New research reveals that most patients with systemic lupus erythematosus (SLE) carry rare, coding variants in genes implicated in SLE risk; moreover, these variants have damaging effects on protein function and ultimately contribute to the development of autoimmunity. Together, the findings of the study by Simon Jiang and colleagues suggest that rare and novel variants are important in the pathogenesis of SLE.

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To date, the prevailing view has been that genetic predisposition to SLE arises from the additive effect of many common variants that have been identified over the past few decades using genome-wide association studies and that individually have modest effect sizes. However, emerging evidence has indicated that rare variants with strong effect sizes contribute to SLE in some individuals.

In an initial investigation in two cohorts of patients with SLE (133 patients in total) and 97 healthy elderly individuals, Jiang et al. found that 82% of patients with SLE and 72% of healthy individuals carried at least one rare nonsynonymous single-nucleotide variant (SNV) in SLE-associated genes. In particular, a substantial proportion of patients with SLE carried rare or low-frequency variants in BLK and/or BANK1.

Further studies demonstrated that the SNVs in BLK (encoding tyrosine-protein kinase BLK) identified in patients with SLE altered the kinase activity of BLK, resulting in impaired phosphorylation of interferon regulatory factor 5 (IRF5) and B-cell scaffold protein with ankyrin repeats (BANK1). SLE-associated BLK variants also failed to repress IRF5-mediated type I interferon expression in comparison with wild-type BLK.

Jiang et al. also demonstrated that a BANK1 SNV promotes type I interferon activity owing to impaired sequestration of TNF receptor-associated factor 6 (TRAF6), which was associated with increased TRAF6-mediated nuclear localization of IRF5.

“We have shown for the first time that rare variants in SLE-associated genes, specifically BLK and BANK1, have deleterious effects on their translated proteins,” says Jiang. “Interestingly, rare variants in these genes in healthy individuals do not affect protein function.”

In lupus-prone Faslpr/lpr mice, introduction of a Blk variant orthologous to one found in SLE led to expansion of pathogenic T cells, demonstrating a contribution to the development of disease in vivo.

rare and novel variants are important in the pathogenesis of SLE

The researchers plan to elucidate the disease-related mechanisms of other rare variants in SLE-associated genes and potential insights into new targets for treatment, such as exploring anti-interferon therapy for patients bearing mutations associated with increased type I interferon activity. “By identifying the genetic mechanisms which contribute to SLE, we may be able to stratify patients further by their genetic variants as well as trial treatments targeted for specific disrupted pathogenic pathways,” concludes Jiang.