Immunogenetics of systemic lupus erythematosus: A comprehensive review

Abstract

Our understanding of the genetic basis of systemic lupus erythematosus has progressed rapidly in recent years. While many genetic polymorphisms have been associated with disease susceptibility, the next major step involves integrating these genetic polymorphisms into the molecular mechanisms and cellular immunology of the human disease. In this review, we summarize some recent work in this area, including the genetics of the type I IFN response in SLE, including polygenic and monogenic factors, as well as epigenetic influences. Contributions of both HLA and non-HLA polymorphisms to the complex genetics of SLE are reviewed. We also review recent reports of specific gene deficits leading to monogenic SLE-like syndromes. The molecular functions of common SLE-risk variants are reviewed in depth, including regulatory variations in promoter and enhancer elements and coding-change polymorphisms, and studies which are beginning to define the molecular and cellular functions of these polymorphisms in the immune system. We discuss epigenetic influences on lupus, with an emphasis on micro-RNA expression and binding, as well as epigenetic modifications that regulate the expression levels of various genes involved in SLE pathogenesis and the ways epigenetic marks modify SLE susceptibility genes. The work summarized in this review provides a fascinating window into the biology and molecular mechanisms of human SLE. Understanding the functional mechanisms of causal genetic variants underlying the human disease greatly facilitates our ability to translate genetic associations toward personalized care, and may identify new therapeutic targets relevant to human SLE disease mechanisms.

Keywords: Autoimmune diseases; Genetics; Interferon; Systemic lupus erythematosus.

Figure 1. Proposed cellular location for gene products described in the review

Major pathways and cell types involved in SLE, with SLE-risk genes shown in the cell type in which they are presumed to function. Panel A shows genes that influence different cell types involved in innate immune response, while panel B shows genes that impact various cell types involved in adaptive immune response.

Figure 2

Schematic showing a generalized gene diagram, with proposed location of functional variants in known regulatory regions, exons, splice sites, introns and intergenic sites discussed in this review. The actual SLE associated variants are located in various regions throughout the genome.