scholarly journals Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Prithvi Raj ◽  
Ran Song ◽  
Honglin Zhu ◽  
Linley Riediger ◽  
Dong-Jae Jun ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Deep Sequencing ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Snp Array ◽  
Low Frequency ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Altered Expression

Abstract Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. Results We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. Conclusions We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

scholarly journals Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis

2018 ◽  
Vol 77 (7) ◽  
pp. 1063-1069 ◽  
Author(s):  
Dag Leonard ◽  
Elisabet Svenungsson ◽  
Johanna Dahlqvist ◽  
Andrei Alexsson ◽  
Lisbeth Ärlestig ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
General Population ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Snp Array ◽  
Inflammatory Rheumatic Diseases ◽  
Systemic Lupus ◽  
Increased Risk

ObjectivesPatients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.MethodsPatients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).ResultsWe identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.ConclusionsThe IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

scholarly journals 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 ◽  
Vol 80 (9) ◽  
pp. 1183-1189
Author(s):  
Sarah Reid ◽  
Niklas Hagberg ◽  
Johanna K Sandling ◽  
Andrei Alexsson ◽  
Pascal Pucholt ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Snp Array ◽  
Interleukin 12 ◽  
Replication Cohort ◽  
Systemic Lupus ◽  
Discovery Cohort ◽  
Increased Risk

ObjectiveTo investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.MethodsPatients 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).ResultsIn 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).ConclusionsSmoking 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.

scholarly journals Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus

2021 ◽  
pp. annrheumdis-2020-218810
Author(s):  
Latanya N Coke ◽  
Hongxiu Wen ◽  
Mary Comeau ◽  
Mustafa H Ghanem ◽  
Andrew Shih ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Secretion ◽  
Lupus Erythematosus ◽  
Conditional Analysis ◽  
Hek293 Cells ◽  
Enzyme Function ◽  
European Ancestry ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Risk Association

ObjectivesTo determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function.MethodsConditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants.ResultsConditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced.ConclusionsSLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.

Different cerebral functional segregation in Sjogren’s syndrome with or without systemic lupus erythematosus revealed by amplitude of low-frequency fluctuation

2021 ◽  
pp. 028418512110324
Author(s):  
Xiao-Dong Zhang ◽  
Jun Ke ◽  
Jing-Li Li ◽  
Yun-Yan Su ◽  
Jia-Min Zhou ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Low Frequency ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Frequency Fluctuation ◽  
Parahippocampal Gyrus ◽  
Systemic Lupus ◽  
The Right ◽  
Left Insula

Background Sjögren’s syndrome (SjS) associated with systemic lupus erythematosus (SjS-SLE) was considered a standalone but often-overlooked entity. Purpose To assess altered spontaneous brain activity in SjS-SLE and SjS using amplitude of low-frequency fluctuation (ALFF). Material and Methods Sixteen patients with SjS-SLE, 17 patients with SjS, and 17 matched controls underwent neuropsychological tests and subsequent resting-state functional magnetic resonance imaging (fMRI) examinations. The ALFF value was calculated based on blood oxygen level dependent (BOLD) fMRI. Statistical parametric mapping was utilized to analyze between-group differences and multiple comparison was corrected with Analysis of Functional NeuroImages 3dClustSim. Then, the ALFFs of brain regions with significant differences among the three groups were correlated to corresponding clinical and neuropsychological variables by Pearson correlation. Results ALFF differences in the bilateral precuneus/posterior cingulate cortex (PCC), right parahippocampal gyrus/caudate/insula, and left insula were found among the three groups. Both SjS-SLE and SjS displayed decreased ALFF in the right parahippocampal gyrus, right insula, and left insula than HC. Moreover, SjS-SLE showed wider decreased ALFF in the bilateral precuneus and right caudate, while the SjS group exhibited increased ALFF in the bilateral PCC. Additionally, patients with SjS-SLE exhibited lower ALFF values in the bilateral PCC and precuneus than SjS. Moreover, ALFF values in the right parahippocampal gyrus and PCC were negatively correlated to fatigue score and disease duration, respectively, in SjS-SLE. Conclusion SjS-SLE and SjS exhibited common and different alteration of cerebral functional segregation revealed by AlFF analysis. This result appeared to indicate that SjS-SLE might be different from SjS with a neuroimaging standpoint.

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated?

2020 ◽  
Author(s):  
Rodolfo Perez-Alamino ◽  
Raquel Cuchacovich ◽  
Luis R. Espinoza ◽  
Constance P. Porretta ◽  
Arnold H. Zea
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Cells ◽  
Systemic Lupus

scholarly journals Serum vitamin D/25(OH)D associated with toll-like receptor (TLR) 2 expression of immune cells in the saliva of Systemic Lupus Erythematosus: a preliminary study

2021 ◽  
Vol 27 (2) ◽  
pp. 22
Author(s):  
Hendri Susanto ◽  
Bagus Soebadi ◽  
Diah Savitri Ernawati ◽  
Adiastuti Endah Pamardiati ◽  
Hening Tuti Hendarti ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Vitamin D ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Serum Vitamin ◽  
Toll Like Receptor ◽  
Systemic Lupus ◽  
Tlr2 Expression ◽  
Cross Sectional ◽  
Serum Vitamin D

Objective: Vitamin D deficiency may contribute to Systemic Lupus Erythematosus (SLE) development. Vitamin D may involve in pathogen recognition through Toll-like receptor (TLR) 2 in immune cells in saliva. This study aimed to determine the correlation between serum vitamin D/25(OH)D and TLR2 expression of immune cells in the saliva of SLE. Materials and methods: This cross-sectional study conducted at the the SLE patients who met the inclusion and exclusion criteria. Those who had signed informed consent involved to underwent unstimulated saliva collection and blood samples for TLR2 and vitamin D/25(OH)D examination. The correlation between serum vitamin D/25(OH)D concentration and salivary TLR2 expression was analyzed using the correlation test, linear regression with 95% confidence level. Results: Thirty SLE patients had a mean serum vitamin D/25(OH)D concentration of 9.98 ± 4.64 ng/ml. The mean of TLR2 expression of CD11b+ cells in saliva was 26.03 ± 20.92%. There was a significant positive correlation between serum vitamin D/25(OH)D concentration and TLR 2 expression of CD11b+ cells in the saliva. (r = 0.434; P < 0.05). Vitamin D/25(OH)D was the only predictor for TLR 2 expression. Conclusion: Serum vitamin D/25(OH)D concentrations associated with TLR2 expression of CD11b+ cells in the saliva of SLE.

Systemic lupus erythematosus—management

2013 ◽  
pp. 938-947
Author(s):  
Ida Dzifa Dey ◽  
David Isenberg
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Immunosuppressive Drugs ◽  
Systemic Lupus ◽  
General Management ◽  
Autoimmune Rheumatic Disease ◽  
The Future

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with varied presentation and a disease course characterized by remission and flares. Over the last 50 years the prognosis of SLE has improved considerably. The introductions of corticosteroids and later of cytotoxic drugs, dialysis, and renal transplantation were the major contributors to this improvement. Nevertheless, the treatment and general management of lupus continues to present a challenge. While lupus may, for some patients, represent a relatively mild set of problems, many others require large doses of immunosuppressive drugs, which carry long-term concerns about side effects. New immunotherapeutic drugs, with actions more closely targeted to the immune cells and molecules involved in the pathogenesis of SLE, are being introduced and the future looks promising. The role of early atherosclerosis and cardiovascular disease as a cause of death in patients with SLE is increasingly recognized and will present further challenges in the future.

scholarly journals Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus

2019 ◽  
Vol 78 (10) ◽  
pp. 1363-1370 ◽  
Author(s):  
Lina Odqvist ◽  
Zala Jevnikar ◽  
Rebecca Riise ◽  
Lisa Öberg ◽  
Magdalena Rhedin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Genetic Alterations ◽  
Genetic Variations ◽  
Negative Regulator ◽  
Systemic Lupus ◽  
Trap Formation ◽  
Autoimmune Pathology ◽  
Extracellular Trap

ObjectivesGenetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.MethodsCRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.ResultsGenetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.ConclusionsWe propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

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