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Sökning: WFRF:(Stridh Pernilla)

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1.
  • Burkill, Sarah, et al. (författare)
  • The DQB1* 03:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis
  • 2020
  • Ingår i: Frontiers in Neurology. - : Frontiers. - 1664-2295 .- 1664-2295. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.
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2.
  • Engdahl, Elin, et al. (författare)
  • Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis
  • 2019
  • Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224 .- 1664-3224. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.
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3.
  • Hedström, Anna Karin, et al. (författare)
  • The influence of human leukocyte antigen-DRB1*15:01 and its interaction with smoking in MS development is dependent on DQA1*01:01 status
  • 2020
  • Ingår i: Multiple Sclerosis Journal. - 1352-4585 .- 1477-0970. ; 26:13, s. 1638-1646
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: HLA-DRB1*15:01, absence of HLA-A*02:01, and smoking interact to increase multiple sclerosis (MS) risk.Objective: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB1*15:01 and absence of A*02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA1*01:01 allele, which confers a protective effect only in the presence of DRB1*15:01.Methods: In two Swedish population-based case-control studies (5838 cases, 5412 controls), subjects with different genotypes and smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals employing logistic regression. Interaction on the additive scale between different genotypes and smoking was evaluated.Results: The DRB1*08:01 allele interacted with smoking to increase MS risk. The interaction between DRB1*15:01 and both the absence of A*02:01 and smoking was confined to DQA1*01:01 negative subjects, whereas no interactions occurred among DQA1*01:01 positive subjects.Conclusion: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB1*15:01 and its interaction with the absence of A*02:01 and smoking is dependent on DQA1*01:01 status which may be due to differences in the responding T-cell repertoires.
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4.
  • Olafsson, Sigurgeir, et al. (författare)
  • Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations
  • Ingår i: npj Genomic Medicine. - : Nature Publishing Group. - 2056-7944. ; 2:1
  • Tidskriftsartikel (refereegranskat)abstract
    • A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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5.
  • Tengvall, Katarina, et al. (författare)
  • Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk
  • 2019
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:34, s. 16955-16960
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 x 10(-36)) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95% CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15: 01 carriage, absence of HLA-A*02: 01, and high anti-EBNA1 antibody levels (OR = 24.9; 95% CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLADRB1*04: 01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95% CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.
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6.
  • Stridh, Pernilla (författare)
  • Inheritance of autoimmune neuroinflammation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Multiple sclerosis (MS) is a chronic neuro-inflammatory disease with anticipated complex etiology. Susceptibility to MS is conferred by numerous genes, with very low odds ratios that explain minute fractions of disease. This indicates that unknown factors are responsible for the remaining genetic contribution, termed the missing heritability . Due to the similarities to MS pathogenesis, we studied myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats as a model for autoimmune neuroinflammation. Inbred rat strains show varying susceptibility to MOG-EAE, which can be explored in different experimental populations to identify influences on disease, including constituents of the missing heritability . This thesis aims to identify components contributing to the heritability of autoimmune neuroinflammation. We established congenic strains, a backcross (BC) and an advanced intercross line (AIL) to genetically map influences on EAE. The polygenic nature of neuroinflammation was demonstrated in these populations (Papers I, II and III). The BC identified 16 quantitative trait loci (QTL) that regulate EAE (Paper III), while one AIL region was resolved to four QTLs (Paper I: Eae24-Eae27) and another was resolved to two QTLs (Paper II: Eae23a and Eae23b). This enabled identification of a candidate gene for Eae23b, ZEB1 (Paper II), which is involved in interleukin 2 (IL2) regulation. In Paper I, we demonstrated that epistatic interactions influence EAE, and that allele combinations are more important than individual QTL effects. Additionally, we identified parent-of-origin effects, a likely component of the missing heritability , to significantly contribute to the inheritance of EAE (Paper III). These findings illustrate the genetic complexity involved in inheritance of autoimmune neuroinflammation, and prompted us to explore the use of a heterogeneous stock (HS) of rats to map EAE. In pilot studies (Paper IV), we determined that the HS can deliver highresolution mapping, and influence from non-major histocompatibility complex (MHC) can be mapped, enabling the study of epistatic interactions involving the MHC. A mixed genetic and epigenetic model of inheritance for autoimmune neuroinflammation is beginning to emerge. This indicates that genes, environment and their interactions, mediated by epigenetic mechanisms, contribute to neuroinflammation. Identifying constituents of this inheritance model will help us understand autoimmune neuroinflammation, and by extrapolation MS.
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