Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and is characterized by chronic inflammation and the production of anti-nuclear auto-antibodies. In the era of genome-wide association studies (GWASs), elucidating the genetic factors present in SLE has been a very successful endeavor; 28 confirmed disease susceptibility loci have been mapped. In this review, we summarize the current understanding of the genetics of lupus and focus on the strongest associated risk loci found to date (P <1.0 × 10−8). Although these loci account for less than 10% of the genetic heritability and therefore do not account for the bulk of the disease heritability, they do implicate important pathways, which contribute to SLE pathogenesis. Consequently, the main focus of the review is to outline the genetic variants in the known associated loci and then to explore the potential functional consequences of the associated variants. We also highlight the genetic overlap of these loci with other autoimmune diseases, which indicates common pathogenic mechanisms. The importance of developing functional assays will be discussed and each of them will be instrumental in furthering our understanding of these associated variants and loci. Finally, we indicate that performing a larger SLE GWAS and applying a more targeted set of methods, such as the ImmunoChip and next generation sequencing methodology, are important for identifying additional loci and enhancing our understanding of the pathogenesis of SLE.
Highlights
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by hyperactive T and B cells, auto-antibody production, and immune complex (IC) deposition [1]
We have shown the importance of these genes in their most relevant related pathways (Figure 1)
To fully understand these associations, fine-mapping studies using targeted genotyping chips, such as the ImmunoChip, will be required. These types of studies will lead to the identification of additional variants that can be used for functional studies to elucidate the molecular mechanisms operating in lupus
Summary
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by hyperactive T and B cells, auto-antibody production, and immune complex. There are a number of associated loci whose gene products play a key role in T-cell development and TCR signaling and have been reported to be associated with SLE. The risk haplotype has been reported to be associated with increased TNFSF4 transcript levels [91,92] This increased expression of OX40L promotes OX40/OX40L interactions and increases the co-stimulatory signal between APCs and T cells, and this in turn increases Tcell survival and thereby propagates autoimmunity. The top associated SNP in SLE, rs280519 (P = 3.88 × 10−8), has been shown to play a role in increasing gene expression and IFN production. This fact suggests that the intergenic associations are pointing toward CD44 as a more likely candidate gene for SLE than PDHX
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