| 1. |
- Abelson, Anna-Karin, et al.
(författare)
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No evidence of association between genetic variants of the PDCD1 ligands and SLE
- 2007
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:1, s. 69-74
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Tidskriftsartikel (refereegranskat)abstract
- PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.
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| 2. |
- Gateva, Vesela, et al.
(författare)
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A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:11, s. 1228-1233
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- Jönsen, Andreas
(författare)
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Studies on Neuropsychiatric Manifestations and Genetic Factors in Systemic Lupus Erythematosus
- 2006
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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.
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| 8. |
- Kozyrev, Sergey V, et al.
(författare)
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Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:2, s. 211-216
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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.
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| 9. |
- Linga-Reddy, M. V. Prasad, et al.
(författare)
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A polymorphic variant in the MHC2TA gene is not associated with systemic lupus erythematosus
- 2007
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Ingår i: Tissue Antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 70:5, s. 412-414
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Tidskriftsartikel (refereegranskat)abstract
- Single-nucleotide polymorphisms (SNPs) in the major histocompatibility complex class II transactivator (MHC2TA) gene encoding the class II transactivator have been associated with multiple sclerosis, rheumatoid arthritis, and myocardial infarction in the Swedish population. We used a case-control approach to investigate the prevalence of a relevant variant in Swedish systemic lupus erythematosus (SLE) cohorts to determine whether SLE shares the same MHC2TA susceptibility allele as the other diseases. No differences were observed between cases and control subjects at either the allele or genotype levels. Furthermore, no significant correlations were found when comparing different clinical and serological SLE phenotypes. This particular polymorphism rs3087456 of the MHC2TA gene does not appear to influence genetic susceptibility to SLE in the Swedish population. We conclude that our data support neither allelic nor genotype association between the MHC2TA SNP and SLE.
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| 10. |
- Nived, Ola, et al.
(författare)
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Progressive multifocal leukoencephalopathy - the importance of early diagnosis illustrated in four cases.
- 2008
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 17:11, s. 1036-1041
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Tidskriftsartikel (refereegranskat)abstract
- Progressive multifocal leukoencephalopathy (PML) is a rare, deadly demyelinating disease of the central nervous system, which is caused by a reactivation of the DNA polyomavirus JC and occurs in immunosuppressed individuals. So far, only 25 cases have been described in patients with SLE and none survived without antiviral therapy and only two cases in RA. We present four additional cases from a defined area, three in SLE, of which one survived without antiviral therapy, and one case in RA, also surviving after reduction of immunosuppressive treatment. In three of these cases, diagnosis could only be confirmed by stereotactical brain biopsy, including the two surviving cases. Thus, this article illustrates the difficulty in diagnosing progressive multifocal leukoencephalopathy, the need for brain biopsy in many cases, the importance of reduced immunosuppression as early as possible and the severe damage progressive multifocal leukoencephalopathy can cause. Furthermore, progressive multifocal leukoencephalopathy might be much more common in SLE than expected with 1 case in 800 patient-years.
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