Systemic lupus erythematosus as a genetic disease

Abstract

Systemic lupus erythematosus is the prototypical systemic autoimmune disease, as it is characterized both by protean multi-organ system manifestations and by the uniform presence of pathogenic autoantibodies directed against components of the nucleus. Prior to the modern genetic era, the diverse clinical manifestations of SLE suggested to many that SLE patients were unlikely to share a common genetic risk basis. However, modern genetic studies have revealed that SLE usually arises when an environmental exposure occurs in an individual with a collection of genetic risk variants passing a liability threshold. Here, we summarize the current state of the field aimed at: (1) understanding the genetic architecture of this complex disease, (2) synthesizing how this genetic risk architecture impacts cellular and molecular disease pathophysiology, (3) providing illustrative examples that highlight the rich complexity of the pathobiology of this prototypical autoimmune disease and (4) communicating this complex etiopathogenesis to patients.

Fig. 1.

Most polygenic effects are common variants of small effect size A) Well-known examples of genetic disease causal variants demonstrating relationship between effect size and minor allele frequency. SCA: Sickle Cell Anemia, HBB: hemoglobin beta subunit; CF: Cystic Fibrosis, CFTR: CF transmembrane conductance regulator; AS: Ankylosing Spondylitis, HLA-B: major histocompatibility complex, class I, B; AMD: Age-Related Macular Degeneration, CFH: complement factor H; CD: Crohn’s disease, IL23R: interleukin 23 receptor, NOD2: nucleotide binding oligomerization domain containing 2; SARD: Systemic Autoimmune/Rheumatic Disease, IRF5: interferon regulatory factor 5, PTPN22: protein tyrosine phosphatase non-receptor type 22. SLE GWAS Hits: Most significantly associated marker in a region B) The vast majority of loci listed in the GWAS catalog (Supplemental Table 1) exhibit small effect size (Odds Ratio < 2) C) Inverse relationship between minor allele frequency and effect size – risk alleles with balanced frequency in the population from Pathway identified genes in GWAS catalog have smaller effects near risk allele frequency of 0.5. ALMD: Autoreactive lymphocyte maintenance and development; CAA: Clearance of autoantigens; IIRNA: Innate immune response to nucleic acid/nucleoprotein complexes; UNK: Unknown relationship to existing SLE pathways.

Fig. 2.

Sexually dimorphic TLR7 signaling pathway contains numerous polygenic SLE risk genes. [Created with BioRender.com].