Genetic Contributions to Manifestations and Prognosis of Systemic Lupus Erythematosus

Sammanfattning: Systemic lupus erythematosus (SLE) is a severe autoimmune disease with a multifactorial aetiology and an extremely heterogenous clinical picture. This thesis explores the impact of SLE genetic variants, through their cumulative effect or gene-environment interactions, on SLE manifestations and complications.Paper I identifies clinical risk factors for permanent organ damage and mortality in 543 Swedish patients with SLE. Several previously undescribed risk factors for organ damage were identified, including pericarditis, lymphopenia and haemolytic anaemia. After a mean disease duration of 17 years, more than half of the patients were found to have developed organ damage, demonstrating that long-term SLE consequences remain a critical challenge.Paper II highlights the impact of a high cumulative genetic risk on disease severity, in 1001 Swedish patients with SLE. A genetic risk score (GRS) based on 57 genetic variants with established SLE association was constructed, and patients with high and low GRSs were compared with regard to clinical manifestations and complications. Patients with a high GRS were found to develop SLE earlier in life, to more often be affected by organ damage, cardiovascular events, nephritis and end-stage renal disease, and to have a higher mortality risk. Paper III demonstrates gene-smoking interactions in two separate samples of Scandinavian patients with SLE, totalling 1 612 patients. In both cohorts, the combination of two SLE risk alleles located within the Signal Transducer and Activator of Transcription 4 (STAT4) and Interleukin-12A (IL12A) genes, which share a connection through the IL12-STAT4 signalling pathway, was associated with a substantial increase in the risk of myocardial infarction (MI). We further demonstrated that smoking enhances the effect of the STAT4 risk allele on MI and is associated with higher levels of phosphorylated STAT4 in CD8+ T cells. Together, these results indicate that IL12-STAT4 pathway activation is associated with MI in SLE.Paper IV describes the cumulative impact of 57 SLE risk variants on disease manifestations in a large biobank cohort comprised primarily of individuals without SLE. A high genetic SLE predisposition was associated with several manifestations resembling SLE, including skin and pleural manifestations, arthritis and hematologic disorders. Furthermore, based on the findings in the biobank cohort, GRSs for several SLE-like manifestations could be constructed which were associated with the corresponding manifestation in patients with SLE. In conclusion, this thesis provides new evidence for the importance of both genetic and clinical factors, and their interaction, for SLE prognosis.