The genetics of lupus: a functional perspective

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]. SLE has a prevalence of approximately 1 in 2,500 in European populations [2] 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 [3]. 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 [4,5].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？8) 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 [6].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 neede