The genetics of lupus: a functional perspective

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.

Figure 1

The impaired immune system in patients with systemic lupus erythematosus (SLE). Defective apoptotic clearance allows deposition of immune complexes which can stimulate B and T cells. Hyperactive B cells then produce auto-antibodies which activate complement, causing tissue damage. Plasmacytoid dendritic cells (pDCs) activated by immune complexes then release excessive interferon α/β (IFNα/β), again causing tissue damage. At each pathway, the known associated loci are indicated. All of the loci produce loss of both self-tolerance and autoimmunity, as seen in SLE. APC, antigen-presenting cell; BANK1, B-cell scaffold protein with ankyrin repeats 1; BLK, B lymphoid tyrosine kinase; HLA-DRB1, human leukocyte antigen-DRB1; IFIH1, interferon-induced helicase 1; IL10, interleukin-10; IRF, interferon regulatory factor; ITGAM, integrin, alpha M; LYN, V-yes-1 Yamaguchi sarcoma viral-related oncogene homolog; MHC, major histocompatibility complex; Mφ, microphage; NCF2, neutrophil cytosolic factor 2; PRDM1-ATG5, PR domain containing 1, with ZNF domain-autophagy-related 5 homolog; PTPN22, protein tyrosine phosphatase, non-receptor type 22; RasGRP3, RAS guanyl releasing protein 3; STAT4, signal transducer and activator of transcription 4; TCR, T-cell receptor; TNFAIP3, tumor necrosis factor, alpha-induced protein 3; TNFSF4, tumor necrosis factor superfamily, member 4; TNIP1, TNFAIP3- interacting protein 1; UBE2L3, ubiquitin-conjugating enzyme E2L 3.

Figure 2

The role of A20 in the nuclear factor-kappa-B (NF-κB) pathway. A20 ubiquitinates TRAF6, which is bound to the IKK complex (IKKγ, IKKα, and IKKβ). The IKK complex then becomes phosphorylated, propagating proteasomal degradation of IKβα and, in turn, allowing NF-κB translocation to the nucleus and propagating target gene transcription. IKK, IκB kinase; IRAK, interleukin-1 receptor-associated kinase; MyD88, myeloid diff erentiation primary response gene (88); P, phosphate; TRAF6, tumor necrosis factor receptor-associated kinase 6.