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- Asad, Samina, et al.
(författare)
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HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
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| 2. |
- Carlström, Karl E., et al.
(författare)
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Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
- 2019
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.
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| 3. |
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| 4. |
- Gyllenberg, Alexandra
(författare)
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Genetic studies of complex autoimmune disease
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In complex autoimmune diseases, there are both genetic and environmental factors that influence our immune system and contribute to the development of disease. The pathways, interactions and mode of inheritance are difficult to unravel, and many discoveries are yet to be done. Here, I have studied three major autoimmune diseases, Type 1 Diabetes (T1D), Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA). They all have an inflammatory component, and share their genetic predisposition in the Human Leucocyte Antigen (HLA) genes. In T1D, the -cells in the pancreatic Islets of Langerhans are very specifically destroyed in an autoimmune attack, lead by the CD8+ T-cells. This leads to the inability to produce insulin, and a lifelong treatment with daily injections is necessary. The elevated blood glucose levels leads to long-term damages of microvascular circulations, and co-morbidities like neuropathy and cardiovascular disease. In MS, auto-reactive lymphocytes enter the central nervous system (CNS) and causes demyelination and neuronal damage. It results in a periodical occurrence of sclerotic plaques in the brain and spinal cord, and leads to increasing neurological disability. RA is a systemic inflammatory disease induced by activation of auto-reactive T-cells, where the release of antibodies and formation of immune complexes contributes to the severity in anti-citrullinated protein antibody (ACPA) positive but not ACPA negative disease. The target tissue is the synovial joints, but other organs like heart and kidney will also be affected. The inflammation breaks down cartilage and bone and can lead to severe pain and disability. In this thesis I present my investigations of two candidate genes, CIITA and VAV1, in these diseases. CIITA is the major control factor for transcription of the HLA class II genes, and associated to all three diseases. In paper I we demonstrate genotype variation for markers in the CIITA gene, depending on age among healthy controls. This finding is also replicated in an independent cohort. The consequence of this can be faulty conclusions in association studies, and hence age should be corrected for in genetic case-control studies. We find that association to T1D remains after controlling for age for rs11074932 (p=0.004) and rs3087456 (p=0.001), two markers in the promoter area that also are found to associate to RA but for the opposite allele (paper III). In paper II we replicate the previously reported association between CIITA rs4774 and MS in cases carrying the HLA-DRB1*15 allele (p=0.01, OR: 1.21) but also report association to MS for the same marker when stratifying for the MS protective HLA allele A*02 (p=0.01, OR: 1.33). Interaction between rs4774 and both MS associated HLA alleles is demonstrated. Finally, in paper III we show that the markers found to associate to T1D, MS and RA control the expression of CIITA and MHC class II genes with minor allele homozygotes leading to lower levels of mRNA of the transcripts. In paper IV we investigate the VAV1 gene, important in regulating signals downstream the T-cell receptor. VAV1 has been shown to associate to MS and lead to increased levels of inflammatory cytokines in the CNS. Here we report that the same rs2546133-rs2617822 C-A haplotype is associated only to the ACPA negative subgroup of Rheumatoid Arthritis (p=0.004, OR: 1.28). We also demonstrate that a SNP in the Vav1 gene in rat affects disease severity in pristane-induced arthritis, but not collagen II-induced arthritis, such that the disease in PIA is less severe. Taken together we suggest that these results for VAV1 reflect the heterogeneity between subgroups in human RA disease. In conclusion I have demonstrated genetic susceptibility factors and pathways that are shared between different autoimmune diseases but also that susceptibility genes can be of different importance in subgroups of patients for one disease.
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