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- Gianfrancesco, MA, et al.
(författare)
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Genetic risk factors for pediatric-onset multiple sclerosis
- 2018
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 24:14, s. 1825-1834
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Tidskriftsartikel (refereegranskat)abstract
- Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.
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- Kular, L, et al.
(författare)
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DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2397-
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Tidskriftsartikel (refereegranskat)abstract
- The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
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- Forsberg, A., et al.
(författare)
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The Immune Response of the Human Brain to Abdominal Surgery
- 2017
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 81:4, s. 572-582
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and long-term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [C-11]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [C-11]PBR28 binding of 26 +/- 26% (mean +/- standard deviation) at 3 to 4 days postoperatively compared to baseline (p=0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 +/- 39%) on the 3rd to 4th postoperative day, corresponding to changes in [C-11]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [C-11]PBR28 binding (p=0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function.
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- Eriksson, C., et al.
(författare)
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Golimumab är effektivt vid ulcerös kolit under svenska förhållanden. Interimsanalys av en svensk prospektiv multi-centerstudie, GO-SWIBREG
- 2018
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Konferensbidrag (refereegranskat)abstract
- Bakgrund: Randomiserade kontrollerade prövningar har visat effekt av golimumab vid ulcerös kolit men studiedeltagare och förhållanden i kliniska prövningar motsvarar inte alltid svensk klinisk vardag. Syftet med denna studie var att utvärdera säkerhet och effekt av behandling med golimumab vid ulcerös kolit under svenska förhållanden.Metod: Detta är en prospektiv kohortstudie med inklusion av patienter från svenska sjukhus. Patienter med måttlig till svår aktiv ulcerös kolit, definierad som endoskopiskt Mayo score ≥2 och som påbörjade golimumab fr.o.m. 1/6-2014 inkluderades efter att informerat samtycke inhämtats. Kliniska karakteristika, behandling, klinisk-, biokemisk- och endoskopisk aktivitet liksom skattning av livskvalité samlades in vid inklusion samt prospektivt med hjälp av ett elektroniskt studieformulär, integrerat i svenska kvalitetsregistret för IBD (SWIBREG). Primärt effektmått var klinisk effekt vid 3 samt 12 månader (definierat som minskat Mayo score med ≥3 poäng eller 30 % från inklusion), samt klinisk remission (definierad som Mayo score ≤ 2 utan några enskilda poäng >1). Kontinuerliga data presenteras som median och kvartilavstånd. För statistisk jämförelse mellan inklusion och uppföljning användes Wilcoxon-signed rank test. Data från induktionsbehandling samt 3-månadersuppföljning presenteras här.Resultat: 50 patienter inkluderades t.o.m. 15/9-2017. Vid studiestart var 24/50 (48 %) samtidigt behandlade med immunmodulerare, 16/50 (32 %) med perorala kortikosteroider samt 27/50 (54 %) med 5-ASA. Totalt hade 35/50 (70 %) tidigare fått behandling med minst en TNF-hämmare (tabell 1). Efter 12 veckor hade 37/50 (74 %), fortfarande behandling med golimumab. Av de patienter som fortsatte med golimumab till vecka 12 var 8 (22 %) i klinisk remission och 13 (35 %) uppvisade klinisk respons. Totalt Mayo score minskade i median från 7 (6-10) vid inklusion till 5 (1-8) vid 12 veckor (p<0.01). Fekalt calprotektin minskade från 710 (275-1850) µg/g till 390 (45-870) µg/g (p=0.02). Livskvalitet hos golimumab-behandlade patienter förbättrades, uppmätt som en signifikant minskning av poäng på short health scale (p=0.04).Slutsats: Golimumab-behandlade patienter i Sverige utgör en svårbehandlad grupp. Trots det kan förbättring av kliniska parametrar, inflammatorisk aktivitet och upplevd livskvalité uppnås redan efter 12 veckors golimumab-behandling.
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- Kroksmark, Anna-Karin, et al.
(författare)
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Long-term follow-up of motor function and muscle strength in the congenital and childhood forms of myotonic dystrophy type 1
- 2017
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 27:9, s. 826-835
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to explore how motor function and muscle strength change over time in the congenital and childhood forms of myotonic dystrophy type 1, further to investigate whether sex, age, disease severity or size of the mutation could explain these changes. Motor function and isometric muscle strength were evaluated at three occasions during 1999-2013 in 57 patients aged 0.7-28.9 years. Median time between first and last assessment was 11.5 years ranging from 9.6 to 13.3 years. The study shows that motor function improves during the first decade, is most pronounced during the first six years, reaches a plateau during adolescence and starts to deteriorate in the beginning of the second decade. The most predictive variables for change are age (p < 0.0001) and number of CTG-repeat expansions (p = 0.0018). Sex or disease severity grade do not predict changes in motor function. Deterioration of muscle strength is most pronounced in ankle dorsiflexors. Knowledge of development and deterioration of motor function is important for clinical decision making and for planning of interventions. This knowledge can also be of interest for patient recruitment in drug trials, since treatment effect might be easier to evaluate in the stable phases of this progressive disorder. (C) 2017 Elsevier B.V. All rights reserved.
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