Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants

• Published in: Nature reviews. Nephrology Vol. 19; no. 9; pp. 558 - 572
• Main Authors: Vinuesa, Carola G., Shen, Nan, Ware, Thuvaraka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2023; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/250/1619/40; 692/4022/1585/1614; 692/699/249/1313/1613; Acids; Autoimmune diseases; Disease; Epigenetics; Genes; Genetics; Genomes; Genomics; Health risk assessment; Hospitals; Immune system; Lupus; Medicine; Medicine & Public Health; Nephrology; Pathogenesis; Proteins; Review Article
• ISSN: 1759-5061; 1759-507X
• DOI: 10.1038/s41581-023-00732-x

The past few years have provided important insights into the genetic architecture of systemic autoimmunity through aggregation of findings from genome-wide association studies (GWAS) and whole-exome or whole-genome sequencing studies. In the prototypic systemic autoimmune disease systemic lupus erythematosus (SLE), monogenic disease accounts for a small fraction of cases but has been instrumental in the elucidation of disease mechanisms. Defects in the clearance or digestion of extracellular or intracellular DNA or RNA lead to increased sensing of nucleic acids, which can break B cell tolerance and induce the production of type I interferons leading to tissue damage. Current data suggest that multiple GWAS SLE risk alleles act in concert with rare functional variants to promote SLE development. Moreover, introduction of orthologous variant alleles into mice has revealed that pathogenic X-linked dominant and recessive SLE can be caused by novel variants in TLR7 and SAT1 , respectively. Such bespoke models of disease help to unravel pathogenic pathways and can be used to test targeted therapies. Cell type-specific expression data revealed that most GWAS SLE risk genes are highly expressed in age-associated B cells (ABCs), which supports the view that ABCs produce lupus autoantibodies and contribute to end-organ damage by persisting in inflamed tissues, including the kidneys. ABCs have thus emerged as key targets of promising precision therapeutics. This Review examines insights from genetic studies of systemic lupus erythematosus (SLE), including observations from reports of monogenic SLE, as well as the role of common and rare variants. The authors also discuss age-associated B cells, as the integration of genetic, epigenetic and transcriptomic data suggests a key role for these cells in SLE. Key points Monogenic systemic lupus erythematosus (SLE) commonly results from defects in degradation or increased sensing of nucleic acids and have led to the development of in vivo models of disease and mechanistic exploration of pathogenesis. The study of high frequency and variably penetrant common variants must be integrated with the study of low frequency, highly penetrant rare, ultra-rare and novel variants to clarify the genetic contribution to disease. Common variants identified through genome-wide association studies (GWAS) highlight a role for complement, immune complex handling, endosomal Toll-like receptors, type I interferon signalling, B cell tolerance and B cell receptor signalling pathways in SLE. The use of online transcriptomic databases to integrate GWAS data highlighted an increased expression of SLE-associated genes in age-associated B cells (ABCs). ABCs are expanded peripherally in patients with SLE, especially in those with lupus nephritis, and in the kidney during episodes of lupus nephritis. Therapeutic regimens that target CD19 + B cells are highly effective at depletion of ABCs, which express high levels of CD19, and had a promising effect in a small study of patients with refractory SLE.