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- Bolin, Karin, 1982-, et al.
(författare)
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Variants in BANK1 are associated with lupus nephritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Lupus nephritis (LN) is a cause of significant morbidity in SLE. While the genetic background to SLE has been well characterized, less is known about genes predisposing to LN.Methods: The study consisted of 2886 SLE patients, including 947 (33%) with LN. The discovery cohort (Sweden, n=1091) and replication cohort 1 (US, n=962) were genotyped on the Immunochip and replication cohort 2 (Norway/Denmark, n=833) on a custom array chip. Allele frequencies were compared between patients with LN, proliferative nephritis, end-stage renal disease and LN negative patients. SNPs with p-value <0.001 in the discovery cohort were analyzed in replication cohort 1. Ten SNPs associated with LN in the discovery cohort (p<0.0002) were genotyped in replication cohort 2. DNA methylation data were available for 180 LN patients from the discovery cohort.Results: In the discovery cohort, six gene loci were associated with LN (p<1x10-4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y and PHCA). SNPs in BANK1 showed the strongest association with LN in replication cohort 1 (p=9.5x10-4), with a tendency for an association in replication cohort 2 (p=0.052). In a meta-analysis of all three cohorts the association between LN and BANK1 rs4699259, was strengthened (p=1.7x10‑7). There were no associations to proliferative nephritis or ESRD in the meta-analysis. Methylation quantitative trait loci (MeQTL) effects between a CpG site and several SNPs in BANK1 were identified.Conclusion: Genetic variations in BANK1 are associated with LN. There is evidence for genetic regulation of DNA methylation within the BANK1 locus, however, the exact role of BANK1 in LN pathogenesis remains to be elucidated.
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- Elbagir, Sahwa, 1983-
(författare)
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Autoimmunity in Africa: Comparing Systemic Lupus Erythematosus and Anti-phospholipid Antibodies in Sudan and Sweden
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic Lupus Erythematosus (SLE) is a chronic immune complex (IC)-mediated disease with variable prevalence worldwide, reported to be more common in Africans, Hispanics and Asians than in Caucasian populations. Expression of autoantibodies might vary between different ethnic populations due to environmental and genetic factors. Antiphospholipid antibodies (aPL) react with several antigenic targets of negatively charged phospholipids and/or associated plasma proteins. In this thesis we have studied the immunological and clinical characteristics of SLE in patients from Sudan and Sweden using an identical methodology. We have also investigated the occurrence of aPL during healthy pregnancies in both countries.Sudanese patients with SLE were younger, had shorter disease duration and suffered from more organ damage compared to Swedish patients. Neurological involvement, predominantly in young patients, was the main contributor to organ damage among the Sudanese patients. When comparing anti-nuclear antibody (ANA) specificities in IC between Sudanese and Swedish patients, different results from ANA detected in serum was observed. While serum ANA levels were mainly higher in Swedish SLE patients, levels of most ANA specificities in IC, particularly anti-chromatin specificities, were increased in Sudanese patients. In both cohorts, ANA in IC associated with more active SLE. Sudanese SLE patients had a higher prevalence of IgA aPL using common assay cut-off points. However, aPL levels among controls were also higher in Sudan, and when cut-offs were adjusted based on national controls the difference in prevalence between the patient groups was no longer evident. A more recently defined test measuring antibody against the phosphatidylserine/prothrombin complex was the best aPL predictor of thrombosis in Swedish SLE patients, independent of cardiovascular risk factors and antiphospholipid antibody syndrome criteria tests. Levels of IgA aPL, particularly anti-β2 glycoprotein I, were higher in normal pregnancies of healthy women from Sudan. This was not observed in Swedish pregnancies, and it was not due to reactivity against domain 1 of the β2 glycoprotein I molecule.Levels of autoantibodies differed both for patients and healthy individuals from Sudan and Sweden, and the occurrence of antibodies among patients depended on the cut-offs used. Adjustments to national cut-offs revealed more associations between autoantibody occurrence and clinical manifestations in Sudan. We recommend that the evaluation of autoantibody prevalence and clinical significance in autoimmune diseases in populations of African origin should rely on cut-offs based on controls from the same population, both in research and clinical contexts.
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| 7. |
- Gunnarsson, Iva
(författare)
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SLE : pathogenetic mechanisms in nephritis and sulphasalazine-induced lupus reactions
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with a multifactorial and largely unknown etiology, in which genetic and environmental factors are known to influence disease susceptibility and expression. Nephritis is a common and severe disease manifestation in which immune complexes and complement deposits in the renal tissue are invariably seen. Anti-C1q antibodies are known to associate with proliferative forms of lupus nephritis. One aim of these studies has been to investigate pathogenetic mechanisms of lupus nephritis, in particular the role of C1q, the first subcomponent of the classical complement cascade, and autoantibodies directed against this molecule. We also aimed to define predisposing factors and underlying pathogenetic mechanisms in sulphasalazine-induced SLE, and to determine the possibility of pathogenetic similarities between idiopathic and sulphasalazine-induced SLE. In studies of ongoing IgG anti-C1q antibody production in peripheral blood mononuclear cells, high levels of IgG anti-C1q producing cells were recorded exclusively in patients with biopsy-proven proliferative lupus nephritis, thus indicating a pathogenetic role. Active production of anti-C1q antibodies was found to be superior in the prediction of proliferative nephritis as compared to analysis of antibodies in the serum. IgA anti-C1q antibodies were detected in patients with the immune complex-associated IgA nephropathy, indicating pathogenetic similarities with SLE nephritis. In a follow-up study of patients with proliferative lupus nephritis, a high proportion of patients still had histological evidence of active renal disease at repeated biopsy after six months of therapy, despite intensive immunosuppressive treatment and apparent clinical improvement. Low serum C1q levels at both first and repeated biopsy predicted and associated with an unfavourable histological outcome. Beneficial prognostic factors at repeated biopsy were determined as low-grade proteinuria, normal C1q, levels and the absence of anti-C1q antibodies. As for the role of predisposing factors in the development of sulphasalazine-induced SLE, slow acetylator genotype of N-acetyltransferase 2, HLA haplotypes in accordance with idiopathic SLE and enhanced IL-10 levels in serum were identified as factors associated with an increased susceptibility to development of lupus-like disease. In contrast to drug-induced SLE in general, anti-dsDNA was a common feature of sulphasalazine-induced SLE. Development of nephritis and persistent SLE occurred after high cumulative dose and long-term treatment with sulphasalazine. Similar pathogenetic mechanisms may be operative in both idiopathic and sulphasalazine-induced SLE, suggesting that sulphasalazine may act as an immunomodulator in genetically predisposed individuals.
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| 10. |
- Idborg, Helena, et al.
(författare)
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STRATIFICATION OF SLE PATIENTS FOR IMPROVED DIAGNOSIS AND TREATMENT
- 2013
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72, s. A80-A80
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background. Systemic autoimmune diseases (SAIDs) affect about 2% of the population in Western countries. Sufficient diagnostic criteria are lacking due to the heterogeneity within diagnostic categories and apparent overlap regarding symptoms and patterns of autoantibodies between different diagnoses. Systemic lupus erythematosus (SLE) is regarded as a prototype for SAIDs and we hypothesise that subgroups of patients with SLE may have different pathogenesis and should consequently be subject to different treatment strategies.Objectives. Our goal is to find new biomarkers to be used for the identification of more homogenous patient populations for clinical trials and to identify sub-groups of patients with high risk of for example cardiovascular events.Methods. In this study we have utilised 320 SLE patients from the Karolinska lupus cohort and 320 age and gender matched controls. The SLE cohort was characterised based on clinical, genetic and serological data and combined by multivariate data analysis in a systems biology approach to study possible subgroups. A pilot study was designed to verify and investigate suggested subgroups of SLE. Two main subgroups were defined: One group was defined as having SSA and SSB antibodies and a negative lupus anticoagulant test (LAC), i.e., a “Sjögren-like” group. The other group was defined as being negative for SSA and SSB antibodies but positive in the LAC test.i.e. an “APS-like” group. EDTA-plasma from selected patients in these two groups and controls were analysed using a mass spectrometry (MS) based proteomic and metabolomic approach. Pathway analysis was then performed on the obtained data.Results. Our pilot study showed that differences in levels of proteins and metabolites could separate disease groups from population controls. The profile/pattern of involved factors in the complement system supported a division of SLE in two major subgroups, although each individual factor was not significantly different between subgroups. Complement factor 2 (C2) and membrane attack complex (MAC) were analysed in the entire cohort with complementary methods and C2 verifies our results while the levels of MAC did not differ between SLE subgroups. The generated metabolomics data clearly separated SLE patients from controls in both gas chromatography (GC)-MS and liquid chromatography (LC)-MS data. We found for example that tryptophan was lower in the SLE patients compared to controls.Conclusions. Our systems biology approach may lead to a better understanding of the disease and its pathogenesis, and assigning patients into subgroups will result in improved diagnosis and better outcome measures of SLE.
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