Comment on: “Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing” (Ann Rheum Dis. 2021; 80(1):109-117. doi: 10.1136/annrheumdis-2020-218636)
Commented by: George Bertsias, Rheumatology Clinic, University of Crete School of Medicine, Greece
SLE is characterized by remarkable clinical and immunological heterogeneity, which likely reflects the variety and complexity of the underlying molecular and cellular networks affecting the disease expression. There is a strong genetic contribution to the disease, although the impact of rare gene variants (i.e., variations in the DNA sequence [MAF: minor allele frequency] occurring at a frequency of <1%) has not been adequately explored. In this article, Sandling et al. performed a targeted sequencing of regulatory and coding regions in a large cohort of 958 Swedish SLE patients and 1026 control individuals.
Their experimental approach yielded 287,354 single-nucleotide variants (SNVs) covering a total 1,832 genes relevant to immune-mediated diseases. Following enrichment analysis, they found that SLE-implicated genes belonged to the T helper cell (especially Th1, Th2) differentiation pathways, followed by antigen processing and presentation. Additional pathways were the complement and coagulation cascades, as well the janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. The adaptive immunity pathway was linked to the HLA, whereas the innate immunity pathway to interferon genes.
Next, using the sequencing data, the Authors calculated pathway polygenic risk scores (PRS) for each individual and each of the immune pathways. The largest proportion of positive (i.e., >97.5 th percentile compared to control individuals) SLE patients was found for the cytokine-cytokine receptor interaction pathway (41%), followed by the JAK-STAT signalling (29%), complement and coagulation (21%), Th cell differentiation and antigen processing-presentation (18% and 16%, respectively). By hierarchical cluster analysis on the pathway PRSs, four clusters of SLE patients were detected, the most prominent being the antigen processing/presentation and Th17 cell differentiation pathways. Notably, these clusters did not differ significantly in major clinical features or survival.
Finally, the Authors performed a focused analysis on specific sets of genes known to be associated with SLE, including monogenic forms, and found that rare variants (MAF <1%) of the monogenic SLE and lupus-like disease gene-sets were significantly associated with disease susceptibility. Importantly, further analysis provided evidence for novel associations with PABPC4 and IFNK, encoding for the Polyadenylate-binding protein 4 (possible cytoplasmic RNA sensor) and IFN-kappa, respectively.
Collectively, this study suggests a novel genetic, pathway-based approach for stratification of SLE patients. These findings, pending verification in additional cohorts and coupled with similar approaches based on gene profiling studies, are expected to enhance our understanding of pathophysiologically-defined subsets of SLE, thus creating opportunities for personalized actions and treatment selection.