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

Nature Reviews Nephrology volume 19, pages 558–572 (2023)Cite this article

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Abstract

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.

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.

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Fig. 1: Mapped common variants identified by SLE GWAS.
Fig. 2: Cell-specific expression of SLE GWAS genes.
Fig. 3: Cell-specific expression of genes characteristic of ABCs.
Fig. 4: Human ABC phenotypes and their clinical correlates in SLE.
Fig. 5: Formation and key molecular phenotype of ABCs and their interactions.
Fig. 6: Therapeutic targets of ABCs.

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Authors and Affiliations

  1. The Francis Crick Institute, London, UK

    Carola G. Vinuesa & Thuvaraka Ware

  2. University College London, London, UK

    Carola G. Vinuesa & Thuvaraka Ware

  3. China Australia Centre for Personalized Immunology (CACPI), Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

    Carola G. Vinuesa

  4. Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

    Nan Shen

  5. Center for Autoimmune Genomics and Aetiology, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Nan Shen

  6. Department of Paediatrics, University of Cincinnati, Cincinnati, OH, USA

    Nan Shen

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote the manuscript. C.G.V. and T.W. reviewed or edited the manuscript before submission.

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GWAS Catalog: https://www.ebi.ac.uk/gwas/

Supplementary information

Glossary

Burden analyses

Using a gene-based approach, these analyses evaluate the aggregate burden of variants in a gene, comparing disease and control cohorts.

Epistasis

The interaction between independently inherited genes leading to a change in the phenotypic expression.

Expressivity

The degree to which a particular genotype is expressed phenotypically, reflecting individual variability owing to the environment, modifier genes and epigenetics.

Neutrophil extracellular traps

(NETs). Net-like structures primarily composed of chromatin and antimicrobial proteins released by dying neutrophils.

Pleiotropy

Denotes that a genetic variation can affect multiple phenotypic traits.

Statistical fine mapping

A process of refinement after a genome-wide association study to identify variants that are likely to be causal; includes rigorous quality control, high confidence in genotyped single nucleotide polymorphisms and analysis of a population large enough to identify genes in linkage disequilibrium.

Trios

Refer to an affected proband and their parents.

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Vinuesa, C.G., Shen, N. & Ware, T. Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants. Nat Rev Nephrol 19, 558–572 (2023). https://doi.org/10.1038/s41581-023-00732-x

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