Abstract and Introduction
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.
Introduction
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by hyperactive T and B cells, auto-antibody production, and immune complex(IC) deposition. SLE has a prevalence of approximately 1 in 2,500 in European populations and is more frequent in those of non-European ancestry. SLE affects predominantly women (the female-to-male ratio is 9:1) of child-bearing age and is characterized by variable clinical features, including malar rash, glomerulonephritis, arthritis, and neuropsychiatric disease. Although the exact etiology of lupus is not fully understood, a strong genetic link has been identified through the use of association and family studies. The heritability of SLE is approximately 66%; the rates of concordance are 24% to 56% in monozygotic twins and 2% to 4% in dizygotic twins.
To date, genome-wide association studies (GWASs) have identified more than 30 associated loci. In Table 1, we show the variants that have reached genome-wide significance (1.0 × 10) in one or more GWASs, a metaanalysis, or replication studies. We have also included the Fcγ locus, because it contains multiple associated variants, including a confirmed copy number variation (CNV) in SLE. However, these loci account for less than 10% of the genetic heritability.
GWASs in SLE have been useful tools for expanding the genetic understanding of SLE by identifying new loci and replicating previously associated loci. In this review, we categorize these risk loci into a number of pathways on the basis of the current understanding of the potential role for the locus in SLE. We note that the clinical heterogeneity of SLE is mirrored by the diversity of the pathways reported to contain the associated loci from the genetic studies, apoptosis, innate immune response, ubiquitination, and phagocytosis (Table 1). Therefore, this review aims to highlight the known function(s) of the associated loci and to indicate where further functional studies are needed to elucidate the pathogenic mechanisms in lupus.