Chapter 3 - Constitutive Genes and Lupus

Abstract

Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease with a strong genetic component that is modified by environmental exposures. The three basic approaches to explore genetic risk factors for diseases are candidate gene association studies, linkage analysis in multiplex families, and genome-wide association studies (GWAS). Non-major histocompatibility complex (MHC) SLE risk loci are grouped into three biologic pathways involved in SLE. These pathways are clearance and processing of immune complexes, toll-like receptor/type I interferon signaling, and immune signal transduction. This chapter describes these genetic associations in each pathway. Furthermore, recent GWAS have identified many novel loci, some of which are not well characterized as yet, or have no obvious connection to known pathways involved in the pathogenesis of SLE. Although the functional roles of these genes and their underlying mechanisms to increase disease risk are poorly understood, some are considered as potential regulators for differentiation, activation, or function of immune cells and some have been identified to be associated with other autoimmune diseases. This chapter summarizes recent advances in the identification of non-HLA genetic variations predisposed to SLE that are generally common SNPs with their genetic associations established in European-derived populations. Similar genetic studies in multiple ethnic groups may identify new genetic associations and help localize causal variants for association with SLE and specific manifestations of SLE, which can provide new clues to explain molecular pathways leading to the heterogeneous disease phenotypes.