Complement Genetics and Clinical Variability of Systemic Lupus Erythematosus

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被大多数人类遗传学家忽视的重要现象：我们基因组中的许多基因在拷贝数上表现出先天的、个体间的变异。许多拷贝数变异（CNV）位点包括参与宿主与环境相互作用的基因，包括免疫反应和感觉功能的基因。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及其相关多态性创造了其基因产物的定性和定量多样性。这种多样性可能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在人类群体中具有非常复杂的多样性。补体C4位于6号染色体短臂上主要组织相容性复合体（MHC）的中心区域，在一个单倍型中可以有1到5个补体C4的结构基因拷贝。我们已经确定了C4A和C4B在欧美SLE患者、大量家庭成员和无关对照中的基因型和表型变异。我们观察到C4基因拷贝数（GCN）低的受试者频率显著增加（GCN<4: SLE患者为42.2%，对照组为28.5%;p=0.000016）。相比之下，高C4 GCN组（GCN bbbb4）在SLE中的出现频率显著降低。我们还在染色体1q23上观察到FCGR2-HSP70B-FCGR3 （FRH）复合体包括FCGR3B和FCGR3A的CNVs。初步结果提示，低GCN的FCGR3B是欧洲裔美国人SLE的一个危险因素。本应用旨在研究基因CNVs作为人类SLE和抗磷脂抗体患者的遗传危险因素和疾病调节剂的作用。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，以及不相关的种族匹配对照。具体目标是：1。确定人类SLE中补体基因的变异，重点关注补体C4和RCCX模块的拷贝数变异和相关多态性；2. 表征和研究人类SLE中FRH模块的节段重复；和3。测定抗磷脂抗体患者补体C4 （RCCX模块）和低亲和力Fc3受体（FRH模块）的CNVs。所获得的知识可以与更有效的疾病诊断和人类SLE管理高度相关。

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.