PT  - JOURNAL ARTICLE
AU  - Hedenstedt, Anna
AU  - Reid, Sarah
AU  - Sayadi, Ahmed
AU  - Eloranta, Maija-Leena
AU  - Skoglund, Elisabeth
AU  - Bolin, Karin
AU  - Frodlund, Martina
AU  - Lerang, Karoline
AU  - Jönsen, Andreas
AU  - Rantapää-Dahlqvist, Solbritt
AU  - Bengtsson, Anders A
AU  - Rudin, Anna
AU  - Molberg, Øyvind
AU  - Sjöwall, Christopher
AU  - Sandling, Johanna K
AU  - Leonard, Dag
TI  - B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
AID  - 10.1136/lupus-2023-000926
DP  - 2023 Oct 01
TA  - Lupus Science & Medicine
PG  - e000926
VI  - 10
IP  - 2
4099  - http://lupus.bmj.com/content/10/2/e000926.short
4100  - http://lupus.bmj.com/content/10/2/e000926.full
SO  - Lupus Sci Med2023 Oct 01; 10
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.