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.
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