| 41. |
- Jönsen, Andreas, et al.
(författare)
-
Mitochondrial DNA polymorphisms are associated with susceptibility and phenotype of systemic lupus erythematosus.
- 2009
-
Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 18:4, s. 309-312
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the possible association between mitochondrial DNA polymorphisms and systemic lupus erythematosus (SLE). A cohort from the Department of Rheumatology, Lund University Hospital, Sweden, consisting of 166 unrelated SLE patients was investigated as well as 190 unrelated healthy blood donors. Mean age at SLE diagnosis was 39 years (range 10-83) and mean follow-up time was 16 years (range 1-44). There were 87% women among the lupus patients, and the control group consisted of 98 women and 92 men from the same geographical area and with a similar age and ethnicity. The mtDNA SNP nt16189C was associated with SLE (OR = 1.98, 95% CI 1.04-3.78, P = 0.05). In addition, SNP nt13708A was associated with SLE in males (OR = 3.46, 95% CI 1.08-11.1, P = 0.04), although the number of male patients was low. Furthermore, SNP nt10398A was associated with secondary anti-phospholipid syndrome (P = 0.017, OR 8.2, 95% CI 1.1-63). In conclusion, in this study, we have for the first time investigated the possible association between SLE disease and mitochondrial DNA polymorphisms. Altogether, these novel results suggest that mtDNA polymorphisms may be associated with development of SLE and may potentially be of importance in SLE pathogenesis.
|
|
| 42. |
- Jönsen, Andreas, et al.
(författare)
-
Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
- 2011
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 13, s. R206-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS). METHODS: The exons of complement inhibitor genes: CD46 and CFH (factor H) were fully sequenced using Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and healthy controls (n = 523). RESULTS: We found non-synonymous, heterozygous mutations in CFH in 6.1% patients with nephritis in comparison to 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two non-synonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients vs 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in non-coding regions of CD46, which were previously implicated in aHUS. CONCLUSION: SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
|
|
| 43. |
|
|
| 44. |
- Jönsen, Andreas
(författare)
-
Studies on Neuropsychiatric Manifestations and Genetic Factors in Systemic Lupus Erythematosus
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease encompassing a wide range of symptoms that can emanate from pathology in virtually any organ system. Severe SLE includes involvement of the central nervous system and kidneys. One of the hallmarks of the disease is a multitude of autoantibodies, indicating a breakdown in self tolerance. The corresponding antigens have been found to be exposed in cells undergoing apoptosis. Increased rate of apoptosis and an impaired clearance machinery for apoptotic material leading to secondary necrosis have been put forward as potential mechanisms by which a genetically prone individual develop an immune response to self antigens. Inherent dysregulation of tolerance and the immune response augment and perpetuate the situation generating autoreactive B- and T-cells, which together with autoantibodies and immune complexes mediate tissue inflammation with subsequent development of clinical symptoms. In this thesis, studies on neuropsychiatric involvement in SLE (NPSLE) and the genetic contribution to susceptibility and phenotypic expression of SLE are presented. Results: In paper I, an association was seen between NPSLE and worse prognosis measured as working incapacity and extent of organ damage, but not with increased mortality, as compared to non-NPSLE patients. In paper II, the conclusion is drawn that cerebrospinal fluid analyses of cytokines and autoantibodies may be of limited value in NPSLE diagnosis, while increased concentrations of anti-ribosomal P protein antibodies in serum could constitute a marker for SLE psychosis. In paper III, polymorphic variants of genes with well-documented roles in different parts of SLE pathogenesis were studied with the hypothesis that gene variant combinations could be informative regarding susceptibility for and pathogenesis in SLE. The extended haplotype HLA DR3-DQ2-C4AQ0 was more common in SLE patients than in controls (p<0.01). Furthermore, an increased prevalence of the combination of the IL-1 Ra 2/2 and the Fc?RIIa R/R genotypes was found in SLE patients compared to healthy controls (p<0.01). In paper IV, several genetic variants were found to influence disease phenotype. Thus, presence of a CRP4 A-allele was associated with SLE nephritis (p<0.01) and inversely correlated with arthritis (p<0.01). Furthermore, the Fc?RIIIa F/F genotype correlated with WHO class III and IV nephritis. Presence of anti-dsDNA or anti-C1q antibodies did not have an additional impact on the genetic susceptibility to nephritis. Additionally, the Fc?RIIIb NA2/NA2 genotype was associated with butterfly rash (p<0.01). Combinations of genotypes revealed an association between seizures and the presence of both the Fc?RIIa R/R and the Fc?RIIIa F/F genotypes (p<0.01), as well as an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele. In paper V, the impact of deficiency in the complement protein mannan-binding lectin (MBL) on cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD) and severe infections was studied. In a multiple logistic regression model smoking (p=0.001), hypertension (p=0.03), alcohol intake (p=0.027) and serum triglyceride concentrations (p=0.026) were associated with CPAD, while MBL deficiency did not reach significance (p=0.098). Alcohol intake (>15 g/month) was inversely correlated with CPAD (OR=0.29, 95%CI 0.096-0.87). Pneumonia and severe infections were not more common in SLE patients with MBL deficiency. There was a significant association between treatment with high-dose glukocorticoids and presence of severe infections (p=0.008). Treatment with cytostatic drugs was also more common in patients with these severe infections, but the correlation did not reach statistical significance (p=0.054). Conclusions: Neuropsychiatric involvement is a severe manifestation of SLE, but is heterogeneous and diagnostic tests in CSF are of limited value. Combination of genetic variants can be of importance in determining SLE susceptibility and the contribution of polymorphic genes to disease phenotype is substantial.
|
|
| 45. |
- Jönsen, Andreas, et al.
(författare)
-
The heterogeneity of neuropsychiatric systemic lupus erythematosus isreflected in lack of association with cerebrospinal fluid cytokineprofiles
- 2003
-
Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 12:11, s. 846-850
-
Tidskriftsartikel (refereegranskat)abstract
- The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.
|
|
| 46. |
|
|
| 47. |
- Kozyrev, Sergey V, et al.
(författare)
-
Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus
- 2008
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:2, s. 211-216
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance(1-3). In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 x 10(-10); OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Delta 2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.
|
|
| 48. |
- Kuchcinski, Grégory, et al.
(författare)
-
MRI BrainAGE demonstrates increased brain aging in systemic lupus erythematosus patients
- 2023
-
Ingår i: Frontiers in Aging Neuroscience. - 1663-4365. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting multiple organs in the human body, including the central nervous system. Recently, an artificial intelligence method called BrainAGE (Brain Age Gap Estimation), defined as predicted age minus chronological age, has been developed to measure the deviation of brain aging from a healthy population using MRI. Our aim was to evaluate brain aging in SLE patients using a deep-learning BrainAGE model. Methods: Seventy female patients with a clinical diagnosis of SLE and 24 healthy age-matched control females, were included in this post-hoc analysis of prospectively acquired data. All subjects had previously undergone a 3 T MRI acquisition, a neuropsychological evaluation and a measurement of neurofilament light protein in plasma (NfL). A BrainAGE model with a 3D convolutional neural network architecture, pre-trained on the 3D-T1 images of 1,295 healthy female subjects to predict their chronological age, was applied on the images of SLE patients and controls in order to compute the BrainAGE. SLE patients were divided into 2 groups according to the BrainAGE distribution (high vs. low BrainAGE). Results: BrainAGE z-score was significantly higher in SLE patients than in controls (+0.6 [±1.1] vs. 0 [±1.0], p = 0.02). In SLE patients, high BrainAGE was associated with longer reaction times (p = 0.02), lower psychomotor speed (p = 0.001) and cognitive flexibility (p = 0.04), as well as with higher NfL after adjusting for age (p = 0.001). Conclusion: Using a deep-learning BrainAGE model, we provide evidence of increased brain aging in SLE patients, which reflected neuronal damage and cognitive impairment.
|
|
| 49. |
- Leffler, Jonatan, et al.
(författare)
-
Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus
- 2013
-
Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354. ; 15:4
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The ability to degrade neutrophil extracellular traps (NETs) is reduced in a subset of patients with systemic lupus erythematosus (SLE). NETs consist of chromatin covered with antimicrobial enzymes and are normally degraded by DNase-I, an enzyme which is known to have reduced activity in SLE. Decreased ability to degrade NETs is associated with disease activity. In the current study we investigated how the ability of serum from SLE patients to degrade NETs varies during the course of SLE as well as what impact this may have for the clinical phenotype of SLE.Methods: Serum from 69 patients with SLE, included in a prospective study, was taken every 60 days for a median of 784 days. The ability of serum to degrade NETs was determined and associated with clinical parameters occurring before and at the time of sampling, as well as after sampling by using conditional logistic regression.Results: As many as 41% of all patients in the study showed decreased ability to degrade NETs at least once, but with a median of 20% of all time points. Decreased degradation was associated with manifestations of glomerulonephritis as well as low complement levels and elevated levels of antibodies directed against histones and DNA. Furthermore, the odds ratio for the patient to develop alopecia and fever after an episode of decreased NETs degradation was increased by four to five times compared to normal.Conclusions: Decreased degradation of NETs is associated with clinical manifestations in SLE and may contribute to disease pathogenesis. Potential therapeutics restoring the ability to degrade NETs could be beneficial for certain patients with SLE.
|
|
| 50. |
- Leonard, Dag, et al.
(författare)
-
Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants
- 2013
-
Ingår i: Circulation: Cardiovascular Genetics. - : BMJ. - 1942-325X .- 1942-3268. ; 72:Suppl. 3, s. 270-270
-
Tidskriftsartikel (refereegranskat)abstract
- Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9x10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.
|
|
