplasms; Maps; Mediating; Methods; Mus; Nature; Opsonin; Other Genetics; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiologic pulse; Population; Population Study; Predisposition; Principal Investigator; Property; Proteins; Pseudogenes; Reporting; Research; Resources; Rheumatism; Risk; SNP genotyping; Sampling; Severities; Severity of illness; Signal Transduction; Source; Structure; Systemic Lupus Erythematosus; TLR7 gene; Testing; Time; Toll-like receptors; Variant; Work; base; cohort; design; disease phenotype; duplicate genes; ethnic minority population; genetic epidemiology; genome wide association study; health disparity; insight; member; neutrophil; novel; programs; promoter; protein expression; receptor

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.

给定基因拷贝数的变异，也称为拷贝数变异 (CNV) 或拷贝数 多态性（CNP），当频率超过1%时，就是一种可遗传的特性。特定靶点的CNV 基因与癌症和炎症性肠病等复杂表型相关。 事实上，目标基因 TLR7 的 CNV 与 BXSB 小鼠的自身免疫表型相关。 人类 Fc 受体基因座的最新数据表明，该区域中性粒细胞特异性基因的 CNV 在自身免疫性疾病中也可能很重要。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 的基因在病理生理学上很重要，我们 假设激活和抑制 FcR 基因的全部功能都参与这些结构 变化可能是最重要的。特别是，大多数人认为是假基因的 FCGR2C 编码 B 细胞上表达的蛋白质，为经典概念提供了平衡信号 FCGR2B 介导的免疫复合物驱动的 B 细胞活性“刹车”。我们假设性质和 与其他人相比，这些 CNV 的频率在非裔美国人（也许还有西班牙裔美国人）中会有所不同 白种人，随着时间的推移，这些差异将导致疾病表型的严重程度 这两个组。在这个计划项目中，我们有独特的机会来定义结构 这个在遗传和病理生理学上重要的区域在少数民族中的变异，并将其联系起来 疾病易感性和疾病严重程度随时间的变化。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) To 定义祖先和拷贝数变异类型之间的关系，3) 检查其他 “调理素/免疫复合物”途径中的基因用于拷贝数变异，并将这种变异与 总体 SLE 风险。项目与 PPG 总体优先事项的关系。拟议的研究计划将 检查 CNV 在 Fc 受体和其他途径基因中的重要性。该项目还将考虑 遗传祖先标记与 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 合作确定区域 AIM，(2) 利用遗传资源中心的专业知识 与区域 AIM 相关的 CNV 设计和分析的流行病学和生物统计学核心， 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) 加强针对 SLE 相关健康差异的研究工作 (5) 为 SLE 作为一种自身免疫表型的遗传病因学提供了新的见解 少数民族人口中的发病率和严重程度不成比例。