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- Reid, Sarah, et al.
(author)
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From genetic predisposition to clinical outcome in systemic lupus erythematosus : construction and validation of sub-phenotype-specific genetic risk scores
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Other publication (other academic/artistic)abstract
- ObjectiveThis study aimed to link known genetic risk factors for systemic lupus erythematosus (SLE) with specific clinical manifestations of the disease, in both a large biobank population and in a clinical cohort of patients with SLE.MethodsScandinavian patients with SLE (n=1487) who fulfilled ≥4 ACR-82/ACR-97/SLICC-2012 classification criteria, were genotyped using the Immunochip or Global Screening array (Illumina). Clinical data was collected from medical records. Summary statistics for 57 established SLE risk SNPs (p<5×10-8 in the European population) with a validated cumulative effect on disease severity in SLE, was retrieved for 30 FinnGen datasets covering manifestations relevant for SLE. Mendelian randomization (MR) analysis was performed using the inverse variance weighed method. Nine datasets were selected for construction of standardized genetic risk scores (GRSs), which were validated in the clinical cohort using gender- and disease duration-adjusted logistic regression.ResultsIn the FinnGen biobank, the cumulative effect of the 57 SLE risk SNPs was associated with an increased risk of rosacea, OR 1.09 (1.03–1.16), polyarthropathies, OR 1.10 (1.06–1.14), pleural effusions, OR 1.09 (1.04–1.14)) and hemolytic anemia, OR 1.32 (1.10–1.58). In the clinical cohort, the GRSs generated from the FinnGen datasets were associated with their corresponding manifestation for arthritis, OR 1.15 (1.02– 1.31), renal disorder, OR 1.15 (1.04–1.29), neurologic disorder, OR 1.24 (1.04–1.47), hematologic disorder, OR 1.12 (1.00–1.24), and immunologic disorder, OR 1.37 (1.22–1.56).ConclusionBy considering associations of SLE risk SNPs with SLE-like manifestations in the FinnGen biobank, construction and validation of GRSs for five of the eleven ACR-82 criteria was possible. The findings may facilitate personalized risk prediction and targeted intervention strategies for patients with SLE.
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| 2. |
- Reid, Sarah, 1985-
(author)
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Genetic Contributions to Manifestations and Prognosis of Systemic Lupus Erythematosus
- 2023
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 3. |
- Reid, Sarah, et al.
(author)
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Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
- 2021
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:9, s. 1183-1189
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Journal article (peer-reviewed)abstract
- Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods: Patients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10-8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45). Results: In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions: Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.
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