Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus

描述（由申请人提供）：在过去的几年中，比较基因组杂交（CGH）和分子遗传学实验揭示了一个重要的现象，这一现象没有引起大多数人类遗传学家的注意：我们基因组中的许多基因表现出先天的、个体间的拷贝数变异。那些拷贝数变异（CNV）基因座中的许多包括参与宿主-环境相互作用的基因，包括用于免疫应答和感觉功能的基因。这一发现为研究数量性状和复杂疾病的遗传基础提供了一个新的令人兴奋的机会。我们假设基因CNVs及其相关的多态性造成了其基因产物的定性和定量差异。这种疾病可导致免疫系统内在强度的差异，并导致对自身免疫性疾病的不同易感性。我们已经证明了补体成分C4在人群中的显着复杂的多样性。位于6号染色体短臂上的主要组织相容性复合体（MHC）的中心区域，在单倍型中可以存在1至5个拷贝的补体C4结构基因。我们已经确定了C4 A和C4 B的基因型和表型变异的欧洲美国SLE患者，大量的家庭成员和无关的控制。我们观察到具有低C4基因拷贝数（GCN）的受试者的频率高度显著增加（GCN<4：SLE中42.2%，对照中28.5%; p=0.000016）。与此相反，在SLE中高C4 GCN组（GCN > 4）的频率显著降低。我们还观察到FCGR 2-HSP 70 B-FCGR 3（FRH）复合物的CNV，包括染色体1 q23处的FCGR 3B和FCGR 3A。初步结果表明，FCGR 3B的低GCN是欧洲裔美国人SLE的危险因素。本申请旨在研究基因CNVs作为人类SLE和抗磷脂抗体患者的遗传风险因子和疾病修饰因子的作用。它将检查来自不同种族的SLE患者的大队列，女性和男性患者及其一级亲属，以及无关的种族匹配对照。具体目标是：1.确定SLE患者补体基因的变异，重点是补体C4和RCCX模块的拷贝数变异和相关的多态性;表征和研究人类SLE中FRH模块的节段性重复;和3.测定抗磷脂抗体患者补体C4（RCCX模块）和低亲和力Fc 3受体（FRH模块）的CNV。所获得的知识对于更有效的疾病诊断和人类SLE的管理具有高度相关性。

DESCRIPTION (provided by applicant): Comparative genomic hybridization (CGH) and molecular genetic experiments in the past few years have revealed an important phenomenon that escaped the attention of most human geneticists: many genes in our genomes exhibit an inborn, inter-individual variation in copy- numbers. Many of those copy-number variation (CNV) loci include genes engaged in host- environment interactions, including those for immune responses and sensory functions. This discovery provides a new and exciting opportunity to examine the genetic basis of quantitative traits and complex diseases. We hypothesize that gene CNVs and their associated polymorphisms create qualitative and quantitative diversities of their gene products. Such diversities can lead to differences in the intrinsic strengths of the immune system, and result in varying susceptibilities to autoimmune diseases. We have demonstrated a remarkably complex diversity of complement component C4 in human populations. Located in the central region of major histocompatibility complex (MHC) on the short arm of the chromosome 6, there can be one to five copies of structural genes for complement C4 in a haplotype. We have determined the genotypic and phenotypic variations of C4A and C4B in European American patients with SLE, large number of family members and unrelated controls. We observed a highly significant increase in the frequency of subjects with low C4 gene copy- number (GCN) (GCN<4: 42.2% in SLE, 28.5% in controls; p=0.000016). By contrast, there is a significant decrease in the frequency of the high C4 GCN group (GCN > 4) in SLE. We have also observed CNVs for the FCGR2-HSP70B-FCGR3 (FRH) complex including FCGR3B and FCGR3A at chromosome 1q23. Preliminary results suggest that low GCN of FCGR3B is a risk factor for SLE in European Americans. This application seeks to investigate the roles of gene CNVs as genetic risk factors and disease modifiers for human SLE and patients with antiphospholipid antibodies. It will examine large cohorts of patients with SLE from different ethnic groups, female and male patients and their first-degree relatives, and unrelated race-matched controls. The specific aims are to: 1. Determine variations of complement genes in human SLE with emphasis on the copy- number variation and associated polymorphisms of complement C4 and RCCX modules; 2. Characterize and investigate the segmental duplication of the FRH modules in human SLE; and 3. Determine CNVs of complement C4 (RCCX modules) and low affinity Fc3 receptors (FRH modules) in patients with antiphospholipid antibodies. The knowledge to be gained can be highly relevant for more effective disease diagnosis and management of human SLE.