RT Journal Article
SR Electronic
T1 B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
JF Lupus Science & Medicine
JO Lupus Sci Med
FD Lupus Foundation of America
SP e000926
DO 10.1136/lupus-2023-000926
VO 10
IS 2
A1 Hedenstedt, Anna
A1 Reid, Sarah
A1 Sayadi, Ahmed
A1 Eloranta, Maija-Leena
A1 Skoglund, Elisabeth
A1 Bolin, Karin
A1 Frodlund, Martina
A1 Lerang, Karoline
A1 Jönsen, Andreas
A1 Rantapää-Dahlqvist, Solbritt
A1 Bengtsson, Anders A
A1 Rudin, Anna
A1 Molberg, Øyvind
A1 Sjöwall, Christopher
A1 Sandling, Johanna K
A1 Leonard, Dag
YR 2023
UL http://lupus.bmj.com/content/10/2/e000926.abstract
AB Objective B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.Methods Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina’s Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.Results Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 −/− (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/− or −/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).Conclusions High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.Data are available upon reasonable request. The datasets generated during the current study are not publicly available due to them containing information that could compromise research participants’ privacy and consent, but are available from the corresponding authors on reasonable request and on a collaborative basis.