RT Journal Article
SR Electronic
T1 Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren’s syndrome highlight T cell-initiated autoimmunity
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 268
OP 275
DO 10.1136/annrheumdis-2019-215533
VO 79
IS 2
A1 Yukai Wang
A1 Shaoqi Chen
A1 Jingyao Chen
A1 Xuezhen Xie
A1 Sini Gao
A1 Chengpeng Zhang
A1 Songxia Zhou
A1 Jing Wang
A1 Ruiqin Mai
A1 Qisheng Lin
A1 Jianqun Lin
A1 Marco Matucci-Cerinic
A1 Guohong Zhang
A1 Daniel E Furst
YR 2020
UL http://ard.bmj.com/content/79/2/268.abstract
AB Objectives Familial aggregation of primary Sjögren’s syndrome (pSS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and co-aggregation of these autoimmune diseases (ADs) (also called familial autoimmunity) is well recognised. However, the genetic predisposition variants that explain this clustering remains poorly defined.Methods We used whole-exome sequencing on 31 families (9 pSS, 11 SLE, 6 RA and 5 mixed autoimmunity), followed by heterozygous filtering and cosegregation analysis of a family-focused approach to document rare variants predicted to be pathogenic by in silico analysis. Potential importance in immune-related processes, gene ontology, pathway enrichment and overlap analyses were performed to prioritise gene sets.Results A range from 1 to 50 rare possible pathogenic variants, including 39 variants in immune-related genes across SLE, RA and pSS families, were identified. Among this gene set, regulation of T cell activation (p=4.06×10−7) and T cell receptor (TCR) signalling pathway (p=1.73×10−6) were particularly concentrated, including PTPRC (CD45), LCK, LAT–SLP76 complex genes (THEMIS, LAT, ITK, TEC, TESPA1, PLCL1), DGKD, PRKD1, PAK2 and NFAT5, shared across 14 SLE, RA and pSS families. TCR-interactive genes P2RX7, LAG3, PTPN3 and LAX1 were also detected. Overlap analysis demonstrated that the antiviral immunity gene DUS2 variant cosegregated with SLE, RA and pSS phenotypes in an extended family, that variants in the TCR-pathway genes CD45, LCK and PRKD1 occurred independently in three mixed autoimmunity families, and that variants in CD36 and VWA8 occurred in both RA-pSS and SLE-pSS families.Conclusions Our preliminary results define common genetic characteristics linked to familial pSS, SLE and RA and highlight rare genetic variations in TCR signalling pathway genes which might provide innovative molecular targets for therapeutic interventions for those three ADs.