Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing

Abstract

ObjectivesSystemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE.MethodsWe undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS).ResultsWe identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes.ConclusionsOur results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

The First Case of Familiar Anti-leucine-rich Glioma-Inactivated1 Autoimmune Encephalitis: A Case Report and Literature Review

“…T lymphocyte differentiation, characterized by HLA, is identified as an independent pathway involved in systemic lupus erythematosus (SLE) susceptibility. Genes in the HLA region dominated associated genes in the T cell differentiation and antigen processing and presentation pathways, which was confirmed by gene-based association testing ( 19 ).…”

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

“…Within the past 13 years, genome-wide association and pathway-centered sequencing studies have identified many polymorphisms in interferon pathway genes that predispose an individual to developing SLE, including polymorphisms affecting the STAT4 , IRF3 , and IFNA1 genes [ 70 , 71 , 72 , 73 , 74 ]. While single polymorphisms may not be sufficient to cause autoimmunity alone, accumulating numbers of risk variants may cause the immune system to become overwhelmed, leading to immune dysregulation [ 24 , 75 ].…”

Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort

“…However, for IIM, comprehensive studies investigating this class of genetic variation are lacking. Large-scale targeted sequencing of patient cohorts now represents a valid and accessible approach to explore genetic variation at the lower range of allele frequency (10). Moreover, the tailored implementation of statistical algorithms based on the aggregation of rare variants into specific analysis units allows for accurate modeling of these variants, thus resulting in increased discovery power (11).…”