All ETDs from UAB

Advisory Committee Chair

Robert P Kimberly

Advisory Committee Members

Devin Absher

Daniel C Bullard

Bruce R Korf

David T Redden

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The human immune system must be able to adapt to a wide spectrum of invading pathogens in order to keep the human body alive. This variation includes directed recombination and mutation at the level of the individual and genetic variation and natural selection at the population level. A direct consequence of the adaptability of the immune system is autoimmunity: as the immune system adapts to a shifting spectrum of antigens, it can shift to self-antigens, and therefore attack the body and cause disease. Since genetic factors are part of this adaptability, they are also connected with autoimmune disease. SLE is a prototypical autoimmune disease with several known genetic risk factors. One form of genetic variation implicated in SLE is CNV of the 1q12 FCGR gene cluster. Prior studies have focused on CNV of one gene, FCGR3B, but other studies have suggested deeper complexity of CNV in the locus. In this thesis, we present a novel pyrosequencing-based method for studying CNV in the 1q23 FCGR gene locus, which has allowed us to better understand the genetic complexity of this locus and its relationship to autoimmunity. We identified novel associations of certain FCGR3B alleles with SLE risk and severity that may partially explain the differences in SLE risk and severity between African Americans and European Americans. We have also identified a novel variant of FCGR2B that appears to be a partial duplication of the FCGR2B locus. This variant doesn't follow the same pattern of CNV observed in previously reported CNVs of FCGR3A and FCGR3B, and is strongly associated with SLE risk. Our findings for FCGR3B and FCGR2B CNV are important to SLE and autoimmunity and also serve as starting points for future studies of the 1q23 FCGR gene cluster.

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