TY - JOUR
T1 - Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing
AU - Sandling, Johanna K.
AU - Pucholt, Pascal
AU - Hultin Rosenberg, Lina
AU - Farias, Fabiana H.G.
AU - Kozyrev, Sergey V.
AU - Eloranta, Maija Leena
AU - Alexsson, Andrei
AU - Bianchi, Matteo
AU - Padyukov, Leonid
AU - Bengtsson, Christine
AU - Jonsson, Roland
AU - Omdal, Roald
AU - Lie, Benedicte A.
AU - Massarenti, Laura
AU - Steffensen, Rudi
AU - Jakobsen, Marianne A.
AU - Lillevang, Søren T.
AU - Lerang, Karoline
AU - Molberg, Øyvind
AU - Voss, Anne
AU - Troldborg, Anne
AU - Jacobsen, Søren
AU - Syvänen, Ann Christine
AU - Jönsen, Andreas
AU - Gunnarsson, Iva
AU - Svenungsson, Elisabet
AU - Rantapää-Dahlqvist, Solbritt
AU - Bengtsson, Anders A.
AU - Sjöwall, Christopher
AU - Leonard, Dag
AU - Lindblad-Toh, Kerstin
AU - Rönnblom, Lars
PY - 2020
Y1 - 2020
N2 - Objectives: Systemic 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. Methods: We 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). Results: We 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. Conclusions: Our 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.
AB - Objectives: Systemic 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. Methods: We 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). Results: We 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. Conclusions: Our 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.
KW - autoimmunity
KW - genetic
KW - lupus erythematosus
KW - polymorphism
KW - systemic
U2 - 10.1136/annrheumdis-2020-218636
DO - 10.1136/annrheumdis-2020-218636
M3 - Journal article
C2 - 33037003
AN - SCOPUS:85096404005
VL - 80
SP - 109
EP - 117
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 1
ER -