| 1. |
- Jönsen, Andreas, et al.
(författare)
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Association between SLE nephritis and polymorphic variants of the CRP and Fc gamma RIIIa genes
- 2007
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 46:9, s. 1417-1421
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding Fc gamma RIIa, Fc gamma RIIIa, Fc gamma RIIIb, CRP and IL-1Ra. Methods. Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. Results. Presence of a CRP4 A-allele was associated with SLE nephritis (P< 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The Fc gamma RIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P=0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P<0.001). Furthermore, the Fc gamma RIIIb NA2/NA2 genotype was associated with butterfly rash (P< 0.01). An association was found between seizures and the presence of both the Fc gamma RIIa R/R and the Fc gamma RIIIa F/F genotypes (P< 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P=0.01). Furthermore, a combination of the Fc gamma RIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P= 0.02) and a similar result was found for the combination of Fc gamma RIIIa F/F and Fc gamma RIIIb NA2/NA2 (P= 0.04). Conclusions. Polymorphic variants of the CRP and Fc gamma-receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.
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| 2. |
- Jönsen, Andreas, et al.
(författare)
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Gene-environment interactions in the aetiology of systemic lupus erythematosus
- 2007
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 40:8, s. 613-617
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.
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| 3. |
- Jönsen, Andreas, et al.
(författare)
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Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus.
- 2007
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 16:4, s. 245-253
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Tidskriftsartikel (refereegranskat)abstract
- Deficiency of mannan-binding lectin (MBL) has been reported to impact susceptibility to severe nfections and atherosclerosis in systemic lupus erythematosus (SLE). In this study, MBL gene polymorphisms were analysed in 143 SLE patients and the frequency of severe infections and organ damage according to SLICC/ACR Damage Index regarding cerebrovascular accidents, angina pectoris, coronary by-pass surgery, myocardial infarction and peripheral arterial disease leading to significant tissue loss, were recorded during a mean follow-up time of 15 years from diagnosis. In a multiple logistic regression model, smoking (P = 0.001), hypertension (P = 0.030), alcohol intake (P = 0.027) and higher triglyceride concentration (P = 0.026) were associated with cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD), while the association with MBL deficiency did not reach significance (P = 0.098). Alcohol intake (> 15 g/month) was inversely correlated with CPAD (OR = 0.29, 95%Cl 0.096-0.87). MBL deficiency was not significantly more common in SLE patients with severe infections in a multivariate analysis (P > 0.3). In conclusion, classical risk factors such as smoking, hypertension, low alcohol intake and elevated triglyceride concentration were relatively more important for development of CPAD than MBL deficiency in SLE. Furthermore, MBL deficiency did not contribute to development of major infections in SLE.
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| 4. |
- Jönsen, Andreas, et al.
(författare)
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Mitochondrial DNA polymorphisms are associated with susceptibility and phenotype of systemic lupus erythematosus.
- 2009
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 18:4, s. 309-312
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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.
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| 5. |
- Jönsen, Andreas, et al.
(författare)
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The heterogeneity of neuropsychiatric systemic lupus erythematosus isreflected in lack of association with cerebrospinal fluid cytokineprofiles
- 2003
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 12:11, s. 846-850
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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.
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| 6. |
- Orbai, A-M, et al.
(författare)
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Anti-C1q antibodies in systemic lupus erythematosus.
- 2015
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 24:1, s. 42-49
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Tidskriftsartikel (refereegranskat)abstract
- Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study.
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| 7. |
- Tjernström, Fredrik, et al.
(författare)
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Synergetic effect between interleukin-1 receptor antagonist allele (IL1RN*2) and MHC class II (DR17,DQ2) in determining susceptibility to systemic lupus erythematosus
- 1999
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 8:2, s. 103-108
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether IL1RN alleles separately or in combination with MHC class II variants, contribute to susceptibility to SLE and to analysed if IL1RN alleles are markers of disease severity. We investigated 81 patients from a defined area in southern Sweden diagnosed between 1981-1992 and 10 consecutive Caucasian families with multiple cases of SLE. As control group 189 healthy blood donors was used. PCR amplification of defined gene sequences was used in determining the IL1RN polymorphism as well as the MHC class II variants. The IL-1RA levels were measured by an immunoassay. We found an increased frequency of IL1RN*2 in both the epidemiological cohort and in the multicase families (P < 0.01). Alone IL1RN*2 and MHC class II (DR17,DQ2) separately increased the SLE risk moderately. The occurrence of IL1RN*2 and MHC class II variants DR17 and DQ2 together increased the risk to develop SLE by a sevenfold. The IL-1RA gene polymorphism did not correlate with disease severity or with renal involvement. We found an association between IL1RN*1 and arthritis (P < 0.001). Serum level of IL-1RA did not correspond to any specific IL1RN allele. An increased frequency of IL1RN*2 suggests the presence of a gene, implemented in SLE-susceptibility, in the IL1RN region of chromosome 2. IL1RN*2 and specific variants of MHC class II act in synergy to increase disease susceptibility. IL1RN*1 may be a marker of risk for development of arthritis.
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| 8. |
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| 9. |
- Truedsson, Lennart, et al.
(författare)
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Sharing of MHC haplotypes among patients with systemic lupus erythematosus from unrelated Caucasian multicase families: disease association with the extended haplotype [HLA-B8, SC01, DR17]
- 1995
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 22:10, s. 1852-1861
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease often clustered in families. We investigated the association between MHC haplotypes and SLE in multicase Caucasian families. METHODS: Ten consecutive families with 2 or more patients with SLE, in total 27 patients among 66 individuals, were studied. MHC haplotypes were determined by typing for HLA-A, B, C, DR, and DQ by serological and DNA methods. Complotypes were determined by protein typing and C4 gene polymorphism by DNA analysis. RESULTS: Fifty-four independent MHC haplotypes were found. Ten of the 31 haplotypes in the patients with SLE were examples of the extended haplotype [HLA-B8,SC01,DR17]. Six of these were found in 2 or more patients with SLE within the same family. All the 14 SLE sib-pairs in the families shared at least one haplotype and in 9 of the sib-pairs the shared haplotype was [HLA-B8,SCO1,DR17]. Three SLE associated haplotypes were [HLA-B7,SC31,DR15]. Four of the 27 patients with SLE were C4A deficient. Two C2 deficient siblings were homozygous for the haplotype [HLA-B18,S042,DR15]. CONCLUSION: We demonstrate that a very limited number of MHC haplotypes are associated with familial SLE. The haplotype [HLA-B8,SCO1,DR17] was closely related with the disease. There was no evidence suggesting familial SLE constitutes a disease subset. Determination of MHC haplotypes in multicase families is of value for assessment of disease susceptibility.
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| 10. |
- Tydén, Helena, et al.
(författare)
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Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus.
- 2013
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 52:11, s. 2048-2055
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Patients with SLE have an increased morbidity and mortality from cardiovascular disease (CVD). The reason for this is not entirely understood, but is believed to be partly related to the long-lasting inflammatory process seen in SLE. The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins S100A8/A9 and S100A12 in SLE.Methods. Serum levels of S100A8/A9 and S100A12 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections, as well as in 100 healthy individuals. Cardiovascular manifestations were defined according to the SLICC/ACR Damage Index (SLICC/ACR-DI).Results. Serum levels of S100A8/A9 were elevated in our inactive SLE patients as compared with healthy individuals (P < 0.0001), which was not seen for S100A12 (P = 0.12). SLE patients with a history of CVD had increased serum levels of both S100A8/A9 and S100A12 compared with patients with no CVD or venous thromboembolism (P = 0.003 and P = 0.006, respectively). The presence of organ damage according to SLICC/ACR-DI was associated with an increase in both S100A8/A9 and S100A12 serum levels (P = 0.001 and P = 0.006, respectively).Conclusion. Elevated serum levels of S100A8/A9 and S100A12 may be used as an indicator of severe disease and CVD in SLE, suggesting that SLE patients with elevated serum S100A8/A9 and S100A12 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment.
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