216 results on '"Benedicte A. Lie"'
Search Results
2. The influence of HLA genotype on the development of metal hypersensitivity following joint replacement
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David J. Langton, Rohan M. Bhalekar, Thomas J. Joyce, Stephen P. Rushton, Benjamin J. Wainwright, Matthew E. Nargol, Nish Shyam, Benedicte A. Lie, Moreica B. Pabbruwe, Alan J. Stewart, Susan Waller, Shonali Natu, Renne Ren, Rachelle Hornick, Rebecca Darlay, Edwin P. Su, and Antoni V. F. Nargol
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Medicine - Abstract
Plain language summary Millions of joint replacement surgeries are carried out across the world annually. In this surgery, the joint is replaced with an artificial implant. Most implants are made of cobalt chrome (CoCr). Some patients develop allergic responses to these implants, resulting in pain and tissue damage and repeat surgery. We identified patients who had developed allergies to their CoCr hip implants and compared their genes to those of patients who remained symptom-free. Having identified genes that increased the likelihood of a patient developing an allergic response, we invited additional patients to contribute samples for gene testing. Using the combined data, we used a computer algorithm to predict allergic responses based on a patient’s genes, age, and gender. The algorithm performed with sufficient accuracy to be usable in clinical practice to guide implant selection preoperatively and guide patient follow-up post-surgery.
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- 2022
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3. Methotrexate Treatment of Newly Diagnosed RA Patients Is Associated With DNA Methylation Differences at Genes Relevant for Disease Pathogenesis and Pharmacological Action
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Kari Guderud, Line H. Sunde, Siri T. Flåm, Marthe T. Mæhlen, Maria D. Mjaavatten, Ellen S. Norli, Ida M. Evenrød, Bettina K. Andreassen, Sören Franzenburg, Andre Franke, Simon Rayner, Kristina Gervin, and Benedicte A. Lie
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Rheumatoid arthritis ,T cells ,CD4 memory ,CD4 naïve ,DNA methylation ,RRBS ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundMethotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4+ T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing.ResultsWe found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations. Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to predict treatment outcome in RA patients when measured in bulk T cells. Furthermore, several of the genes, including STAT3, annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX.ConclusionWe detected CpG sites that were associated with MTX treatment in CD4+ naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome.
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- 2021
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4. Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations
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Lisa E. Creary, Sridevi Gangavarapu, Stacy J. Caillier, Paola Cavalcante, Rita Frangiamore, Benedicte A. Lie, Mats Bengtsson, Hanne Flinstad Harbo, Susanna Brauner, Jill A. Hollenbach, Jorge R. Oksenberg, Pia Bernasconi, Angelina Hatlø Maniaol, Lennart Hammarström, Renato Mantegazza, and Marcelo A. Fernández-Viña
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myasthenia gravis ,human leukocyte antigen ,next-generation sequencing ,European ,susceptibility ,protection ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P
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- 2021
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5. Author Correction: The influence of HLA genotype on the development of metal hypersensitivity following joint replacement
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David J. Langton, Rohan M. Bhalekar, Thomas J. Joyce, Stephen P. Rushton, Benjamin J. Wainwright, Matthew E. Nargol, Nish Shyam, Benedicte A. Lie, Moreica B. Pabbruwe, Alan J. Stewart, Susan Waller, Shonali Natu, Renee Ren, Rachelle Hornick, Rebecca Darlay, Edwin P. Su, and Antoni V. F. Nargol
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Medicine - Published
- 2022
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6. MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients
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Fatima Heinicke, Xiangfu Zhong, Siri T. Flåm, Johannes Breidenbach, Magnus Leithaug, Marthe T. Mæhlen, Siri Lillegraven, Anna-Birgitte Aga, Ellen S. Norli, Maria D. Mjaavatten, Espen A. Haavardsholm, Manuela Zucknick, Simon Rayner, and Benedicte A. Lie
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miRNA ,microRNA ,rheumatoid arthritis ,CD19+ B cells ,methotrexate ,NGS ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
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- 2021
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7. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study
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Ingrid G. Rekeland, Alexander Fosså, Asgeir Lande, Irini Ktoridou-Valen, Kari Sørland, Mari Holsen, Karl J. Tronstad, Kristin Risa, Kine Alme, Marte K. Viken, Benedicte A. Lie, Olav Dahl, Olav Mella, and Øystein Fluge
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myalgic encephalomyelitis ,chronic fatigue syndrome ,ME ,CFS ,cyclophosphamide ,clinical trial ,Medicine (General) ,R5-920 - Abstract
Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02444091.
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- 2020
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8. Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells
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Kari Guderud, Line H. Sunde, Siri T. Flåm, Marthe T. Mæhlen, Maria D. Mjaavatten, Siri Lillegraven, Anna-Birgitte Aga, Ida M. Evenrød, Ellen S. Norli, Bettina K. Andreassen, Sören Franzenburg, Andre Franke, Espen A. Haavardsholm, Simon Rayner, Kristina Gervin, and Benedicte A. Lie
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rheumatoid arthritis ,T cells ,CD4 memory ,CD4 naïve ,DNA methylation ,RRBS ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N = 11), methotrexate (MTX) treated RA patients (N = 18), and healthy controls (N = 9) matched for age, gender and smoking status.Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4+ memory T cells.Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.
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- 2020
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9. Accurate Adapter Information Is Crucial for Reproducibility and Reusability in Small RNA Seq Studies
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Xiangfu Zhong, Fatima Heinicke, Benedicte A. Lie, and Simon Rayner
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adapter trimming ,adapter ,small rna ,microrna ,ngs ,reproducibility ,reusability ,Genetics ,QH426-470 - Abstract
A necessary pre-processing data analysis step is the removal of adapter sequences from the raw reads. While most adapter trimming tools require adapter sequence as an essential input, adapter information is often incomplete or missing. This can impact quantification of features, reproducibility of the study and might even lead to erroneous conclusions. Here, we provide examples to highlight the importance of specifying the adapter sequence by demonstrating the effect of using similar but different adapter sequences and identify additional potential sources of errors in the adapter trimming step. Finally, we propose solutions by which users can ensure their small RNA-seq data is fully annotated with adapter information.
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- 2019
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10. Correction: Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy.
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Olga Gorlova, Jose-Ezequiel Martin, Blanca Rueda, Bobby P. C. Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, Jasper C. Broen, Madelon C. Vonk, Carmen P. Simeon, Behrooz Z. Alizadeh, Marieke J. H. Coenen, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L. C. M. van Riel, Marie Vanthuyne, Ruben van 't Slot, Annet Italiaander, Roel A. Ophoff, Nicolas Hunzelmann, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A. González-Gay, Francisco J. García-Hernández, María F. González-Escribano, Paolo Airo, Jacob van Laar, Jane Worthington, Roger Hesselstrand, Vanessa Smith, Filip de Keyser, Fredric Houssiau, Meng May Chee, Rajan Madhok, Paul G. Shiels, Rene Westhovens, Alexander Kreuter, Elfride de Baere, Torsten Witte, Leonid Padyukov, Annika Nordin, Raffaella Scorza, Claudio Lunardi, Benedicte A. Lie, Anna-Maria Hoffmann-Vold, Øyvind Palm, Paloma García de la Peña, Patricia Carreira, John Varga, Monique Hinchcliff, Annette T. Lee, Pravitt Gourh, Christopher I. Amos, Frederick M. Wigley, Laura K. Hummers, J. Lee Nelson, Gabriella Riemekasten, Ariane Herrick, Lorenzo Beretta, Carmen Fonseca, Christopher P. Denton, Peter K. Gregersen, Sandeep Agarwal, Shervin Assassi, Filemon K. Tan, Frank C. Arnett, Timothy R. D. J. Radstake, Maureen D. Mayes, and Javier Martin
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Genetics ,QH426-470 - Published
- 2011
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11. HLA‐DQ2 is associated with anti‐drug antibody formation to infliximab in patients with immune‐mediated inflammatory diseases
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Marthe Kirkesæther Brun, Kristin Hammersbøen Bjørlykke, Marte K. Viken, Grethe‐Elisabeth Stenvik, Rolf A. Klaasen, Johanna E. Gehin, David John Warren, Joseph Sexton, Øystein Sandanger, Tore K. Kvien, Cato Mørk, Espen A. Haavardsholm, Jørgen Jahnsen, Guro Løvik Goll, Benedicte A. Lie, Nils Bolstad, Kristin Kaasen Jørgensen, and Silje Watterdal Syversen
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Internal Medicine - Published
- 2023
12. Supplementary figures legends from Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients
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Martha Chekenya, Stein Atle Lie, Einar Kristoffersen, Gro Njølstad, Per Øyvind Enger, Benedicte Alexandra Lie, Morten Lund-Johansen, Vessela Kristensen, Elling Ulvestad, Christèle Retière, Surendra Kumar, Aminur Mohummad Rahman, Andrea Gras Navarro, and Mev Dominguez–Valentin
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Supplementary figures legends
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- 2023
13. Supplementary materials and methods from Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients
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Martha Chekenya, Stein Atle Lie, Einar Kristoffersen, Gro Njølstad, Per Øyvind Enger, Benedicte Alexandra Lie, Morten Lund-Johansen, Vessela Kristensen, Elling Ulvestad, Christèle Retière, Surendra Kumar, Aminur Mohummad Rahman, Andrea Gras Navarro, and Mev Dominguez–Valentin
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Supplementary materials and methods. Detailed bioinformatics analysis methods (softwares commands and parameters) used to analyse in silicon TCGA and OKG exam sequencing data.
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- 2023
14. Supplementary figures and tables from Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients
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Martha Chekenya, Stein Atle Lie, Einar Kristoffersen, Gro Njølstad, Per Øyvind Enger, Benedicte Alexandra Lie, Morten Lund-Johansen, Vessela Kristensen, Elling Ulvestad, Christèle Retière, Surendra Kumar, Aminur Mohummad Rahman, Andrea Gras Navarro, and Mev Dominguez–Valentin
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Supplementary figures and tables for bioinformatic analyses. Fig S1 TCGA bioinformatics analysis workflow chart Fig S2 alignment plots of quality score accuracy Fig S3 Screenshot of region of interest on Chr 19 indicating genotype information on KIR2DS4 variant call Table SI Characteristics of the patients and control population used in this study Table SII Clinical data of 300 GBM patient obtained from The Cancer Genome Atlas (TCGA) project. Table SIII Description of the 2504 control population from 1000 Genome Project. Table SIV Antibodies used for Flow cytometry
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- 2023
15. Data from Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients
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Martha Chekenya, Stein Atle Lie, Einar Kristoffersen, Gro Njølstad, Per Øyvind Enger, Benedicte Alexandra Lie, Morten Lund-Johansen, Vessela Kristensen, Elling Ulvestad, Christèle Retière, Surendra Kumar, Aminur Mohummad Rahman, Andrea Gras Navarro, and Mev Dominguez–Valentin
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By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4*00101 was independently prognostic of prolonged survival. KIR2DS4*00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4*00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4*00101 alleles, where protection was greatest among Caucasian individuals. Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma. Cancer Res; 76(18); 5326–36. ©2016 AACR.
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- 2023
16. Small extracellular vesicles have distinct CD81 and CD9 tetraspanin expression profiles in plasma from rheumatoid arthritis patients
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Anne Rydland, Fatima Heinicke, Siri T. Flåm, Maria D. Mjaavatten, and Benedicte A. Lie
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
Extracellular vesicles (EVs) are implicated in the pathogenesis of rheumatoid arthritis (RA) but little is known about the composition of specific small EV (sEV) subpopulations. This study aimed to characterize the CD63, CD81 and CD9 tetraspanin profile in the membrane of single EVs in plasma from treatment naïve RA patients and assess potential discrepancies between methotrexate (MTX) responder groups. EVs isolated from plasma were characterized using transmission electron microscopy, and detection of surface markers (CD63, CD81 and CD9) on single EVs was performed on the ExoView platform. All RA patients (N = 8) were newly diagnosed, treatment naïve, females, ACPA positive and former smokers. The controls (N = 5) were matched for age and gender. After three months of MTX treatment, responders (N = 4) were defined as those with ΔDAS28 > 1.2 and DAS28 ≤ 3.2 post-treatment. The isolated EVs were 50–200 nm in size. The RA patients had a higher proportion of both CD9 and CD81 single positive sEVs compared to healthy controls, while there was a decrease in CD81/CD9 double positive sEVs in patients. Stratification of RA patients into MTX responders and non-responders revealed a distinctly higher proportion of CD81 single positive sEVs in the responder group. The proportion of CD81/CD9 double positive sEVs (anti-CD9 captured) was lower in the non-responders, but increased upon 3 months of MTX treatment. Our exploratory study revealed distinct tetraspanin profiles in RA patients suggesting their implication in RA pathophysiology and MTX treatment response.
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- 2023
17. Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection
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Marte Heimli, Siri Tennebø Flåm, Hanne Sagsveen Hjorthaug, Don Trinh, Michael Frisk, Karl-Andreas Dumont, Teodora Ribarska, Xavier Tekpli, Mario Saare, and Benedicte Alexandra Lie
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Immunology ,Immunology and Allergy - Abstract
To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymus. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ or CD8+ lineage commitment, while markers of different agonist selected T cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff), and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localisation, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use.
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- 2023
18. Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci
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Asgeir Lande, Anne Rydland, Marte K. Viken, Riad Hajdarevic, Ola Didrik Saugstad, Ingrid Gurvin Rekeland, Benedicte A. Lie, Elin Bolle Strand, Torstein Egeland, Lisa E. Creary, Øystein Fluge, Daysi Duarte Sosa, and Olav Mella
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Genetics ,Canada ,Linkage disequilibrium ,Fatigue Syndrome, Chronic ,Valine-tRNA Ligase ,Endocrine and Autonomic Systems ,Immunology ,Peptide binding ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Major histocompatibility complex ,Major Histocompatibility Complex ,Behavioral Neuroscience ,HLA Antigens ,HLA-DQ Antigens ,biology.protein ,Humans ,SNP ,Alleles ,HLA Complex ,Genetic association - Abstract
This is an open access article under the CC BY license. The etiology of myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is unknown, but involvement of the immune system is one of the proposed underlying mechanisms. Human leukocyte antigen (HLA) associations are hallmarks of immune-mediated and autoimmune diseases. We have previously performed high resolution HLA genotyping and detected associations between ME/CFS and certain HLA class I and class II alleles. However, the HLA complex harbors numerous genes of immunological importance, and there is extensive and complex linkage disequilibrium across the region. In the current study, we aimed to fine map the association signals in the HLA complex by genotyping five additional classical HLA loci and 5,342 SNPs in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria, and 480 healthy Norwegian controls. SNP association analysis revealed two distinct and independent association signals (p ≤ 0.001) tagged by rs4711249 in the HLA class I region and rs9275582 in the HLA class II region. Furthermore, the primary association signal in the HLA class II region was located within the HLA-DQ gene region, most likely due to HLA-DQB1, particularly the amino acid position 57 (aspartic acid/alanine) in the peptide binding groove, or an intergenic SNP upstream of HLA-DQB1. In the HLA class I region, the putative causal locus might map outside the classical HLA genes as the association signal spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotype. Taken together, our results implicate the involvement of the MHC, and in particular the HLA-DQB1 gene, in ME/CFS. These findings should be replicated in larger cohorts, particularly to verify the putative involvement of HLA-DQB1, a gene important for antigen-presentation to T cells and known to harbor alleles providing the largest risk for well–established autoimmune diseases.
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- 2021
19. <scp>HLA‐B</scp> *27 typing using a triplex real time <scp>PCR</scp> in routine laboratory
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Tore Jensen, Line M. L. Boulland, Benedicte A. Lie, Menaka Andersen, Marte K. Viken, and Alice L Pedersen
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Histocompatibility Testing ,Immunology ,Routine laboratory ,Biology ,Real-Time Polymerase Chain Reaction ,Virology ,HLA-B ,Real-time polymerase chain reaction ,HLA-B Antigens ,Genetics ,Humans ,Immunology and Allergy ,Multiplex ,Typing ,Laboratories ,Alleles - Abstract
We have established an in-house HLA-B*27 multiplex typing assay by using a combination of previously published, newly designed and commercial primers and probes for use with real-time PCR instruments. Hence, facilitating quick and large-scale HLA-B*27 typing.
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- 2021
20. Increased muscle activity during sleep and more RBD symptoms in H1N1-(Pandemrix)-vaccinated narcolepsy type 1 patients compared with their nonnarcoleptic siblings
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Rannveig Viste, Louise F Follin, Birgitte R Kornum, Benedicte A Lie, Marte K Viken, Per M Thorsby, Terje Rootwelt, Julie A E Christensen, and Stine Knudsen-Heier
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Narcolepsy type 1 ,RESTLESS LEGS SYNDROME ,H1N1 INFLUENZA ,MOVEMENTS ,NORWEGIAN CHILDREN ,disease continuum in first-degree relatives ,CHILDHOOD NARCOLEPSY ,NT1 ,REM sleep behavior disorder ,DIAGNOSIS ,muscle activity in sleep ,leg movements in sleep ,periodic leg movements ,post Pandemrix NT1 ,REM-SLEEP ,Physiology (medical) ,T-CELLS ,CSF hypocretin-1 deficiency ,CSF HYPOCRETIN-1 LEVELS ,dream enactment ,Neurology (clinical) ,POST-H1N1 VACCINATION - Abstract
Study ObjectivesNarcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity.MethodsRBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5–15 s); short (0.1–0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed.ResultsRBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p < 0.001). Patients with undetectable CSF hypocretin-1 levels (ConclusionIncreased REM and NREM muscle activity and more RBD symptoms is characteristic of NT1, and muscle activity severity is predicted by hypocretin deficiency severity but not by H1N1-(Pandemrix)-vaccination status. In the patients’ non-narcoleptic siblings, neither RBD symptoms, core narcoleptic symptoms, nor the major NT1 risk factors is associated with muscle activity during sleep, hence not indicative of a phenotypic continuum Study Objectives Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity. Methods RBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5-15 s); short (0.1-0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed. Results RBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p < 0.001). Patients with undetectable CSF hypocretin-1 levels (
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- 2022
21. Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement
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Maria Dehli Vigeland, Siri Tennebø Flåm, Magnus Dehli Vigeland, Ansgar Espeland, Per Martin Kristoffersen, Nils Vetti, Monica Wigemyr, Lars Christian Haugli Bråten, Elisabeth Gjefsen, Elina Iordanova Schistad, Anne Julsrud Haugen, Anne Froholdt, Jan Sture Skouen, John-Anker Zwart, Kjersti Storheim, Linda Margareth Pedersen, Benedicte Alexandra Lie, and the AIM Study Group
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Adult ,Male ,Science ,Chronic pain ,Article ,Bone Marrow ,Predictive Value of Tests ,Humans ,Randomized Controlled Trials as Topic ,Musculoskeletal system ,Multidisciplinary ,Disease genetics ,Gene Expression Profiling ,Middle Aged ,Magnetic Resonance Imaging ,Spine ,Gene Expression Regulation ,Osteoimmunology ,Medicine ,Female ,Gene expression ,Transcriptome ,Gene expressions ,Low Back Pain - Abstract
Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most infammatory MC state. We found the expression of 37 genes signifcantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels signifcantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identifed as signifcantly enriched among the upregulated genes in all three analyses. Our results point to infammation and immunological defense as important players in MC biology in patients with chronic LBP. Tis work was supported by governmental organisations Helse Sør-Øst (Grant number 2015090); Helse Vest (Grant numbers HV 911938, HV 911891); and Klinbeforsk (Grant number 2017201).
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- 2022
22. Identification of Novel Loci Shared by Juvenile Idiopathic Arthritis Subtypes Through Integrative Genetic Analysis
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Jin Li, Yun R. Li, Joseph T. Glessner, Jie Yang, Michael E. March, Charlly Kao, Courtney N. Vaccaro, Jonathan P. Bradfield, Junyi Li, Frank D. Mentch, Hui‐Qi Qu, Xiaohui Qi, Xiao Chang, Cuiping Hou, Debra J. Abrams, Haijun Qiu, Zhi Wei, John J. Connolly, Fengxiang Wang, James Snyder, Berit Flatø, Susan D. Thompson, Carl D. Langefeld, Benedicte A. Lie, Jane E. Munro, Carol Wise, Patrick M. A. Sleiman, and Hakon Hakonarson
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Rheumatology ,Genetic Loci ,Immunology ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Polymorphism, Single Nucleotide ,Arthritis, Juvenile ,Genome-Wide Association Study - Abstract
Objective Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. Methods We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. Results In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. Conclusion This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.
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- 2022
23. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
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Saedis, Saevarsdottir, Lilja, Stefansdottir, Patrick, Sulem, Gudmar, Thorleifsson, Egil, Ferkingstad, Gudrun, Rutsdottir, Bente, Glintborg, Helga, Westerlind, Gerdur, Grondal, Isabella C, Loft, Signe Bek, Sorensen, Benedicte A, Lie, Mikael, Brink, Lisbeth, Ärlestig, Asgeir Orn, Arnthorsson, Eva, Baecklund, Karina, Banasik, Steffen, Bank, Lena I, Bjorkman, Torkell, Ellingsen, Christian, Erikstrup, Oleksandr, Frei, Inger, Gjertsson, Daniel F, Gudbjartsson, Sigurjon A, Gudjonsson, Gisli H, Halldorsson, Oliver, Hendricks, Jan, Hillert, Estrid, Hogdall, Søren, Jacobsen, Dorte Vendelbo, Jensen, Helgi, Jonsson, Alf, Kastbom, Ingrid, Kockum, Salome, Kristensen, Helga, Kristjansdottir, Margit H, Larsen, Asta, Linauskas, Ellen-Margrethe, Hauge, Anne G, Loft, Bjorn R, Ludviksson, Sigrun H, Lund, Thorsteinn, Markusson, Gisli, Masson, Pall, Melsted, Kristjan H S, Moore, Heidi, Munk, Kaspar R, Nielsen, Gudmundur L, Norddahl, Asmundur, Oddsson, Thorunn A, Olafsdottir, Pall I, Olason, Tomas, Olsson, Sisse Rye, Ostrowski, Kim, Hørslev-Petersen, Solvi, Rognvaldsson, Helga, Sanner, Gilad N, Silberberg, Hreinn, Stefansson, Erik, Sørensen, Inge J, Sørensen, Carl, Turesson, Thomas, Bergman, Lars, Alfredsson, Tore K, Kvien, Søren, Brunak, Kristján, Steinsson, Vibeke, Andersen, Ole A, Andreassen, Solbritt, Rantapää-Dahlqvist, Merete Lund, Hetland, Lars, Klareskog, Johan, Askling, Leonid, Padyukov, Ole Bv, Pedersen, Unnur, Thorsteinsdottir, Ingileif, Jonsdottir, and Kari, Stefansson
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Proteomics ,rheumatoid arthritis ,autoantibodies ,Janus Kinases/genetics ,Immunology ,polymorphism, genetic ,General Biochemistry, Genetics and Molecular Biology ,polymorphism ,Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics ,Arthritis, Rheumatoid ,Rheumatology ,genetic ,Immunology and Allergy ,Humans ,Genetic Predisposition to Disease ,Medicinsk genetik ,Rheumatology and Autoimmunity ,Janus Kinases ,Reumatologi och inflammation ,Genetic Predisposition to Disease/genetics ,Biochemistry and Molecular Biology ,Interferon-alpha ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Arthritis, Rheumatoid/genetics ,STAT Transcription Factors/genetics ,STAT Transcription Factors ,Signal Transduction/genetics ,Medical Genetics ,Biokemi och molekylärbiologi ,Genome-Wide Association Study ,Signal Transduction - Abstract
Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen
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- 2022
24. T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
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Muhammad Ali, Eirini Giannakopoulou, Yingqian Li, Madeleine Lehander, Stina Virding Culleton, Weiwen Yang, Cathrine Knetter, Mete Can Odabasi, Ravi Chand Bollineni, Xinbo Yang, Zsofia Foldvari, Maxi-Lu Böschen, Eli Taraldsrud, Erlend Strønen, Mireille Toebes, Amy Hillen, Stefania Mazzi, Arnoud H. de Ru, George M. C. Janssen, Arne Kolstad, Geir Erland Tjønnfjord, Benedicte A. Lie, Marieke Griffioen, Sören Lehmann, Liv Toril Osnes, Jochen Buechner, K. Christopher Garcia, Ton N. Schumacher, Peter A. van Veelen, Matthias Leisegang, Sten Eirik W. Jacobsen, Petter Woll, and Johanna Olweus
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Cancer och onkologi ,T-Lymphocytes ,Biomedical Engineering ,Receptors, Antigen, T-Cell ,Bioengineering ,Hematopoietic Stem Cells ,Applied Microbiology and Biotechnology ,Mice ,DNA Nucleotidylexotransferase ,Cancer and Oncology ,Molecular Medicine ,Animals ,Lymphocytes ,Biotechnology - Abstract
Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.Engineered T cells kill leukemic cells with little off-target toxicity.
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- 2021
25. The influence of hla genotype on the development of metal hypersensitivity following joint replacement
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Rebecca Darlay, Matthew E. Nargol, Edwin P. Su, Rohan M. Bhalekar, Rachelle Hornick, Shonali Natu, Benedicte A. Lie, Moreica B. Pabbruwe, Alan Stewart, Benjamin Wainwright, Renee Ren, Thomas J. Joyce, Nish Shyam, Antoni V.F. Nargol, David J. Langton, and Susan Waller
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Hla genotype ,business.industry ,Joint replacement ,medicine.medical_treatment ,Immunology ,Medicine ,business - Abstract
Joint replacement surgery provides pain relief and restoration of mobility for millions of patients around the world each year.[1] However, the release of wear debris from implant surfaces can limit the lifespan of a prosthesis through the promotion of inflammatory responses.[2] Implants must therefore be constructed from materials with sufficient durability and biocompatibility. One such material is cobalt chrome alloy, which is used in the majority of joint replacements.[3] Unfortunately, it is recognised that some patients develop lymphocyte mediated delayed type hypersensitivity (DTH) responses to this material,[4] a response which may result in extensive bone and soft tissue destruction.[5] A genetic predisposition to DTH has been proposed[6], though specific genes have yet to be identified, or the effects quantified. Here we show that variation in HLA class II genotype influences an individual’s susceptibility to DTH. HLA-DQ haplotypes encoding peptide binding grooves with greater affinity for the N terminal peptide sequence of albumin (containing two recognised metal binding sites) confer a greater risk of DTH. We describe the development and validation of a machine learning algorithm to investigate the possibility that a patient’s genotype and basic clinical parameters may be used to predict DTH. Incorporating this novel finding, gradient boosted survival analysis machine learning models were trained and validated using results from 606 patients from three international units. These models were assessed using Uno’s c-index, time-dependent AUROCs, and integrated calibration index performance statistics. At present, there are no tests in widespread clinical use which use a patient’s genetic profile to guide implant selection or inform post-operative management. The algorithm described herein may address this issue.
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- 2021
26. No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
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Marthe Ueland, Riad Hajdarevic, Olav Mella, Elin B. Strand, Daisy D. Sosa, Ola D. Saugstad, Øystein Fluge, Benedicte A. Lie, and Marte K. Viken
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Cohort Studies ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Fatigue Syndrome, Chronic ,Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) ,Humans ,genetics ,Fatigue Syndrome ,Polymorphism, Single Nucleotide ,Biological Psychiatry ,Genetic Association Studies ,Genome-Wide Association Study - Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants. We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value −8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls). We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value
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- 2021
27. Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci
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Riad Hajdarevic, Asgeir Lande, Jesper Mehlsen, Anne Rydland, Daisy D. Sosa, Elin B. Strand, Olav Mella, Flemming Pociot, Øystein Fluge, Benedicte A. Lie, and Marte K. Viken
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Cohort Studies ,Behavioral Neuroscience ,Fatigue Syndrome, Chronic ,Endocrine and Autonomic Systems ,immunochip ,Immunology ,GWAS ,Humans ,Self Report ,ME/CFS ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study - Abstract
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/ CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10− 7 ), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.
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- 2021
28. Systematic assessment of commercially available low-input miRNA library preparation kits
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Melanie A. Hussong, Marianne Dalland, Sabrina Shore, Xiangfu Zhong, Jordana M. Henderson, Benedicte A. Lie, Arvind Y. M. Sundaram, Fatima Heinicke, Johannes Breidenbach, Hoichong Karen Yip, Pamela Moll, Andrew Farmer, Simon Rayner, Magnus Leithaug, Jana Vitkovska, Jonathan Shaffer, Siri Tennebø Flåm, Amanda McNulty, Gregor D. Gilfillan, Loan T. Nguyen, and Manuela Zucknick
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Library preparation ,Sequencing bias ,Total rna ,Differentially expressed mirnas ,Computational biology ,Biology ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Next generation sequencing ,microRNA ,Humans ,Molecular Biology ,Gene Library ,030304 developmental biology ,Low RNA input ,0303 health sciences ,VDP::Landbruks- og Fiskerifag: 900 ,Sequence Analysis, RNA ,Mirna sequencing ,Low input ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,RNA ,MicroRNA ,Cell Biology ,UMI ,MicroRNAs ,NGS ,030220 oncology & carcinogenesis ,Genetic Engineering ,MiRNA ,Small RNA-seq ,Research Paper - Abstract
High-throughput sequencing is increasingly favoured to assay the presence and abundance of micro RNAs (miRNAs) in biological samples, even from low RNA amounts, and a number of commercial vendors now offer kits that allow miRNA sequencing from sub-nanogram (ng) inputs. However, although biases introduced during library preparation have been documented, the relative performance of current reagent kits has not been investigated in detail. Here, six commercial kits capable of handling
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- 2019
29. Maternal and Newborn Vitamin D–Binding Protein, Vitamin D Levels, Vitamin D Receptor Genotype, and Childhood Type 1 Diabetes
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Ketil Størdal, Marte K. Viken, Pål R. Njølstad, Arieh Cohen, Karl Mårild, Lars C. Stene, Benedicte A. Lie, Sandra Rinne Dahl, Nicolai A Lund-Blix, German Tapia, Torild Skrivarhaug, and Geir Joner
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Adult ,Male ,Vitamin ,medicine.medical_specialty ,Adolescent ,Genotype ,Vitamin D-binding protein ,Offspring ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,030209 endocrinology & metabolism ,Polymorphism, Single Nucleotide ,Calcitriol receptor ,Cohort Studies ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,CYP24A1 ,Pregnancy ,Internal medicine ,Internal Medicine ,medicine ,Vitamin D and neurology ,Humans ,030212 general & internal medicine ,Epidemiology/Health Services Research ,Age of Onset ,Vitamin D ,Child ,2. Zero hunger ,Advanced and Specialized Nursing ,Type 1 diabetes ,Norway ,business.industry ,Vitamin D-Binding Protein ,Infant, Newborn ,medicine.disease ,Diabetes Mellitus, Type 1 ,Endocrinology ,chemistry ,Case-Control Studies ,Receptors, Calcitriol ,Female ,business - Abstract
OBJECTIVE Circumstantial evidence links 25-hydroxy vitamin D [25(OH)D], vitamin D–binding protein (DBP), vitamin D–associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D. RESEARCH DESIGN AND METHODS From a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography–tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (GC, DHCR7, CYP2R1, CYP24A1, CYP27B1, and VDR). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders. RESULTS Higher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 [95% CI 0.74–0.98] per μmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 [95% CI 0.77–0.98] per 10 nmol/L increase) in children carrying the VDR rs11568820 G/G genotype (Pinteraction = 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions. CONCLUSIONS Higher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on VDR genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include VDR genotype and DBP levels.
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- 2019
30. Allele imputation for the Killer cell Immunoglobulin-like Receptor KIR3DL1/S1
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Jonathan A. Shortt, Viken Mk, Harrison Ea, Laura Ann Leaton, Christopher R. Gignoux, Benedicte A. Lie, Genelle F. Harrison, Stephen Leslie, Damjan Vukcevic, and Paul Norman
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Genetics ,education.field_of_study ,Population ,Killer-cell immunoglobulin-like receptor ,Genotype ,Human genetic variation ,Human leukocyte antigen ,Biology ,KIR3DL1 ,education ,Genotyping ,Imputation (genetics) - Abstract
Highly polymorphic interactions of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of cancer treatment, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation that distinguishes individuals and populations, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data, and designed to represent a substantial component of human genetic diversity. We show that our Global model is effective at imputing KIR3DL1/S1 alleles with an accuracy ranging from 89% in Africans to 97% in East Asians, with mean specificity of 99.8% and sensitivity of 99% for named alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 and HLA-A and B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable. All code, imputation models, test data and documentation are available at https://github.com/NormanLabUCD/PONG.Author SummaryNatural killer (NK) cells are cytotoxic lymphocytes that identify and kill infected or malignant cells and guide immune responses. The effector functions of NK cells are modulated through polymorphic interactions of KIR3DL1/S1 on their surface with the human leukocyte antigens (HLA) that are found on most other cell types in the body. KIR3DL1/S1 is highly polymorphic and differentiated across human populations, affecting susceptibility and course of multiple immune-mediated diseases and their treatments. Genotyping KIR3DL1/S1 for direct medical application or research has been encumbered by the complex sequence and structural variation, which requires targeted approaches and extensive domain expertise to generate and validate high-resolution allele calls. We therefore developed Pulling Out Natural Killer Cell Genomics (PONG) to impute KIR3DL1/S1 alleles from whole genome SNP data, and which we implemented as an open-source R package. We assessed imputation performance using data from five broad population groups that represent a substantial portion of human genetic diversity. We can impute KIR3DL1/S1 alleles with an accuracy ranging from 89% in Africans and South Asians to 97% in East Asians. Globally, imputation of KIR3DL1/S1 alleles having frequency >1% has a mean sensitivity of 94% and specificity of 99.8%. Thus, the PONG method both enables highly sensitive individual-level calling and makes large scale medical genetic studies of KIR3DL1/S1 possible.
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- 2021
31. MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients
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Simon Rayner, Siri Tennebø Flåm, Fatima Heinicke, Anna-Birgitte Aga, E.S. Norli, Espen A Haavardsholm, Siri Lillegraven, Manuela Zucknick, Johannes Breidenbach, Marthe T. Maehlen, Xiangfu Zhong, M.D. Mjaavatten, Benedicte A. Lie, and Magnus Leithaug
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lcsh:Immunologic diseases. Allergy ,rheumatoid arthritis ,0301 basic medicine ,Cell type ,Antigens, CD19 ,Immunology ,methotrexate ,CD19 ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,PRDM1 ,microRNA ,medicine ,Humans ,Immunology and Allergy ,Gene Regulatory Networks ,B cell ,Original Research ,miRNA ,030203 arthritis & rheumatology ,B-Lymphocytes ,biology ,Gene Expression Profiling ,Autoantibody ,Computational Biology ,Disease Management ,High-Throughput Nucleotide Sequencing ,medicine.disease ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,NGS ,Rheumatoid arthritis ,Cancer research ,biology.protein ,RNA Interference ,CD19+ B cells ,Disease Susceptibility ,lcsh:RC581-607 ,Biomarkers ,Immunosuppressive Agents - Abstract
Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
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- 2021
32. Narcolepsy type 1 patients have lower levels of effector memory CD4
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Rannveig, Viste, Benedicte A, Lie, Marte K, Viken, Terje, Rootwelt, Stine, Knudsen-Heier, and Birgitte R, Kornum
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CD4-Positive T-Lymphocytes ,Influenza A Virus, H1N1 Subtype ,Influenza Vaccines ,Siblings ,Influenza, Human ,Vaccination ,Leukocytes, Mononuclear ,HLA-DQ beta-Chains ,Humans ,Narcolepsy - Abstract
Evidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings.Peripheral blood mononuclear cells were collected in parallel and analysed with flow cytometry in 31 NT1 patients with disease onset after the 2009 influenza A (H1N1) pandemic and/or Pandemrix™ vaccination and 45 of their non-narcoleptic siblings (29/31 and 34/45 vaccinated, respectively).We observed significantly lower effector memory CD4We confirm that NT1 is associated with lower levels of effector memory CD4
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- 2021
33. THE INFLUENCE OF HLA GENOTYPE ON SUSCEPTIBILITY TO, AND SEVERITY OF, COVID-19 INFECTION
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Carlos Echevarria, Benedicte A. Lie, Stephen Bourke, David J. Langton, John Burn, Shonali Natu, Gabrielle Reiff, and Rebecca Darlay
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medicine.medical_specialty ,education.field_of_study ,business.industry ,Mortality rate ,Population ,Haplotype ,Context (language use) ,Genome-wide association study ,Human leukocyte antigen ,Asymptomatic ,Internal medicine ,medicine ,medicine.symptom ,education ,business ,Allele frequency - Abstract
BackgroundThe impact of COVID-19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might influence this variation.MethodsUsing next generation sequencing, we analysed the class I and class II classical HLA genes of 147 white British patients with variable clinical outcomes. 49 of these patients were admitted to hospital with severe COVID infection. They had no significant pre-existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allelic frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n=13) or systemic symptoms not requiring hospital treatment (n=16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology.FindingsWe found a significant difference in the allelic frequency of HLA-DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% versus 16.7%, p=0.003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 in the asymptomatic group compared to the background population (p=0.007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID-19 observed in the cohorts.InterpretationThis study provides evidence that patient age, sex, BMI and HLA genotype interact to determine the clinical outcome of COVID-19 infection.Research in contextEvidence before this studyHLA genes are implicated in host resistance or susceptibility to a range of pathogens. No studies thus far have compared HLA allele frequencies in patients requiring hospital admission following COVID-19 exposure to a group of asymptomatic individuals.Added value of this studyThe results indicate that the presence of HLA-DRB1*04:01 might confer protection from the development of respiratory failure following exposure to COVID. Individuals remaining asymptomatic following exposure to COVID are less likely to carry the haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 compared to the background population. This may indicate a host defence pathway not primarily dependent on an IgG response for clearance of infection. These findings conflict with larger genome wide association studies which compared HLA allelic frequencies of severely unwell patients with the background population.Implications of all the available evidenceThe findings could have implications for targeted vaccination regimes as well as helping assess the impact of social restrictions on mortality rates in different populations.
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- 2021
34. Polymorphisms in the TP53-MDM2-MDM4-axis in patients with rheumatoid arthritis
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Benedicte A. Lie, Marthe T. Maehlen, Per Eystein Lønning, Stian Knappskog, Kristian Hveem, Liv B. Gansmo, Lars J. Vatten, and Pål Richard Romundstad
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0301 basic medicine ,Adult ,Male ,Risk ,Locus (genetics) ,Cell Cycle Proteins ,Biology ,medicine.disease_cause ,Linkage Disequilibrium ,Autoimmunity ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Polymorphism (computer science) ,Proto-Oncogene Proteins ,Genotype ,Genetics ,medicine ,SNP ,Data Mining ,Humans ,Genetic Predisposition to Disease ,Alleles ,Aged ,Aged, 80 and over ,Polymorphism, Genetic ,Models, Genetic ,Haplotype ,Proto-Oncogene Proteins c-mdm2 ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Case-Control Studies ,Immunology ,biology.protein ,Mdm2 ,Female ,Tumor Suppressor Protein p53 ,Genome-Wide Association Study ,Signal Transduction - Abstract
Background In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity. Methods We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA. Results For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79–0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74–0.99 and OR: 0.79; CI 0.63–0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02–1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285–309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18–2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele. Conclusion We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.
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- 2021
35. Narcolepsy type 1 patients have lower levels of effector memory CD4+ T cells compared to their siblings when controlling for H1N1-(Pandemrix™)-vaccination and HLA DQB1∗06:02 status
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Marte K. Viken, Terje Rootwelt, Benedicte A. Lie, Birgitte Rahbek Kornum, Stine Knudsen-Heier, and Rannveig Viste
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Narcolepsy type 1 ,HLA-DQB1 ,business.industry ,T cell ,CD69 activation markers ,T cell differentiation ,General Medicine ,Human leukocyte antigen ,Post influenza A (H1N1) pandemic ,Vaccination ,medicine.anatomical_structure ,Immune system ,H1N1 (Pandemrix™) vaccination ,Immunology ,medicine ,Pandemrix ,CD25 activation markers ,IL-2 receptor ,business ,CD8 - Abstract
Study objectives: Evidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings. Methods: Peripheral blood mononuclear cells were collected in parallel and analysed with flow cytometry in 31 NT1 patients with disease onset after the 2009 influenza A (H1N1) pandemic and/or Pandemrix™ vaccination and 45 of their non-narcoleptic siblings (29/31 and 34/45 vaccinated, respectively). Results: We observed significantly lower effector memory CD4+ T cell levels in NT1 patients compared to their siblings, when controlling for HLA DQB1∗06:02 and vaccination status. Further, within the sibling group, vaccination status significantly affected frequencies of central memory and CD8+CD25+ T cells, and HLA DQB1∗06:02 status significantly affected frequencies of CD4+CD25+ T cells. Conclusion: We confirm that NT1 is associated with lower levels of effector memory CD4+ T cells in peripheral blood. Importantly, this finding was only significant when controlling for vaccination and HLA status in both patients and controls. We thus demonstrate the importance of characterizing such factors (eg HLA and vaccination) when studying T cell subsets in NT1. This might explain earlier conflicting results.
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- 2021
36. High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y11protein levels in narcolepsy type 1
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Benedicte A. Lie, Sebjørg E H Nordstrand, Birgitte Rahbek Kornum, Hilde T Juvodden, Stine Knudsen-Heier, Marte K. Viken, Per Medbøe Thorsby, Rannveig Viste, and Terje Rootwelt
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medicine.medical_specialty ,P2Y11 ,T-Lymphocytes ,Single-nucleotide polymorphism ,Neurological Disorders ,P2RY11 ,03 medical and health sciences ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Polymorphism (computer science) ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Pandemrix ,sleep fragmentation ,AcademicSubjects/MED00385 ,Allele ,First-degree relatives ,narcolepsy 1 ,Narcolepsy ,030304 developmental biology ,0303 health sciences ,AcademicSubjects/SCI01870 ,business.industry ,T lymphocyte ,P2Y ,medicine.disease ,Endocrinology ,Influenza Vaccines ,Sleep Deprivation ,Neurology (clinical) ,Sleep ,business ,030217 neurology & neurosurgery ,CD8 ,AcademicSubjects/MED00370 - Abstract
Study Objectives Narcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls. Methods The P2RY11 SNP was genotyped in 100 patients (90/100 H1N1-(Pandemrix)-vaccinated), 119 related and 123 non-related controls. CD4 and CD8 T lymphocyte P2Y11 protein levels were quantified using flow cytometry in 167 patients and relatives. Symptoms and sleep recording parameters were also collected. Results We found an association between NT1 and the rs2305795 A allele (OR = 2, 95% CI (1.3, 3.0), p = 0.001). T lymphocyte P2Y11 protein levels were significantly lower in patients and relatives homozygous for the rs2305795 risk A allele (CD4: p = 0.012; CD8: p = 0.007). The nocturnal sleep fragmentation index was significantly negatively correlated with patients’ P2Y11 protein levels (CD4: p = 0.004; CD8: p = 0.006). Mean MSLT sleep latency, REM-sleep latency, and core clinical symptoms were not associated with P2Y11 protein levels. Conclusions We confirmed that the P2RY11 polymorphism rs2305795 is associated with NT1 also in a mainly H1N1-(Pandemrix)-vaccinated cohort. We demonstrated that homozygosity for the A risk allele is associated with lower P2Y11 protein levels. A high level of nocturnal sleep fragmentation was associated with low P2Y11 levels in patients. This suggests that P2Y11 has a previously unknown function in sleep-wake stabilization that affects the severity of NT1.
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- 2021
37. The influence of HLA genotype on the severity of COVID-19 infection
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Stephen Bourke, Shonali Natu, Benedicte A. Lie, John Burn, Gabrielle Reiff, Carlos Echevarria, David J. Langton, and Rebecca Darlay
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medicine.medical_specialty ,Genotype ,Immunology ,Population ,Human leukocyte antigen ,virus ,Asymptomatic ,HLA-DQ alpha-Chains ,Gene Frequency ,COVID‐19 ,Internal medicine ,HLA-DQ Antigens ,Immunology and Allergy ,Medicine ,HLA-DQ beta-Chains ,Humans ,genetics ,Allele ,education ,Allele frequency ,Alleles ,COVID ,education.field_of_study ,business.industry ,SARS-CoV-2 ,Haplotype ,COVID-19 ,latitude ,Original Articles ,HLA ,Haplotypes ,Original Article ,Ordered logit ,medicine.symptom ,business ,HLA-DRB1 Chains - Abstract
The impact of COVID-19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might influence this variation. Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID-19 infection. Forty-nine of these patients were admitted to hospital with severe respiratory disease. They had no significant pre-existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allele frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n = 13) or systemic symptoms not requiring hospital treatment (n = 16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology. We found a significant difference in the allele frequency of HLA-DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% vs. 16.7%, P = .003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01-DQB1*05:01-DRB1*01:01 in the asymptomatic group compared to the background population (P = .007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID-19 observed in the cohorts. These alleles are found in greater frequencies in the North Western European population. This regional study provides evidence that HLA genotype influences clinical outcome in COVID-19 infection. Validation studies must take account of the complex genetic architecture of the immune system across different geographies and ethnicities.
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- 2021
38. 101: GENETIC PREDISPOSITION TO INFLIXIMAB IMMUNOGENICITY IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASES – SECONDARY ANALYZES FROM A RANDOMIZED TRIAL
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Kristin H. Bj⊘rlykke, Marthe K. Brun, Marte K. Viken, Grethe-Elisabeth Stenvik, Rolf A. Klaasen, Johanna E. Gehin, David J. Warren, Joe Sexton, Espen A. Haavardsholm, Jorgen Jahnsen, Benedicte A. Lie, Guro L. Goll, Nils Bolstad, Silje W Syversen, and Kristin K. J⊘rgensen
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Hepatology ,Gastroenterology - Published
- 2022
39. Erik Thorsby (1938–2021)
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Torstein Egeland, Dag E. Undlien, Benedicte A. Lie, John T. Vaage, and Marte K. Viken
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Text mining ,business.industry ,Immunology ,Genetics ,MEDLINE ,Immunology and Allergy ,Library science ,Biology ,business - Published
- 2021
40. The effect of infliximab in patients with chronic low back pain and Modic changes (the BackToBasic study): study protocol of a randomized, double blind, placebo-controlled, multicenter trial
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Elisabeth Gjefsen, Anne Julsrud Haugen, Fredrik Granviken, Thor Einar Holmgard, Magnhild Hammersland Dagestad, Nils Bolstad, Elina Iordanova Schistad, Thomas Kadar, John-Anker Zwart, Lars Grøvle, Kaja Kristine Selmer, Anne Froholdt, Aksel Thuv Nilsen, G. L. Goll, Tore K Kvien, Benedicte A. Lie, Ansgar Espeland, Morten Valberg, Espen A Haavardsholm, Lars Christian Haugli Bråten, Nils Vetti, Monica Wigemyr, Kjersti Storheim, Jan Sture Skouen, Gunn Hege Marchand, Gunnstein Bakland, and Jens Ivar Brox
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lcsh:Diseases of the musculoskeletal system ,law.invention ,Study Protocol ,Clinical trials ,Tumor necrosis factor (TNF)-α inhibitors ,0302 clinical medicine ,Randomized controlled trial ,law ,TNF- α inhibitor ,Multicenter Studies as Topic ,Medicine ,Orthopedics and Sports Medicine ,030212 general & internal medicine ,Pain Measurement ,Randomized Controlled Trials as Topic ,education.field_of_study ,Lumbar Vertebrae ,Norway ,Middle Aged ,Low back pain ,Oswestry Disability Index ,Clinical trial ,Treatment Outcome ,Randomized controlled trials ,Chronic Pain ,medicine.symptom ,Modic changes ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Placebo ,Young Adult ,03 medical and health sciences ,Rheumatology ,Multicenter trial ,Internal medicine ,Humans ,education ,Aged ,Inflammation ,business.industry ,Low back pains ,Infliximab ,lcsh:RC925-935 ,business ,human activities ,030217 neurology & neurosurgery - Abstract
Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes.Methods/design: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18–65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients’ clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes..Discussion: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data
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- 2020
41. Maternal Microchimerism in Cord Blood and Risk of Celiac Disease in Childhood
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Marte Katrine Viken, Ketil Størdal, Georgina L. Mortimer, German Tapia, Karl Mårild, Saranna Chipper-Keating, Jody Ye, Benjamin Thomas Gillard, Kathleen M Gillespie, Lars C. Stene, and Benedicte A. Lie
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Disease ,Human leukocyte antigen ,Chimerism ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,030225 pediatrics ,medicine ,Humans ,Enteropathy ,Child ,Fetus ,business.industry ,Gastroenterology ,Infant, Newborn ,Odds ratio ,medicine.disease ,Fetal Blood ,Celiac Disease ,Cord blood ,Case-Control Studies ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Immunology ,030211 gastroenterology & hepatology ,Female ,business - Abstract
Objectives: During pregnancy, small quantities of maternal cells are naturally transmitted to the fetus. This transmission, termed maternal microchimerism (MMc), has been implicated in autoimmune diseases but its potential role is unclear. We aimed to investigate if MMc at birth predicted childhood celiac disease (CD) risk, a common immune-mediated enteropathy often presenting in childhood. Methods: We designed a case-control study, nested in the Norwegian Mother, Father and Child Cohort. Participants were HLA class II typed to determine noninherited, nonshared maternal alleles (NIMA). Droplet digital (dd) PCR assays specific for common HLA class II NIMAs (HLA-DQB1∗03:01, ∗04:02 and ∗06:02/03) were used to estimate the quantity of maternal DNA, as a marker of maternal cells, in cord blood DNA from 124 children who later developed clinically diagnosed CD (median age at end of study 7.4 years, range 3.6–12.9) and 124 random controls. We tested whether presence of MMc was associated with CD using logistic regression, and compared ranks between cases and controls. Results: MMc, for example, maternal HLA antigens not inherited by the child, was found in 42% of cases and 43% of controls, and not associated with CD (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.58–1.60). The ranks of MMc quantities in cases and controls were also similar (Mann-Whitney U-test, P = 0.71). The subgroup with HLA-DQB1:03∗01 as their NIMA had a potential association with MMc, where levels greater than median was associated with CD (OR 3.78, 95% CI 1.28–11.18). Conclusion: MMc measured in cord blood was not associated with later risk of CD.
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- 2020
42. Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells
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Ingvild Synnøve Matre Gabrielsen, Hanna Helgeland, Benedicte A. Lie, Siri Tennebø Flåm, Arvind Y. M. Sundaram, and H E Akselsen
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Adult ,CD4-Positive T-Lymphocytes ,lcsh:QH426-470 ,Biological adhesion ,medicine.medical_treatment ,lcsh:Biotechnology ,T cells ,Thymus Gland ,Biology ,CD8-Positive T-Lymphocytes ,Autoimmune Diseases ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,T-Lymphocyte Subsets ,lcsh:TP248.13-248.65 ,Genetics ,medicine ,Cytotoxic T cell ,Humans ,Child ,030304 developmental biology ,0303 health sciences ,Gene Expression Profiling ,Cell Differentiation ,Cell cycle ,Molecular biology ,Thymus ,Thymic Tissue ,lcsh:Genetics ,Cytokine ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,RNA-seq ,CD8 ,Biotechnology ,Research Article ,Human - Abstract
Background The thymus is a highly specialized organ of the immune system where T cell precursors develop and differentiate into self-tolerant CD4+ or CD8+ T cells. No studies to date have investigated how the human transcriptome profiles differ, between T cells still residing in the thymus and T cells in the periphery. Results We have performed high-throughput RNA sequencing to characterize the transcriptomes of primary single positive (SP) CD4+ and CD8+ T cells from infant thymic tissue, as well as primary CD4+ and CD8+ T cells from infant and adult peripheral blood, to enable the comparisons across tissues and ages. In addition, we have assessed the expression of candidate genes related to autoimmune diseases in thymic CD4+ and CD8+ T cells. The thymic T cells showed the largest number of uniquely expressed genes, suggesting a more diverse transcription in thymic T cells. Comparing T cells of thymic and blood origin, revealed more differentially expressed genes, than between infant and adult blood. Functional enrichment analysis revealed an over-representation of genes involved in cell cycle and replication in thymic T cells, whereas infant blood T cells were dominated by immune related terms. Comparing adult and infant blood T cells, the former was enriched for inflammatory response, cytokine production and biological adhesion, while upregulated genes in infant blood T cells were associated with cell cycle, cell death and gene expression. Conclusion This study provides valuable insight into the transcriptomes of the human primary SP T cells still residing within the thymus, and offers a unique comparison to primary blood derived T cells. Interestingly, the majority of autoimmune disease associated genes were expressed in one or more T cell subset, however ~ 11% of these were not expressed in frequently studied adult peripheral blood.
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- 2020
43. An extension to: Systematic assessment of commercially available low-input miRNA library preparation kits
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Johannes Breidenbach, Xiangfu Zhong, Magnus Leithaug, Marianne Dalland, Manuela Zucknick, Siri Tennebø Flåm, Fatima Heinicke, Benedicte A. Lie, Simon Rayner, Arvind Y. M. Sundaram, and Gregor D. Gilfillan
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Computer science ,Library preparation ,Next Generation Sequencing ,Computational biology ,Biology ,Brief Communication ,03 medical and health sciences ,0302 clinical medicine ,Laboratory Chemicals ,microRNA ,Overall performance ,Differential expression ,Molecular Biology ,030304 developmental biology ,Gene Library ,miRNA ,0303 health sciences ,low RNA input ,NEXTflex ,Sequence Analysis, RNA ,Low input ,RNA ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,NEBNext ,Cell Biology ,MicroRNAs ,030220 oncology & carcinogenesis ,NGS ,sequencing bias ,Other ,Genetic Engineering ,small RNA-seq ,library preparation - Abstract
High-throughput sequencing has emerged as the favoured method to study microRNA (miRNA) expression, but biases introduced during library preparation have been reported. To assist researchers choose the most appropriate library preparation kit, we recently compared the performance of six commercially-available kits on synthetic miRNAs and human RNA, where library preparation was performed by the vendors. We hereby supplement this study with data from two further commonly used kits (NEBNext, NEXTflex) whose manufacturers initially declined to participate. As before, performance was assessed with respect to sensitivity, reliability, titration response and differential expression. Despite NEXTflex employing partially-randomised adapter sequences to minimise bias, we reaffirm that biases in miRNA abundance are kit-specific, complicating the comparison of miRNA datasets generated using different kits.
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- 2020
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44. Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
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Asgeir Lande, Ola Didrik Saugstad, Elin Bolle Strand, Marte K. Viken, Daisy Duarte Sosa, Benedicte A. Lie, Torstein Egeland, Øystein Fluge, Olav Mella, and Siri Tennebø Flåm
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Adult ,Male ,musculoskeletal diseases ,Linkage disequilibrium ,Adolescent ,Genes, MHC Class II ,lcsh:Medicine ,Genes, MHC Class I ,Human leukocyte antigen ,Severity of Illness Index ,Linkage Disequilibrium ,Article ,Young Adult ,HLA Antigens ,Severity of illness ,Genetics research ,Chronic fatigue syndrome ,medicine ,Humans ,Genetic Predisposition to Disease ,lcsh:Science ,Genotyping ,Alleles ,Aged ,Autoimmune disease ,Multidisciplinary ,Fatigue Syndrome, Chronic ,ME ,business.industry ,Norway ,lcsh:R ,Case-control study ,Middle Aged ,medicine.disease ,Human Leukocyte Antigen ,Risk factors ,Case-Control Studies ,Immunology ,Etiology ,Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) ,lcsh:Q ,Female ,business - Abstract
The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort. We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives. We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4–3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1–2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3–2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.
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- 2020
45. Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1
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Genelle F. Harrison, Laura Ann Leaton, Erica A. Harrison, Katherine M. Kichula, Marte K. Viken, Jonathan Shortt, Christopher R. Gignoux, Benedicte A. Lie, Damjan Vukcevic, Stephen Leslie, and Paul J. Norman
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Receptors, KIR3DS1 ,Genotype ,Ecology ,Receptors, KIR3DL1 ,Cellular and Molecular Neuroscience ,Receptors, KIR ,Computational Theory and Mathematics ,HLA-B Antigens ,Modeling and Simulation ,Genetics ,Humans ,Molecular Biology ,Alleles ,Ecology, Evolution, Behavior and Systematics - Abstract
Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.
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- 2022
46. Lack of Association among Peptidyl Arginine Deiminase Type 4 Autoantibodies,PADI4Polymorphisms, and Clinical Characteristics in Rheumatoid Arthritis
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Benedicte A. Lie, Øyvind Molberg, Gry B. N. Nordang, Bettina Kulle Andreassen, Kari Guderud, Siri Tennebø Flåm, Marthe T. Maehlen, and Marte K. Viken
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,biology ,business.industry ,Immunology ,Autoantibody ,medicine.disease ,Serology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Rheumatoid arthritis ,PADI4 ,PADI4 Gene ,biology.protein ,Immunology and Allergy ,Medicine ,Antibody ,business ,Genotyping ,Arginine deiminase - Abstract
Objective.We aimed to jointly investigate the role of antipeptidyl arginine deiminase type 4 antibodies (anti-PAD4) and polymorphisms in thePADI4gene together with clinical variables in rheumatoid arthritis (RA).Methods.Serum IgG autoantibodies to human recombinant PAD4 were identified by DELFIA technique in 745 patients with RA (366 available from previous studies). Genotyping ofPADI4was performed using TaqMan assays in 945 patients and 1118 controls. Clinical data, anticitrullinated protein antibodies (ACPA) status, shared epitope status, and a combined genetic risk score were also available.Results.Anti-PAD4 antibodies were detected in 193 (26%) of 745 patients with RA; 149 (77%) of these were also ACPA-positive. No association was observed between anti-PAD4 status and clinical characteristics,PADI4polymorphisms, or genetic risk scores after stratification for ACPA status.Conclusion.Taken together, the results from these combined serological, genetic, and clinical analyses suggest that anti-PAD4 appears to be a bystander autoantibody with no current clinical utility in RA.
- Published
- 2018
47. Fetal and Maternal Genetic Variants Influencing Neonatal Vitamin D Status
- Author
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Margareta Haugen, German Tapia, Ketil Størdal, Karl Mårild, Arieh Cohen, Lars C. Stene, and Benedicte A. Lie
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Adult ,0301 basic medicine ,medicine.medical_specialty ,Cord ,Genotype ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Mothers ,Nutritional Status ,030209 endocrinology & metabolism ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Biochemistry ,Cohort Studies ,Andrology ,Young Adult ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Genetic Predisposition to Disease ,Vitamin D ,Allele ,Maternal-Fetal Exchange ,Prenatal Nutritional Physiological Phenomena ,Clinical Research Articles ,business.industry ,Biochemistry (medical) ,Infant, Newborn ,Prenatal Care ,Vitamin D Deficiency ,Confidence interval ,030104 developmental biology ,Dietary Supplements ,Female ,business ,Cohort study - Abstract
Objective Several genetic polymorphisms determine vitamin D status. We aimed to estimate the strength of association of established 25-hydroyxvitamin D (25OHD)-associated variants in the mother and in the fetus, with 25OHD concentration in newborn umbilical cord plasma. Methods We randomly selected 578 mother and child dyads from the prospective Norwegian Mother and Child Cohort study. 25OHD was assayed in maternal samples taken shortly after delivery and in cord samples. We genotyped the mother and child for single nucleotide polymorphisms in or near GC, DHCR7, CYP2R1, and CYP24A1, previously confirmed to be associated with 25OHD, and computed genetic risk score (GRS). The genetic associations were replicated in an independent sample of 594 subjects. Results Although both fetal and maternal GRS were associated with cord 25OHD, only fetal GRS remained significantly associated with cord 25OHD in a regression model with maternal and fetal GRS simultaneously (1.6 nmol/L per fetal 25OHD-increasing allele; 95% confidence interval, 0.6 to 2.5, P = 0.0001). Two fetal single nucleotide polymorphisms in the GC gene (rs2282679 and rs222040) were the strongest genetic predictors of cord 25OHD [4.0 (2.1 to 5.9) and 3.0 (1.3 to 4.8) nmol/L per fetal allele, P < 0.001], followed by rs12785878 in DHCR7 [2.0 (0.1 to 3.8) nmol/L, P = 0.037]. The independent replication sample gave similar results. With fetal genotype included in a regression model with environmental factors, R2 for cord 25OHD was 0.28. Conclusions We show that fetal 25OHD-modifying genotype was a stronger predictor of cord 25OHD than corresponding maternal genotype. This raises interesting questions about fetal acquisition and placental transfer of 25OHD.
- Published
- 2017
48. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry
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Johannes R. Hov, Stuart C. Gordon, Kidist K. Yimam, Konstantinos N. Lazaridis, Brian D. Juran, Trine Folseraas, Marte K. Viken, B. Eksteen, L. Yu, Eva Kristine Klemsdal Henriksen, Rinse K. Weersma, Christopher L. Bowlus, Daniel Gotthardt, Michael Wittig, Espen Melum, Simon M. Rushbrook, E. Goode, Sören Mucha, Olivier Chazouillères, Benedicte A. Lie, Tom H. Karlsen, Kristian Holm, Cyriel Y. Ponsioen, David S. Goldberg, Pietro Invernizzi, Andre Franke, Martti Färkkilä, Gideon M. Hirschfield, and Marco Carbone
- Subjects
0301 basic medicine ,Genetics ,education.field_of_study ,Linkage disequilibrium ,endocrine system diseases ,Immunology ,Population ,Haplotype ,Human leukocyte antigen ,Biology ,medicine.disease ,Primary sclerosing cholangitis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,immune system diseases ,medicine ,Immunology and Allergy ,Chronic Cholangitis ,education ,Allele frequency ,030217 neurology & neurosurgery ,HLA Complex - Abstract
Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.
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- 2017
49. HLA class II alleles in Norwegian patients with coexisting type 1 diabetes and celiac disease
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Marte K. Viken, Siri Tennebø Flåm, Geir Joner, Ludvig M. Sollid, A K Drivvoll, Benedicte A. Lie, Knut Dahl-Jørgensen, Silja Svanstrøm Amundsen, and Torild Skrivarhaug
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musculoskeletal diseases ,0301 basic medicine ,medicine.medical_specialty ,endocrine system diseases ,Immunology ,Human leukocyte antigen ,Disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,030225 pediatrics ,Internal medicine ,Genetics ,medicine ,Immunology and Allergy ,Allele ,HLA-DRB1 ,Type 1 diabetes ,HLA-DQB1 ,business.industry ,fungi ,Haplotype ,nutritional and metabolic diseases ,medicine.disease ,030104 developmental biology ,Cohort ,business - Abstract
Background Type 1 diabetes (T1D) and celiac disease (CeD) are 2 distinct diseases, but there is an increased risk of developing CeD for T1D patients. Both diseases are associated with HLA-class II alleles, such as DQB1 *02:01 and DQB1 *03:02; however, their risk contribution vary between the diseases. Materials and Methods We genotyped HLA-DRB1 and – DQB1 in 215 patients with coexisting T1D and CeD identified from a T1D cohort, and compared them to patients with T1D (N = 487) and CeD (N = 327), as well as healthy controls (N = 368). Results The patients with coexisting T1D and CeD had an intermediate carrier frequency (72.8%) of the DRB1 *03:01- DQB1 *02:01- DQA1 *05:01 haplotype compared to T1D (64.1%) and CeD (88.7%) patients. The DRB1 *03:01- DQB1 *02:01- DQA1 *05:01/ DRB1 *04- DQB1 *03:02- DQA1 *03 haplotype combination, encoding DQ2.5 and DQ8 molecules, was equally frequent among patients with both T1D and CeD (52.6%) and T1D patients (46.8%) but significantly lower in CeD patients (9.5%). Conclusion Overall, the patients with coexisting T1D and CeD had an HLA profile more similar to T1D patients than CeD patients.
- Published
- 2017
50. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study
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Benedicte A. Lie, Asgeir Lande, Marte Katrine Viken, Kristin Risa, Alexander Fosså, Kari Sørland, Kine Alme, Øystein Fluge, Irini Ktoridou-Valen, Karl Johan Tronstad, Olav Mella, Ingrid Gurvin Rekeland, Mari H. Holsen, and Olav Dahl
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0301 basic medicine ,medicine.medical_specialty ,Cyclophosphamide ,CFS ,Nausea ,medicine.medical_treatment ,chronic fatigue syndrome ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Chronic fatigue syndrome ,medical treatment ,Adverse effect ,Chemotherapy ,lcsh:R5-920 ,business.industry ,ME ,Repeated measures design ,General Medicine ,medicine.disease ,Clinical Trial ,Clinical trial ,myalgic encephalomyelitis ,HLA ,030104 developmental biology ,Medicine ,cyclophosphamide ,medicine.symptom ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial. Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles. Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients. Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.
- Published
- 2019
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