↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Träfflista för sökning "WFRF:(Kockum Ingrid) "

Sökning: WFRF:(Kockum Ingrid)

Resultat 1-50 av 86

Sortera/gruppera träfflistan

Sortering: Träffar per sida:

Numrering	Referens	Omslagsbild	Hitta
1.	Sanjeevi, Carani B., et al. (författare) The risk conferred by HLA-DR and DQ for type 1 diabetes in 0-35-year age group are different in different regions of Sweden 2008 Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. - 9781573317337 ; 1150, s. 106-11 Tidskriftsartikel (refereegranskat)abstract HLA DR4-DQ8 and DR3-DQ2 haplotypes account for 89% of newly diagnosed cases of type 1 diabetes (T1D) in Sweden. The presence of a single copy of DQ6 confers protection. The aim of the present study is to evaluate whether the risk conferred by high risk HLA DR and DQ to T1D is similar in all regions of Sweden and see whether there are any significant regional differences. The subjects comprised 799 consecutively diagnosed T1D patients and 585 age-, sex-, and geography-matched healthy controls in the age group 0-35 years. HLA typing for high-risk haplotypes was previously performed using PCR-SSOP and RFLP. The results showed that HLA DR3-DR4 gave an odds ratio of 8.14 for the whole of Sweden. However, when the study group was divided into six geographical regions, subjects from Stockholm had the highest OR, followed by those from Lund, Linköping, Gothenburg, Umeå, and Uppsala. Absolute protection was conferred by the presence of DQ6 in subjects from the Linköping region, but varied in the other regions. The frequency of DR3 and DQ2, DR4 and DQ8, DR15, and DQ6 in patients showed high linkage for each region, but were different between regions. In conclusion: The risk conferred by high-risk HLA varies in different regions for a homogenous population in Sweden. The results highlight the important role played by the various environmental factors in the precipitation of T1D.
2.	Tengvall, Katarina, 1980-, 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-DRB115: 01 carriage, absence of HLA-A02: 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.
3.	Alping, Peter, et al. (författare) Validation of the Swedish Multiple Sclerosis Register Further Improving a Resource for Pharmacoepidemiologic Evaluations 2019 Ingår i: Epidemiology. - : Lippincott Williams & Wilkins. - 1044-3983 .- 1531-5487. ; 30:2, s. 230-233 Tidskriftsartikel (refereegranskat)abstract The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of >3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data.
4.	Ambrosi, Aurelie, et al. (författare) Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern 2012 Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:3, s. 334-340 Tidskriftsartikel (refereegranskat)abstract Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. less thanbrgreater than less thanbrgreater thanMethods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. less thanbrgreater than less thanbrgreater thanResults There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (pandlt;0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (pandlt;0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. less thanbrgreater than less thanbrgreater thanConclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.
5.	Andersson, Cecilia K, et al. (författare) Islet cell antibodies (ICA) identify autoimmunity in children with new onset diabetes mellitus negative for other islet cell antibodies. 2014 Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 15:5, s. 336-344 Tidskriftsartikel (refereegranskat)abstract The aim of this study was to explore whether islet cell antibodies (ICA) could be identified in children with newly onset diabetes mellitus but negative for autoantibodies against glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA), or any of the three variants with arginine (R), tryptophan (W), or glutamine (Q) at position 325 of the zinc transporter 8 (ZnT8A).
6.	Andrén, Margareta, et al. (författare) Coupling between mineral reactions, chemical changes in groundwater, and earthquakes in Iceland 2016 Ingår i: Journal of Geophysical Research - Solid Earth. - 2169-9313 .- 2169-9356. ; 121:4, s. 2315-2337 Tidskriftsartikel (refereegranskat)abstract Chemical analysis of groundwater samples collected from a borehole at Hafralækur, northernIceland, from October 2008 to June 2015 revealed (1) a long-term decrease in concentration of Si and Naand (2) an abrupt increase in concentration of Na before each of two consecutive M > 5 earthquakes whichoccurred in 2012 and 2013, both 76 km from Hafralækur. Based on a geochemical (major elements and stableisotopes), petrological, and mineralogical study of drill cuttings taken from an adjacent borehole, we areable to show that (1) the long-term decrease in concentration of Si and Na was caused by constant volumereplacement of labradorite by analcime coupled with precipitation of zeolites in vesicles and along fracturesand (2) the abrupt increase of Na concentration before the ﬁrst earthquake records a switchover tononstoichiometric dissolution of analcime with preferential release of Na into groundwater. We attributedecay of the Na peaks, which followed and coincided with each earthquake to uptake of Na along fracturedor porous boundaries between labradorite and analcime crystals. Possible causes of these Na peaks are anincrease of reactive surface area caused by fracturing or a shift from chemical equilibrium caused by mixingbetween groundwater components. Both could have been triggered by preseismic dilation, which was alsoinferred in a previous study by Skelton et al. (2014). The mechanism behind preseismic dilation so far from thefocus of an earthquake remains unknown.
7.	Asad, Samina, et al. (författare) HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13 2012 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5 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.
8.	Ayoglu, Burcu, et al. (författare) Anoctamin 2 identified as an autoimmune target in multiple sclerosis 2016 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 113:8, s. 2188-2193 Tidskriftsartikel (refereegranskat)abstract Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
9.	Badam, Tejaswi V. S., et al. (författare) A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis 2021 Ingår i: BMC Genomics. - : BioMed Central. - 1471-2164. ; 22:1 Tidskriftsartikel (refereegranskat)abstract Background: There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules. Result: We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10− 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS. Conclusions: We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases.
10.	Beecham, Ashley H, et al. (författare) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. 2013 Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60 Tidskriftsartikel (refereegranskat)abstract Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
11.	Beleza-Meireles, Ana, et al. (författare) Complex aetiology of an apparently Mendelian form of mental retardation 2008 Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9, s. 6- Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Mental Retardation is a common heterogeneous neurodevelopment condition, which causes are still largely elusive. It has been suggested that half of the phenotypic variation of intelligence is explained by genetic variation. And genetic or inherited factors indeed account for most of the cases of mental retardation with an identifiable cause. However, only a few autosomal genes have been mapped and identified to date. In this report, the genetic causes for an apparently recessive form of mental retardation, in a large nordern swedish pedigree, are investigated. METHODS: After extensive evaluation of the patients, which ruled out recognizable patterns of malformation and excluded known causes of MR, a comprehensive genome-wide linkage analysis, with 500 microsatellite markers, was performed in 24 members of this family. Additionally, a genome-wide copy number analysis, using an affimetrix 250 K SNP chip, was performed in this pedigree. RESULTS: No significant LOD score was found with either parametric and non-parametric linkage analysis. The highest scores are located at chromosomes 13, 15 and 17. Genome-wide copy number analysis identified no clear cause for the disorder; but rather, several variants were present in the family members, irrespective of their affected status. CONCLUSION: These results suggest that mental retardation in this family, unlikely what was expected, has a heterogeneous aetiology; and that several lower effect genes variants might be involved. To demonstrate such effects, our family may be too small. This study also indicates that the ascertainment of the cause of MR may be challenging, and that a complex aetiology may be present even within a pedigree, constituting an additional obstacle for genetic counselling. Variants in genes involved in molecular mechanisms of cellular plasticity, in genes involved in the development of underlying neural architectures, and in genes involved in neurodevelopment and in the ongoing function of terminally differentiated neurons may underlie the phenotypic variation of intelligence and explain instances of intellectual impairment.
12.	Biström, Martin, et al. (författare) Epstein-Barr virus infection after adolescence and Human herpesvirus 6A as risk factors for multiple sclerosis 2021 Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 28:2, s. 579-586 Tidskriftsartikel (refereegranskat)abstract Background and purpose: Infections with human herpesvirus 6A (HHV-6A) and Epstein–Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS.Methods: In this nested case–control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6–2.7).Conclusions: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.
13.	Bomfim, Izaura Lima, et al. (författare) IRF5 implicated in the pathogenesis of multiple sclerosis. Annan publikation (övrigt vetenskapligt/konstnärligt)
14.	Bronge, Mattias, et al. (författare) Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis 2022 Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17 Tidskriftsartikel (refereegranskat)abstract Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
15.	Burkill, Sarah M., et al. (författare) Pain and Painkiller Use Among Multiple Sclerosis Patients in Sweden 2017 Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 26:Suppl. 2, s. 634-634 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Multiple sclerosis is an autoimmune disease which leads to demyelination and subsequent damage of axons and neurons. Pain is known to commonly affect MS patients, however the clinical characteristics of this pain are not fully described. Prescribed pain medication identifies more severe and chronic pain and different drug types can be used to identify other pain characteristics.Objectives: To assess whether MS patients in Sweden are at increased risk of receiving medication for pain relative to non-MS comparators. We aim to study overall pain, neuropathic pain, musculoskeletal pain and migraine.Methods: This cohort study using data on 5,555 MS patients in Sweden individually matched to 5,555 non-MS Swedish residents on sex, year of birth and place of residence at the time of MS diagnosis. We used Cox PH models using date of entry or 1stJuly 2006 as the beginning of follow up, whichever occurred later, and end of study was date of death, date of prescription of a painkiller or December 31st 2014, whichever occurred first. Painkillers were identified through relevant ATC codes. For neuropathic pain, pregabalin, gabapentin, amitriptyline, capsaicin or nortriptyline were used for identification, and for migraine prescriptions of anti-migraine preparations were included in the outcome. Musculoskeletal pain was identified primarily through topical products for joint and muscular pain.Results: Cox PH models showed MS patients to be at a 2.43 (CI 2.31–2.55) times increased risk of being prescribed any painkiller. The risk increased to 5.63 (CI 5.03–6.31) for neuropathic painkillers, however there was no significant difference for musculoskeletal painkillers (RR = 0.92 (CI 0.79–1.07)). MS patients were at a 1.28 (CI 1.10-1.50) times increased risk of being prescribed anti-migraine preparations. Restricting the data to MS patients showed that exposure to neuropathic painkillers was present in 32.8% of MS patients, and is associated with lower educational attainment and female sex. Conclusions: MS patients are at significantly increased risk of pain overall, with a particularly elevated risk for neuropathic pain. It seems that lower educational attainment and female sex are risk factors of neuropathic pain. However, the reason for this is not fully understood.*We would like to acknowledge the funding from the Science for Life - Astra Zeneca collaborative grant that supported this research
16.	Burkill, Sarah, et al. (författare) The association between multiple sclerosis and pain medications 2019 Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 160:2, s. 424-432 Tidskriftsartikel (refereegranskat)abstract Patients with multiple sclerosis (MS) are at greater risk of pain than people without the disease; however, the occurrence and characteristics of pain among these patients are incompletely described. We aimed to assess characteristics of pain amongst MS patients using MS patients who were recruited to participate in 3 studies in Sweden (n = 3877) and were matched with individuals without MS (n = 4548) by sex, year of birth, and region of residence. The Prescribed Drugs Register identified prescribed pain medication, overall and restricted to those given 4 or more prescriptions in 1 year to assess chronic pain. Anatomical therapeutic chemical codes classified whether pain was neuropathic, musculoskeletal, or migraine. Cox-proportional hazard models were used to estimate associations. Our findings showed patients with MS were at increased risk of pain treatment, with a hazard ratio (HR) of 2.52 (95% confidence interval 2.38-2.66). The largest magnitude HR was for neuropathic pain (5.73, 5.07-6.47) for which 34.2% (n = 1326) of the MS and 7.15% (n = 325) of the non-MS cohort were prescribed a treatment. The HR for chronic pain treatment was 3.55 (3.27-3.84), indicating an increased effect size relative to any pain treatment. Chronic neuropathic pain showed the largest HR at 7.43 (6.21-8.89). Neuropathic pain was shown to be the primary mechanism leading to increased risk of pain in patients with MS.
17.	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. ; 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 DQB103:02 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 DQB103:02 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 DQB103:02 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 DQB103:02 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.
18.	Carlström, Karl E., et al. (författare) Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes 2019 Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1, s. 1-13 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.
19.	Delcoigne, Bénédicte, et al. (författare) Blood neurofilament light levels segregate treatment effects in multiple sclerosis 2020 Ingår i: Neurology. - 1526-632X. ; 94 Tidskriftsartikel (refereegranskat)abstract Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. OBJECTIVE: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS). METHODS: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide). RESULTS: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations. CONCLUSION: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
20.	Delli, Ahmed, et al. (författare) Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study 2012 Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:10, s. 2556-2564 Tidskriftsartikel (refereegranskat)abstract We examined whether zinc transporter 8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish patients due to different polymorphisms of SLC30A8, HLA-DQ, or both. Newly diagnosed autoimmune (andgt;= 1 islet autoantibody) type 1 diabetic patients (n = 2,964, andlt;18 years, 55% male) were ascertained in the Better Diabetes Diagnosis study. Two subgroups were identified: Swedes (n = 2,160, 73%) and immigrants (non-Swedes; n = 212, 7%). Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%). ZnT8-RA (57 and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) than Swedes (46%). We tested whether this inconsistency was due to HLA-DQ as 2/X (2/2; 2/y; y is anything but 2 or 8), which was a major genotype in non-Swedes (40%) compared with Swedes (14%). In the non-Swedes only, 2/X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA. Molecular simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lack of tolerance to ZnT8-R. At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC30A8 CC (RR) genotypes.
21.	Dominguez, Cecilia A., et al. (författare) The DQB103:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation 2013 Ingår i:* Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 154:3, s. 427-433 Tidskriftsartikel (refereegranskat)abstract Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n = 189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB104 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB103:02 allele together with DRB104 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n = 258), where carriers of the DQB103:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB104 - DQB103:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.
22.	Eliaeson, Karin, et al. (författare) Relationships of geochemistry and multiple sclerosis 2009 Rapport (övrigt vetenskapligt/konstnärligt)abstract The main aim of this study has been to investigate how registers and databases of geochemistry can be combined with registers of patient data in epidemiological studies. By testing the hypothesis that Multiple Sclerosis (MS) varies with geography and investigating if the variation can be explained by natural variability of zinc in different media, difficulties have been identified and recommendations for future epidemiological studies with similar scope are given. Multiple sclerosis (MS) is a chronic neurological illness that affects nerve cells in the central nervous system (CNS). It belongs to a group of illnesses called autoimmune diseases where the immune system attacks the body's own tissue. The onset of autoimmune reactions is not fully understood. Autoimmune diseases are believed to be multifactorial where both intrinsic factors (e.g. genetics, age, hormones) and environmental factors (e.g. infections, diet, drugs, chemicals etc.) may contribute to the induction, development and progression of the disease. There is a general believe that the epidemiological pattern of MS vary with geography, but even though the systematic study of MS started in 1929 the comparison of prevalence studies over the world still is very difficult and the results are not reliable. Iron, zinc, manganese, copper and molybdenum are examples of important building blocks for almost all living organisms and are thus termed essential elements. They originally derive from the Earth's crust and are taken up in organisms from soil, air and water. For some metals, no biological, nutritional or biochemical function has been established (yet) and they are thus termed non-essentials. The level of exposure to essential and non-essential elements is of crucial importance for the effect on living organisms. A too high dose can be toxic while a too low dose of essential elements will cause deficiency and consequent higher vulnerability for the exposure to toxic compounds or non-essential elements. In this study we have initially focused to check if the occurrence of MS could be correlated to background levels of zinc (Zn) since zinc is an element that participates in several important reactions in the body. We used the Swedish MS-register, which includes almost all MS-patients in Sweden. The best resolution on where the patients live is given on post code areas. Spatially distributed census data over postcode areas, valid for December 2005 and compiled by Official Statistics of Sweden, Statistics Sweden (SCB), were used in this study. Geochemical data from soil (till), stream-water and groundwater from the Swedish Geological Survey have been compiled into postcode areas. The analyzed data on the distribution of MS-patients indicate that a geographical pattern could be found with higher prevalence of MS in the county of Västerbotten and clusters around larges cities. No north -south or east-west gradient of the prevalence was found. However, visual interpretation of prevalence measures is strongly biased towards large post code areas, masking the variation of prevalence measures of small areas. This effect is striking in larger cities always having a large number of small post code areas. Combination of the patient registers and the geochemical registers was evaluated with multivariate analysis (MVA) and as a univariate study for zinc solely, but no correlation between the prevalence of MS and the occurrence of natural background levels of elements were found. Registers were analyzed both separately and together, but none of these models increased the degree to which variance was explained. This does not mean that no relationship between MS and geochemistry is possible but that correlations could not be found with the data, methods and models used in this project. The most important conclusion from this study is that to combine patient data with any kind of exposure data with a geographical variation, the administrative division (i.e. parishes, post code areas etc) are less appropriate. Divisions with respect to natural (geographical) borders such as catchment areas would be more useful for epidemiological purposes where a geographic component is of interest. To fulfil this, population data for catchment areas is needed. The density of the patient data and the exposure data is also of crucial importance. Moreover, there must be a variation in the exposure data large enough to result in a difference between areas. It is recommended that also the areas where no disease is found to be included in epidemiological studies. In these regions high or low levels of elements can also be present. The use of average values over districts is problematic. A high density of sampling in an area does not necessarily mean that the calculated mean value is representative for the whole area. How well an average value for a district describes the actual value depends both on the natural variability of substances in the media as well as the sampling density (i.e. high variance but many samples could give the same average value as low variance and few samples).
23.	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. ; 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 DRB113:01-DQA101:03-DQB106:03 haplotype while the main association for IE1B was DRB113:02-DQA101:02-DQB106:04. 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.
24.	Frisén, Louise, et al. (författare) GENOME-WIDE LINKAGE ANALYSIS FOR HYPOSPADIAS SUSCEPTIBILITY GENES. 2004 Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 172:4, Part 1 Of 2, s. 1460-1463 Tidskriftsartikel (refereegranskat)
25.	Gopalakrishnan, Shyam, et al. (författare) The population genomic legacy of the second plague pandemic 2022 Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 32:21, s. 4743-4751.e6 Tidskriftsartikel (refereegranskat)abstract Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.
26.	Graham, Jinko, et al. (författare) Negative association between type 1 diabetes and HLA DQB10602-DQA10102 is attenuated with age at onset 1999 Ingår i: European Journal of Immunogenetics. - : Wiley. - 0960-7420 .- 1365-2370. ; 26, s. 117- Tidskriftsartikel (refereegranskat)abstract HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB10201-A10502/B10302-A10301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB10602-A10102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype ether than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB10604-A10102 (DQ6.4) and that the peak risk for the negatively associated DQB10301-A10501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB10303-A10301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.
27.	Grut, Viktor, et al. (författare) Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis : a presymptomatic case-control study 2021 Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 28:9, s. 3072-3079 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Epstein-Barr virus (EBV) and Human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with Cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, we sought to increase the understanding of CMV in MS aetiology.METHODS: We performed a nested case-control study with presymptomatically collected blood samples identified through cross-linkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95 % confidence intervals (CI) for CMV seropositivity as risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating attributable proportion due to interaction (AP).RESULTS: Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65).CONCLUSIONS: CMV seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.
28.	Grut, Viktor, et al. (författare) Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis 2024 Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 147:1, s. 177-185 Tidskriftsartikel (refereegranskat)abstract Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A.A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI).Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis).In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.
29.	Grut, Viktor, et al. (författare) Interactions between high seroreactivity to human herpes virus 6A and Epstein–Barr virus in MS development : a presymptomatic case–control study 2024 Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 96:2, s. 302-305 Tidskriftsartikel (refereegranskat)abstract Synergistic interactions between human herpesvirus 6A (HHV-6A) and Epstein–Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV-6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV-6A and EBNA-1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV-6A and EBV infections interact in MS development. ANN NEUROL 2024.
30.	Gupta, Manu, et al. (författare) Association between the transmembrane region polymorphism of MHC class I chain related gene-A and type 1 diabetes mellitus in Sweden 2003 Ingår i: Human Immunology. - 0198-8859. ; 64:5, s. 553-561 Tidskriftsartikel (refereegranskat)abstract Major histocompatibility complex (MHC) class I chain related gene-A (MIC-A) is associated with type 1 diabetes mellitus (T1DM) in other populations. We tested the association of MIC-A gene polymorphism with T1DM in Swedish Caucasians; if it has an age-dependent association; and if the association has an effect on gender. We studied 635 T1DM patients and 503 matched controls in the age group of 0-35 years old. MIC-A5 was significantly increased in T1DM compared with controls (odds ratio [OR] =1.81, p(c) < 0.0005). Logistic regression analysis revealed MIC-A5 association was independent of HLA. MIC-A5 with DR4-DQ8 or MIC-A5 with DR3-DQ2 gave higher OR than the OR obtained with either of them alone (OR = 1.81, 7.1, and 3.6, respectively). MIC-A5 was positively (OR = 2.48, p(c) < 0.0005) and MIC-A6 negatively associated (OR = 0.61, p(c) = 0.035) with the disease in less than or equal to 20 years of age. The negative association of MIC-A6 in young onset was confirmed by logistic regression analysis. MIC-A5 was associated with the disease in males (OR = 2.05, p(c) = 0.0005). MIC-A6 conferred protection (OR = 0.098, p(c) = 0.032) in females heterozygous for DR3/DR4. In conclusion, MIC-A5 is associated with T1DM; the association was higher in individuals less than or equal to 20 years old; and negative association of MIC-A6 was stronger in younger onset patients than in older onset patients.
31.	Gustafsson, Mika, et al. (författare) A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases 2015 Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 7:313 Tidskriftsartikel (refereegranskat)abstract Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
32.	Gustafsson, Mika, et al. (författare) Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment 2014 Ingår i: Genome Medicine. - : BioMed Central. - 1756-994X. ; 6:17 Tidskriftsartikel (refereegranskat)abstract Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.
33.	Gyllenberg, Alexandra, et al. (författare) Age Dependent Variation of Genotypes in MHCII Transactivator Gene (CIITA) in Controls and Association to Type 1 Diabetes in SCANDINAVIAN JOURNAL OF IMMUNOLOGY, vol 76, issue 2, pp 202-203 2012 Ingår i: SCANDINAVIAN JOURNAL OF IMMUNOLOGY. - : Blackwell Publishing. ; , s. 202-203 Konferensbidrag (refereegranskat)abstract n/a
34.	Hagopian, William A., et al. (författare) Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children 1995 Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 95:4, s. 1505-1511 Tidskriftsartikel (refereegranskat)abstract Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA10501/B10201 (DQ2; P = 0.007) but not DQA10301/B10302 (DQ8), and IAA with DQA10301/B10302 (DQ8; P = 0.03) but not DQA10501/B10201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population.
35.	Hedström, Anna Karin, et al. (författare) Association between exposure to combustion-related air pollution and multiple sclerosis risk 2023 Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 52:3, s. 703-714 Tidskriftsartikel (refereegranskat)abstract Background: Smoking and occupational pulmonary irritants contribute to multiple sclerosis (MS) development. We aimed to study the association between ambient air pollution and MS risk and potential interaction with the human leukocyte antigen (HLA)-DRB115:01 allele.Methods: Exposure to combustion-related air pollution was estimated as outdoor levels of nitrogen oxides (NOx) at the participants’ residence locations, by spatially resolved dispersion modelling for the years 1990–18. Using two population-based case-control studies (6635 cases, 8880 controls), NOx levels were associated with MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Interaction between high NOx levels and the HLA-DRB115:01 allele regarding MS risk was calculated by the attributable proportion due to interaction (AP). In addition, a register study was performed comprising all MS cases in Sweden who had received their diagnosis between 1993 and 2018 (n = 22 173), with 10 controls per case randomly selected from the National Population register.Results: Residential air pollution was associated with MS risk. NOx levels (3-year average) exceeding the 90th percentile (24.6 µg/m3) were associated with an OR of 1.37 (95% CI 1.10–1.76) compared with levels below the 25th percentile (5.9 µg/m3), with a trend of increasing risk of MS with increasing levels of NOx (P <0.0001). A synergistic effect was observed between high NOx levels (exceeding the lower quartile among controls) and the HLA-DRB1*15:01 allele regarding MS risk (AP 0.26, 95% CI 0.13–0.29).Conclusions: Our findings indicate that moderate levels of combustion-related ambient air pollution may play a role in MS development.
36.	Hedström, Anna Karin, et al. (författare) Organic solvents and MS susceptibility Interaction with MS risk HLA genes 2018 Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 91:5, s. E455-E462 Tidskriftsartikel (refereegranskat)abstract Objective We hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes. Methods Using a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction. Results Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2-1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB115, and absence of HLA-A02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure. Conclusion The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.
37.	Hedström, Anna Karin, et al. (författare) The influence of human leukocyte antigen-DRB115:01 and its interaction with smoking in MS development is dependent on DQA101:01 status 2020 Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 26:13, s. 1638-1646 Tidskriftsartikel (refereegranskat)abstract Background: HLA-DRB115:01, absence of HLA-A02:01, and smoking interact to increase multiple sclerosis (MS) risk.Objective: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB115:01 and absence of A02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA101:01 allele, which confers a protective effect only in the presence of DRB115:01.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 DRB108:01 allele interacted with smoking to increase MS risk. The interaction between DRB115:01 and both the absence of A02:01 and smoking was confined to DQA101:01 negative subjects, whereas no interactions occurred among DQA101:01 positive subjects.Conclusion: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB115:01 and its interaction with the absence of A02:01 and smoking is dependent on DQA101:01 status which may be due to differences in the responding T-cell repertoires.
38.	Hedström, Anna Karin, et al. (författare) The interaction between smoking and HLA genes in multiple sclerosis : replication and refinement 2017 Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 23:1, s. 37-37 Tidskriftsartikel (refereegranskat)abstract Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB15 and absence of HLA-A02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB115 and lacking HLA-A02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.
39.	Hellberg, Sandra, et al. (författare) Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis 2016 Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 16:11, s. 2928-2939 Tidskriftsartikel (refereegranskat)abstract Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
40.	Hössjer, Ola, et al. (författare) Quantifying and estimating additive measures of interaction from case-control data 2017 Ingår i: Modern stochastics: theory and applications. - 2351-6054. ; 4:2, s. 109-125 Tidskriftsartikel (refereegranskat)abstract In this paper we develop a general framework for quantifying how binary risk factors jointly influence a binary outcome. Our key result is an additive expansion of odds ratios as a sum of marginal effects and interaction terms of varying order. These odds ratio expansions are used for estimating the excess odds ratio, attributable proportion and synergy index for a case-control dataset by means of maximum likelihood from a logistic regression model. The confidence intervals associated with these estimates of joint effects and interaction of risk factors rely on the delta method. Our methodology is illustrated with a large Nordic meta dataset for multiple sclerosis. It combines four studies, with a total of 6265 cases and 8401 controls. It has three risk factors (smoking and two genetic factors) and a number of other confounding variables.
41.	Ingvarsson, Jens, et al. (författare) Rubella virus seropositivity after infection or vaccination as a risk factor for multiple sclerosis 2024 Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. Tidskriftsartikel (refereegranskat)abstract Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting.Methods: In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression.Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9).Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.
42.	Ivarsson, Sten-A., et al. (författare) Glutamate decarboxylase antibodies in non-diabetic pregnancy precedes insulin-dependent diabetes in the mother but not necessarily in the offspring 1997 Ingår i: Autoimmunity. - 0891-6934. ; 26:4, s. 261-269 Tidskriftsartikel (refereegranskat)abstract We studied the risk for diabetes of glutamate decarboxylase (GAD65Ab) and islet cell (ICA) autoantibodies in non-diabetic pregnant mothers and their children. Pregnancy and cord blood sera were collected in 1970-87 from about 35,000 mothers who delivered a child in the city of Malmo, Sweden. A total of 42 mothers were identified in 1988 who, 1-18 years after their pregnancies, had developed either insulin-dependent (n = 22) or non-insulin dependent (n = 20) diabetes mellitus. First, in 123 pregnant mothers selected as controls, 0.8% had GAD65Ab and 0.8% ICA. Second, among the mothers with non-insulin dependent diabetes, 7/20 (35%) had GAD65Ab eight months to 13 years, 10 months before clinical diagnosis. Third, in mothers who later developed insulin-dependent diabetes, 12/22 (55%) had GAD65Ab and 10/22 (45%) had ICA in pregnancies preceding the clinical diagnosis by 13 months to 9 years, 4 months. In 1996, none of the children born to the 42 mothers have developed diabetes. GAD65Ab and ICA in non-diabetic pregnancies may predict insulin-dependent diabetes in the mother but not necessarily in the offspring.
43.	James, Tojo, et al. (författare) Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients 2018 Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:5, s. 912-928 Tidskriftsartikel (refereegranskat)abstract Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
44.	Jensen, Richard A., et al. (författare) Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects 2007 Ingår i: Journal of diabetes and its complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 21:4, s. 205-213 Tidskriftsartikel (refereegranskat)abstract Objective: The aim of this study is to identify risk factors for the loss of measurable plasma C-peptide in newly diagnosed 15- to 35-year-old diabetic subjects. Methods: This Swedish study included 778 subjects. C-peptide levels were obtained each year for 6 years after diagnosis. Loss of measurable C-peptide was defined as a level at or below the lower detection limit of the local assay (0.13 nmol/l). In addition to C-peptide, other baseline covariates included gender, age, body mass index, HLA genotype, and autoantibody levels. Results: Compared with autoantibody-negative subjects, autoantibody-positive subjects had lower median baseline C-peptide (0.27 vs. 0.50, P<001), their levels declined over the study period, and the risk of losing measurable C-peptide was significantly higher when more than one autoantibody was present [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.13-7.54]. Among autoantibody-positive individuals, the presence of GAD65Ab (OR, 1.8; 95% Cl, 1.24-2.51) and islet cell antibodies (OR, 1.6; 95% CI, 1.19-2.18) conferred a higher risk for loss of measurable C-peptide as did female gender (OR, 1.6; 95% CI, 1.17-2.11) and time after diagnosis (OR, 1.5 for each additional year postdiagnosis; 95% CI, 1.41-1.57). Higher baseline C-peptide levels were protective (OR, 0.5 for each additional log nanomoles per liter; 95% CI, 0.36-0.58). Conclusions: This study identified autoantibody status, gender, and baseline C-peptide levels as factors that will be useful for predicting the disease course of 15- to 35-year-old diabetic individuals.
45.	Jons, Daniel, et al. (författare) Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis 2023 Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 39-40 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Introduction: Multiple sclerosis (MS) and presymptomatic axonal injury appears to develop only after an Epstein-Barr virus (EBV) infection. Anoctamin2 (ANO2), a chloride channel expressed in glial cells and neurons, was identified as a possible MS autoantigen. We here examine serum neurofilament (sNfL), a comprehensive EBV seroreactivity and antibodies against ANO2 in pre-symptomatic MS.Objectives/Aims: To study whether the appearance of EBV seroreactivity in the pre-symptomatic phase of MS precedes cumulating MS-induced neuroaxonal damage and whether it is associated with an incipient autoreactivity against a reported MS autoantigen (ANO2).Methods: We performed a case-control study with presymptomatic serum samples identified through cross-linkage of the Swedish MS register and Swedish biobanks. We assayed serum antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18 (VCAp18), EBV glycoprotein 350 (gp350), anoctamin 2 (ANO2), and serum neurofilament light (sNfL) in 669 pre-MS cases and matched controls.Results: EBNA1 seroreactivity increased in the pre-MS group from 20–15 years before MS onset, followed by gp350 seroreactivity (p=0.001–0.002, 15–10 years before onset). This appeared before the elevation of sNfL in EBV seropositive pre-MS cases (p=8⋅10-5, 10–5 years before onset). No significant sNfL increase was observed in the EBV seronegative group (p=0.95). Pre-MS cases with the highest sNfL levels cumulated in the EBV seropositive group (p=0.038). ANO2 seropositivity appeared virtually only in the EBNA1 seropositive group, in 16.7 % of EBNA1 seropositive pre-MS samples and in 10.0 % of corresponding controls (p=0.001). Combined EBNA1 and ANO2 seropositivity showed a higher association with subsequent MS than EBNA1 independent of ANO2 (p=0.002–0.028). In the EBNA1 seropositive stratum, ANO2 seropositivity was associated with 26% higher sNfL.Conclusion: In presymptomatic MS an antibody response against EBV, associated with ANO2 autoimmunity, was detectable before elevated sNfL, which cumulated in the EBV seropositive group. ANO2 seropositivity was associated with higher sNfL. An increase in ANO2 seroreactivity did not appear until after EBV seroconversion, limited to a subgroup of the EBV seropositive stratum. Thus, this specific cross-reaction could contribute to MS pathogenesis in a subgroup. This further implicates EBV in the pathogenesis of MS.
46.	Jons, Daniel, 1974, et al. (författare) Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage 2023 Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 1468-330X .- 0022-3050. ; 95 Tidskriftsartikel (refereegranskat)abstract Background: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. Methods: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. Results: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). Conclusions: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.
47.	Kakhki, Majid Pahlevan, et al. (författare) A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis 2024 Ingår i: Nature Communications. - : NATURE PORTFOLIO. - 2041-1723. ; 15:1 Tidskriftsartikel (refereegranskat)abstract Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.
48.	Karlsen, Allan E, et al. (författare) Immune-mediated beta-cell destruction in vitro and in vivo-A pivotal role for galectin-3. 2006 Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 344:1, s. 406-415 Tidskriftsartikel (refereegranskat)
49.	Kockum, Ingrid, et al. (författare) Genetic and immunological findings in patients with newly diagnosed insulin-dependent diabetes mellitus 1996 Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 28:7, s. 344-347 Tidskriftsartikel (refereegranskat)abstract Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune markers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recombination frequency within the HLA region. The frequency of the DR3-DQA1 * 0501-DQB1 * 0201 haplotype and the DR3-DQA1 * 0501 DQB1 * 0201 (DQ2)/DR4-DQA1 * 0301-DQB1 * 0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30. The negatively associated haplotype, DR15-DQA1 * 0102-DQB1 * 0602 was absent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tandem repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive but not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onset and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest sensitivity (54%) was in 0-10 year old boys, while age did not affect the sensitivity in girls. In contrast, the sensitivity of IAA was highest (46%) before the age of 15 but decreased thereafter as did the sensitivity for ICA. Classification of patients who develop IDDM above 20-25 years of age was inadequate since many patients classified with NIDDM either had GAD65Ab or ICA or developed these antibodies after 1-2 years of NIDDM. We conclude that not only age but also gender affects the risk for IDDM associated with HLA, other IDDM genes as well as commonly used immunological markers for IDDM.
50.	Kockum, Ingrid (författare) Population-based analysis of the HLA associated risk for IDDM 1995 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Insulin dependent diabetes (IDDM) is one of the most common chronic illnesses among children and young adults in Sweden. The disease has a complex pattern of inheritance and environmental factors are important. The strongest linkage to IDDM is found on chromosome 6p21 in the Major Histocompatibility Complex (MHC) region. A strong linkage disequilibrium in the MHC have made identification of the alleles responsible for the primary association difficult. The aim of this project was to Identify the primary association of Human leukocyte antigens (HLA) to IDDM in Swedish population-based case-control studies and to analyse the interaction of these factors age, gender and islet cell autoantibody levels. In addition the transmission of IDDM associated HLA haplotypes were investigated in patient and control families. Patients and controls from three population-based case-control studies were HLA typed for DQA1, DQB1 and DRB. A comparison of allele frequencies between patients and controls showed that two haplotypes DR3-DQA10501-DQB10201 and DR4-DQA10301-DQBl-0302, were positively associated with IDDM. The genotype associated with the highest risk for IDDM was DR3-DQA10501-DQB10201/DR4-DQAl0301-DQB10302. All other positively associated genotypes contained either the DR3-DQA10501-DQB10201 or DR4-DQA10301-DQB10302 haplotype. A total of 6 haplotypes showed a negative association: DR15-DQA1-0102-D9B10602,DR4-DQA 10301 -DQB10301, DR13-DQA10103-DQB10603, DR11-DQA10501-DQB10301, DR14-DQA10101-DQB10503 and DR7-DQA10201-DQB10303. The relative predisposing allele test, employed to asses if all negatively associated haplotypes were protective for IDDM, showed that only DR15-DQA10102-DQB10602 was protective in this analysis. This was further conflrmed bythe observation that all genotypes with a negative association contained DR15-DQA10102-DQB10602 or alleles on this haplotype. The 95% confidence intervals of the OR estimates of alleles occurring on the same haplotype overlapped extensively and could therefore not be used to distinguish which allele was responsilble for the association. Stratification analysis and the predisposing allele test revealed that DQB10302 on the DR4-DQA10301-DQB10302, DR3 on the DR3-DQA10501-DQB10201 and DQBl0602 on the DR15-DQAl0102-DQBl0602 haplotype showed the strongest association toIDDM. Additional risk to that associated with DQB10302, was conferred by DRB10401 on theDR4-DQA10301-DQB10302 haplotype. The highest absolute risk (1/54) was observed for the combination of DR3 and DQBl0302. Kendalls rank order correlation demonstrated a correlation between the rank of OR associated with different genotypes and age at onset. This correlation remained after correcting for the correlation between age and islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GAD65Ab). The DR3-DQA10501-DQB10201 haplotype and the DR3-DQA10501-DQB10201/DR4-DQA10301-DQB10302 genotype showed a significantly lower frequency among patients diagnosed before the age of 7 compared with those diagnosed after 28. DR15-DQA10102-DQB10602 was not found among patients diagnosed before the age of 8 but showed a significant trend in association with age. DR15-DQA10102-DQBl0602 was more common among male than female patients. Logistic regression modelling showed an interaction between DR3 and gender, DQB10602 and age and DQB10302 and season at onset while GAD65Ab showed an interaction with season and age at onset. Hence not only age but also season at onset as well as gender affect the risk for IDDM conferred by HLA. Offspring to diabetic fathers have a higher risk for developing IDDM than offspring to diabetic mothers. This has been suggested to be due to an increased transmission of IDDM risk HLA haplotypes from fathers to their offspring compared with mothers. Transmission rates were analysed in both IDDM and control families. In the control families there was no deviation from expected transmission rates. In IDDM families, DR4 haplotypes show an increased and DR2 haplotypes a decreased transmission to patients. No significant differences in transmission rates from mothers and fathers were detected. The haplotype that the mother do not transmit to her offspring, the non-inherited maternal haplotype (NIMH) showed a decrease in positively associated haplotypes, while the non-inherited paternal haplotype (NIPH), did not differ compared with control haplotypes. Hence development of tolerance to antigens coded for on the NIMH may affect the risk of developing IDDM later in life. Swedish population-based case-control studies have identified HLA high-risk haplotypes and uncovered significant effects of age and gender. Studies of the 0-35 year olds show that the protective effect of DQB10602 decreases with Increasing age at onset.

Skapa referenser, mejla, bekava och länka

Länka till träfflistan

Resultat 1-50 av 86

Avgränsa träffmängd

Typ av publikation: tidskriftsartikel (79); annan publikation (2); doktorsavhandling (2); rapport (1); konferensbidrag (1); bokkapitel (1); visa fler...; visa färre...

Typ av innehåll: refereegranskat (77); övrigt vetenskapligt/konstnärligt (8); populärvet., debatt m.m. (1)

Författare/redaktör: Kockum, Ingrid (82); Olsson, Tomas (50); Alfredsson, Lars (31); Hillert, Jan (19); Piehl, Fredrik (16); Lernmark, Åke (13); visa fler...; Khademi, Mohsen (12); Landin-Olsson, Mona (11); Sundström, Peter (10); Waterboer, Tim (10); Huang, Jesse (10); Carlsson, Annelie (9); Jagodic, Maja (9); Ludvigsson, Johnny (8); Marcus, Claude (8); Gustafsson, Mika (8); Lindblad, Bengt (6); Ivarsson, Sten (6); Hedström, Anna Karin (6); Hössjer, Ola (6); Brenner, Nicole (6); Butt, Julia (6); Ernerudh, Jan (5); Fogdell-Hahn, Anna (5); Gunnarsson, Martin, ... (5); Dahlquist, Gisela (5); Larsson, Helena (5); Samuelsson, Ulf (5); Forsander, Gun (5); Gustafsson, Rasmus (5); Biström, Martin, 198 ... (5); Luthman, Holger (4); Lycke, Jan, 1956 (4); Benson, Mikael (4); Andersen, Oluf, 1941 (4); Montgomery, Scott, 1 ... (4); Padyukov, Leonid (4); Salzer, Jonatan (4); Sundkvist, Göran (4); Ortqvist, Eva (4); Törn, Carina (4); Bergström, Tomas (4); Tengvall, Katarina, ... (4); Gyllenberg, Alexandr ... (4); Bomfim, Izaura Lima (4); Nestor, Colm (4); Lindén, Magdalena (4); Martin, Roland (4); Sundqvist, Emilie (4); Jons, Daniel, 1974 (4); visa färre...

Lärosäte: Karolinska Institutet (70); Lunds universitet (27); Uppsala universitet (25); Linköpings universitet (24); Umeå universitet (18); Göteborgs universitet (13); visa fler...; Stockholms universitet (12); Örebro universitet (12); Kungliga Tekniska Högskolan (4); Högskolan i Skövde (3); Chalmers tekniska högskola (2); Malmö universitet (1); Linnéuniversitetet (1); IVL Svenska Miljöinstitutet (1); visa färre...

Språk: Engelska (84); Svenska (2)

Forskningsämne (UKÄ/SCB): Medicin och hälsovetenskap (66); Naturvetenskap (16); Humaniora (2); Teknik (1); Lantbruksvetenskap (1); Samhällsvetenskap (1)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se

Stäng

Kopiera och spara länken för att återkomma till aktuell vy