Publications by authors named "Ingrid Kockum"

149 Publications

Seasonal variability of serum 25-hydroxyvitamin D on multiple sclerosis onset.

Sci Rep 2021 Oct 25;11(1):20989. Epub 2021 Oct 25.

Center of Molecular Medicine, Karolinska University Hospital, Solna, Sweden.

Vitamin D deficiency is associated with an increased risk of multiple sclerosis (MS). However, its effect on the age of disease onset remains unclear. This study examines the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and age of first symptom onset among recently diagnosed MS patients. Serum 25(OH)D was measured from forty MS patients sampled near disease onset. After correcting seasonal variability, the association between 25(OH)D levels, along with other clinical measures such as IgG index, and age at MS onset was examined using multivariable linear regression. Serum 25(OH)D was not correlated with age at onset (P > 0.5). We observed bias among previously reported associations between 25(OH)D and MS disease measures resulting from non-random distribution of sampling by season. After correcting for seasonal 25(OH)D and other clinical measures, only CSF IgG index remained significantly associated with age at disease onset (β = - 5.35, P = 0.028). In summary, we observed no association between age at onset and serum 25(OH)D levels but observed a negative correlation with CSF IgG index, although this will require further investigation.
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http://dx.doi.org/10.1038/s41598-021-00344-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546079PMC
October 2021

Deep characterization of paired chromatin and transcriptomes in four immune cell types from multiple sclerosis patients.

Epigenomics 2021 Oct 22;13(20):1607-1618. Epub 2021 Oct 22.

Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 17165, Sweden.

The putative involvement of chromatin states in multiple sclerosis (MS) is thus far unclear. Here we determined the association of chromatin-accessibility with concurrent genetic, epigenetic and transcriptional events. We generated paired assay for transposase-accessible chromatin sequencing and RNA-sequencing profiles from sorted blood immune CD4 and CD8 T cells, CD14 monocytes and CD19 B cells from healthy controls (HCs) and MS patients. We identified differentially accessible regions between MS patients and HCs, primarily in CD4 and CD19. CD4 regions were enriched for MS-associated single nucleotide polymorphisms and differentially methylated loci. In the vicinity of differentially accessible regions of CD4 cells, 42 differentially expressed genes were identified. The top two dysregulated genes identified in this multilayer analysis were and . These findings provide new insight into the primary role of CD4 and CD19 cells in MS.
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http://dx.doi.org/10.2217/epi-2021-0205DOI Listing
October 2021

Assessing the Preanalytical Variability of Plasma and Cerebrospinal Fluid Processing and Its Effects on Inflammation-Related Protein Biomarkers.

Mol Cell Proteomics 2021 Sep 29;20:100157. Epub 2021 Sep 29.

Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Proteomics studies are important for the discovery of new biomarkers as clinical tools for diagnosis and disease monitoring. However, preanalytical variations caused by differences in sample handling protocol pose challenges for assessing biomarker reliability and comparability between studies. The purpose of this study was to examine the effects of delayed centrifuging on measured protein levels in plasma and cerebrospinal fluid (CSF). Blood from healthy individuals and patients with multiple sclerosis along with CSF from patients with suspected neurological disorders were left at room temperature for different periods (blood: 1, 24, 48, 72 h; CSF: 1 and 6 h) prior to centrifuging. Ninety-one inflammation-related proteins were analyzed using a proximity extension assay, a high-sensitivity multiplex immunoassay. Additional metabolic and neurology-related markers were also investigated in CSF. In summary, many proteins, particularly in plasma, had increased levels with longer delays in processing likely due in part to intracellular leakage. Levels of caspase 8, interleukin 8, interleukin 18, sirtuin 2, and sulfotransferase 1A1 increased 2-fold to 10-fold in plasma after 24 h at room temperature. Similarly, levels of cathepsin H, ectonucleoside triphosphate diphosphohydrolase 5, and WW domain containing E3 ubiquitin protein ligase 2 differentiated in CSF with <6 h delay in processing. However, the rate of change for many proteins was relatively consistent; therefore, we were able to characterize biomarkers for detecting sample handling variability. Our findings highlight the importance of timely and consistent sample collection and the need for increased awareness of protein susceptibility to sample handling bias. In addition, suggested biomarkers may be used in certain situations to detect and correct for preanalytical variation in future studies.
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http://dx.doi.org/10.1016/j.mcpro.2021.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554621PMC
September 2021

A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis.

BMC Genomics 2021 Aug 30;22(1):631. Epub 2021 Aug 30.

Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Linköping, Sweden.

Background: There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules.

Result: We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS.

Conclusions: We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases.
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http://dx.doi.org/10.1186/s12864-021-07935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404328PMC
August 2021

Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology.

Eur J Neurol 2021 Dec 8;28(12):4146-4152. Epub 2021 Sep 8.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk.

Methods: We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP).

Results: Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01 status.

Conclusions: Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.
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http://dx.doi.org/10.1111/ene.15082DOI Listing
December 2021

Alcohol Consumption and Risk of Common Autoimmune Inflammatory Diseases-Evidence From a Large-Scale Genetic Analysis Totaling 1 Million Individuals.

Front Genet 2021 22;12:687745. Epub 2021 Jun 22.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

Observational studies have suggested a protective effect of alcohol intake with autoimmune disorders, which was not supported by Mendelian randomization (MR) analyses that used only a few (<20) instrumental variables. We systemically interrogated a putative causal relationship between alcohol consumption and four common autoimmune disorders, using summary-level data from the largest genome-wide association study (GWAS) conducted on inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). We quantified the genetic correlation to examine a shared genetic similarity. We constructed a strong instrument using 99 genetic variants associated with drinks per week and applied several two-sample MR methods. We additionally incorporated excessive drinking as reflected by alcohol use disorder identification test score. We observed a negatively shared genetic basis between alcohol intake and autoimmune disorders, although none was significant ( = -0.07 to -0.02). For most disorders, genetically predicted alcohol consumption was associated with a slightly (10-25%) decreased risk of onset, yet these associations were not significant. Meta-analyzing across RA, MS, and IBD, the three Th1-related disorders yielded to a marginally significantly reduced effect [OR = 0.70 (0.51-0.95), = 0.02]. Excessive drinking did not appear to reduce the risk of autoimmune disorders. With its greatly augmented sample size and substantially improved statistical power, our MR study does not convincingly support a beneficial role of alcohol consumption in each individual autoimmune disorder. Future studies may be designed to replicate our findings and to understand a causal effect on disease prognosis.
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http://dx.doi.org/10.3389/fgene.2021.687745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258244PMC
June 2021

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

Ann Neurol 2021 08 14;90(2):193-202. Epub 2021 Jul 14.

Department of Medical & Molecular Genetics, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways.

Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed.

Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache.

Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.
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http://dx.doi.org/10.1002/ana.26150DOI Listing
August 2021

Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis-a presymptomatic case-control study.

Eur J Neurol 2021 09 27;28(9):3072-3079. Epub 2021 Jun 27.

Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden.

Background And Purpose: Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology.

Methods: A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP).

Results: Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65).

Conclusions: Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.
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http://dx.doi.org/10.1111/ene.14961DOI Listing
September 2021

The genetic structure of Norway.

Eur J Hum Genet 2021 Nov 17;29(11):1710-1718. Epub 2021 May 17.

Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity, and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway's long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been an isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.
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http://dx.doi.org/10.1038/s41431-021-00899-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560852PMC
November 2021

Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology.

Proc Natl Acad Sci U S A 2021 04;118(17)

Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, SE-171 76 Stockholm, Sweden;

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system (CNS). Small non-coding RNAs (sncRNAs) and, in particular, microRNAs (miRNAs) have frequently been associated with MS. Here, we performed a comprehensive analysis of all classes of sncRNAs in matching samples of peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells, and cell-free CSF from relapsing-remitting (RRMS, = 12 in relapse and = 11 in remission) patients, secondary progressive (SPMS, = 6) MS patients, and noninflammatory and inflammatory neurological disease controls (NINDC, = 11; INDC, = 5). We show widespread changes in miRNAs and sncRNA-derived fragments of small nuclear, nucleolar, and transfer RNAs. In CSF cells, 133 out of 133 and 115 out of 117 differentially expressed sncRNAs were increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65 out of 67 differentially expressed PBMC sncRNAs were decreased in RRMS compared to NINDC. The striking contrast between the periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation, and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the CNS target organ.
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http://dx.doi.org/10.1073/pnas.2011574118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092379PMC
April 2021

DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies.

J Neurol Neurosurg Psychiatry 2021 Jul 9;92(7):717-722. Epub 2021 Mar 9.

Karolinska Institute, Stockholm, Sweden.

Objective: We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for .

Methods: Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.

Results: The effect of each allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between and each assessed environmental factor was of similar magnitude regardless of the number of alleles, although ORs were affected. When any of the environmental factors were present in carriers without the protective allele, a three-way interaction occurred and rendered high ORs, especially among homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).

Conclusions: The strikingly increased MS risk among homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.
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http://dx.doi.org/10.1136/jnnp-2020-325676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223646PMC
July 2021

Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS.

BMC Med 2020 11 4;18(1):298. Epub 2020 Nov 4.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str 22, 81675, Munich, Germany.

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.

Methods: We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.

Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81-4.48), p = 2.1 × 10) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69-4.72), p = 6.6 × 10). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29-3.61), p = 7.4 × 10) while DR3-DQ2 was protective (OR = 0.37 (0.27-0.52), p = 3.7 × 10). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33-12.47), p = 1.5 × 10). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85-0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8-463.6, p = 4.4 × 10) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0-63.3, p = 7.5 × 10).

Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.
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http://dx.doi.org/10.1186/s12916-020-01769-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641861PMC
November 2020

Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling.

PLoS Genet 2020 10 26;16(10):e1009199. Epub 2020 Oct 26.

Rheumatology and Science for Life Laboratories, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD-CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.
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http://dx.doi.org/10.1371/journal.pgen.1009199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644105PMC
October 2020

Pregnancy does not modify the risk of MS in genetically susceptible women.

Neurol Neuroimmunol Neuroinflamm 2020 11 9;7(6). Epub 2020 Oct 9.

From the Divisions of Epidemiology and Biostatistics (C.J.A., S.L.W.), School of Public Health, University of California, Berkeley, Berkeley, CA; Genetic Epidemiology and Genomics Laboratory (X.S., L.F.B.), University of California, Berkeley, Berkeley, CA; School of Public Health (P.T.B.), University of California, Berkeley, Berkeley, CA, USA; Department of Research & Evaluation (E.G., J.B.S., A.H.X.), Kaiser Permanente Southern California, Los Angeles, CA; Kaiser Permanente Division of Research (K.H.B., T.C., C.S.), Kaiser Permanente Northern California, Oakland, CA; University of Oslo (S.D.B.), Institute of Clinical Medicine & Oslo University Hospital, Department of Neurology, Oslo, Norway; Oslo University Hospital (M.W.-H.), Department of Neurology, Oslo, Norway; Department of Clinical Neuroscience (T.O.), Karolinska Instituet, Stockholm, Sweden; Department of Clinical Neuroscience (I.K.), Karolinska Institutet, Stockholm, Sweden; Southern California Permanente Medical Group/Kaiser Permanente (A.M.L.-G.), Department of Neurology, Los Angeles, CA; and Institute of Environmental Medicine (L.A.), Karolinska Institutet and Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden.

Objective: To use the case-only gene-environment (G [Formula: see text] E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.

Methods: We studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) [Formula: see text] live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.

Results: Evidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.

Conclusion: Our findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.
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http://dx.doi.org/10.1212/NXI.0000000000000898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673284PMC
November 2020

The DQB103:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis.

Front Neurol 2020 4;11:993. Epub 2020 Sep 4.

Department of Medicine Solna, Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, Sweden.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB103:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB103:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB103:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB103:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB103:02 allele effect is modified by the presence of MS.
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http://dx.doi.org/10.3389/fneur.2020.00993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500133PMC
September 2020

Cigarette smoking patterns preceding primary Sjögren's syndrome.

RMD Open 2020 Sep;6(3)

Division of Rheumatology, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjögren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.

Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.

Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.

Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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http://dx.doi.org/10.1136/rmdopen-2020-001402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547543PMC
September 2020

Towards standardization guidelines for in silico approaches in personalized medicine.

J Integr Bioinform 2020 Jul 24;17(2-3). Epub 2020 Jul 24.

Medical Informatics Laboratory, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Despite the ever-progressing technological advances in producing data in health and clinical research, the generation of new knowledge for medical benefits through advanced analytics still lags behind its full potential. Reasons for this obstacle are the inherent heterogeneity of data sources and the lack of broadly accepted standards. Further hurdles are associated with legal and ethical issues surrounding the use of personal/patient data across disciplines and borders. Consequently, there is a need for broadly applicable standards compliant with legal and ethical regulations that allow interpretation of heterogeneous health data through in silico methodologies to advance personalized medicine. To tackle these standardization challenges, the Horizon2020 Coordinating and Support Action EU-STANDS4PM initiated an EU-wide mapping process to evaluate strategies for data integration and data-driven in silico modelling approaches to develop standards, recommendations and guidelines for personalized medicine. A first step towards this goal is a broad stakeholder consultation process initiated by an EU-STANDS4PM workshop at the annual COMBINE meeting (COMBINE 2019 workshop report in same issue). This forum analysed the status quo of data and model standards and reflected on possibilities as well as challenges for cross-domain data integration to facilitate in silico modelling approaches for personalized medicine.
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http://dx.doi.org/10.1515/jib-2020-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756614PMC
July 2020

Smoking and Epstein-Barr virus infection in multiple sclerosis development.

Sci Rep 2020 07 3;10(1):10960. Epub 2020 Jul 3.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

It is unclear whether smoking interacts with different aspects of Epstein-Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case-control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2-0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI - 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004-0.4), but not between past smoking and IM history (AP - 0.06, 95% CI - 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.
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http://dx.doi.org/10.1038/s41598-020-67883-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335184PMC
July 2020

FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Nature 2020 08 24;584(7822):619-623. Epub 2020 Jun 24.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10) and coeliac disease (OR = 1.62, P = 1.20 × 10). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.
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http://dx.doi.org/10.1038/s41586-020-2436-0DOI Listing
August 2020

Inflammation-related plasma and CSF biomarkers for multiple sclerosis.

Proc Natl Acad Sci U S A 2020 06 26;117(23):12952-12960. Epub 2020 May 26.

Neuroimmunology Unit, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska University Hospital, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease ( < 4 × 10, < 4 × 10), and plasma CCL20 was associated with disease severity ( = 4 × 10), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.
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http://dx.doi.org/10.1073/pnas.1912839117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293699PMC
June 2020

Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis.

Neurology 2020 06 20;94(23):e2457-e2467. Epub 2020 May 20.

From the Department of Clinical Neuroscience (A.M., P.S., M.K., F.P., T.O., I.K.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Karolinska Institutet; Centre for Molecular Medicine (A.M., P.S., M.K., F.P., T.O., I.K.), Karolinska University Hospital, Stockholm, Sweden; Departments of Medicine, Biomedicine, and Clinical Research (D.L., C.B., Z.M., L.K., J.K.), Neurologic Clinic and Policlinic, University Hospital Basel, University of Basel; Clinical Trial Unit (P.B.), Department of Clinical Research, University Hospital Basel, University of Switzerland; Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Gothenburg; Institute of Environmental Medicine (L.A.), Karolinska Institutet, Stockholm; and Centre for Occupational and Environmental Medicine (L.A.), Stockholm County Council, Sweden.

Objective: To investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.

Methods: Concentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).

Results: The median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS ( < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.

Conclusions: Elevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
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http://dx.doi.org/10.1212/WNL.0000000000009571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455371PMC
June 2020

Low fish consumption is associated with a small increased risk of MS.

Neurol Neuroimmunol Neuroinflamm 2020 05 10;7(3). Epub 2020 Apr 10.

From the Department of Clinical Neuroscience (A.K.H., T.O., I.K., J.H.), Institute of Environmental Medicine (A.K.H., L.A.), Center for Molecular Medicine (T.O., I.K., J.H.), Karolinska Institutet, Stockholm, Sweden; and Centre for Occupational and Environmental Medicine (L.A.), Region Stockholm, Stockholm, Sweden.

Objective: We aimed to investigate the influence of lean and fatty fish consumption on MS risk and to what extent a potential effect may be mediated by vitamin D. We also studied the interplay between fish consumption, sun exposure, , and .

Methods: We used 2 population-based case-control studies (6,914 cases and 6,590 controls). Subjects with different fish consumption habits were compared regarding MS risk by calculating ORs with 95% CIs using logistic regression models. The mediation effect of vitamin D on the relationship between fish consumption and MS risk was assessed. Potential interactions between fish consumption, sun exposure, and MS-associated HLA genes were assessed on the additive scale.

Results: Irrespective of sun exposure habits, low fish consumption, including both lean and fatty fish, was associated with increased MS risk (OR 1.2, 95% CI 1.1-1.4) and interacted with the allele (AP 0.3, < 0.0001). The mediation analysis did not support vitamin D as a mediator of the association between fish consumption and MS risk. There was no interaction between fish consumption and sun exposure habits with regard to MS risk.

Conclusions: Low fish consumption and low sun exposure seem to be separate risk factors for MS. Our findings suggest that fish consumption predominantly influences MS risk by other means than by effecting vitamin D status, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.
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http://dx.doi.org/10.1212/NXI.0000000000000717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176247PMC
May 2020

Blood neurofilament light levels segregate treatment effects in multiple sclerosis.

Neurology 2020 03 11;94(11):e1201-e1212. Epub 2020 Feb 11.

From the Department of Medicine Solna, Clinical Epidemiology Division (B.D.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience (A.M., I.K., T.O., F.P.), and Institute of Environmental Medicine (L.A.), Karolinska Institutet; Centre for Molecular Medicine (A.M., I.K., T.O., F.P.), Karolinska University Hospital, Stockholm, Sweden; Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research (C.B., Z.M., L.K., D.L., J.K.), and Clinical Trial Unit, Department of Clinical Research (P.B.), University Hospital Basel, University of Basel, Switzerland; Sanofi Genzyme (J.A.T.), Stockholm, Sweden; Biogen (T.P., B.C.K.), Cambridge, MA; Department of Neurology, Medical Faculty (B.C.K.), Heinrich-Heine University, Duesseldorf, Germany; and Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Sweden.

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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http://dx.doi.org/10.1212/WNL.0000000000009097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387108PMC
March 2020

Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis.

Front Immunol 2019 26;10:2715. Epub 2019 Nov 26.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, = 9 × 10), and increased risk of future MS (OR = 2.22, = 2 × 10). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, = 6 × 10). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, = 6 × 10). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB113:01-DQA101:03-DQB106:03 haplotype while the main association for IE1B was DRB113:02-DQA101:02-DQB106:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.
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http://dx.doi.org/10.3389/fimmu.2019.02715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988796PMC
November 2020

High Levels of Epstein-Barr Virus Nuclear Antigen-1-Specific Antibodies and Infectious Mononucleosis Act Both Independently and Synergistically to Increase Multiple Sclerosis Risk.

Front Neurol 2019 24;10:1368. Epub 2020 Jan 24.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Elevated levels of anti-EBNA-1 antibodies and infectious mononucleosis (IM) history have consistently been associated with multiple sclerosis (MS) risk. We aimed to study whether these aspects of Epstein-Barr virus (EBV) infection represent separate risk factors for MS and whether they both interact with MS-associated HLA genes in disease development. Two Swedish-population-based case-control studies were used, comprising 5,316 cases and 5,431 matched controls. Subjects with different HLA alleles, EBNA-1, and IM status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Causal mediation analysis was used to assess to what extent the relationship between IM history and MS risk was mediated by high anti-EBNA-1 antibody levels and vice versa. The causal mediation analysis revealed that both aspects of EBV infection mainly act directly on MS risk. The direct effect of elevated anti-EBNA-1 antibody levels on MS risk, expressed on the OR scale, was 2.8 (95% CI 2.5-3.1), and the direct effect of IM history on MS risk was 1.7 (95% CI 1.5-2.0). A significant interaction between the two aspects of EBV infection was observed (RERI 1.2, 95% CI 0.3-2.0), accounting for about 50% of the total effect. Further, both aspects of EBV infection interacted with DRB115:01 and absence of A02:01. Elevated anti-EBNA-1 antibody levels and IM history are different risk factors for MS. The two aspects of EBV infection act synergistically to increase MS risk, indicating that they partly are involved in the same biological pathways.
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http://dx.doi.org/10.3389/fneur.2019.01368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992610PMC
January 2020

Confounding effect of blood volume and body mass index on blood neurofilament light chain levels.

Ann Clin Transl Neurol 2020 01 1;7(1):139-143. Epub 2020 Jan 1.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Blood Neurofilament light chain (NfL) has been suggested as a promising biomarker in several neurological conditions. Since blood NfL is the consequence of leaked NfL from the cerebrospinal fluid, differences in individuals' Body Mass Index (BMI) or blood volume (BV) might affect its correlation to other biomarkers and disease outcomes. Here, we investigated the correlation between plasma NfL, BMI, and BV in 662 controls and 2,586 multiple sclerosis cases. We found a significant negative correlation between plasma NfL, BMI/BV in both groups. Our results highlight the potential confounding effect of BMI/BV on associations between blood NfL and disease outcomes.
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http://dx.doi.org/10.1002/acn3.50972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952306PMC
January 2020

Low sun exposure increases multiple sclerosis risk both directly and indirectly.

J Neurol 2020 Apr 17;267(4):1045-1052. Epub 2019 Dec 17.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Objective: We aimed to study (1) to what extent the influence of low sun exposure on multiple sclerosis (MS) risk is mediated by low vitamin D levels; (2) whether low sun exposure or vitamin D deficiency act synergistically with HLA-DRB1*15:01 and absence of HLA-A*02:01.

Methods: We used two population-based case-control studies (7069 cases, 6632 matched controls). Subjects with different HLA alleles, sun exposure habits and vitamin D status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Mediation analysis was used to identify the potential mediation effect of vitamin D on the relationship between low sun exposure and MS risk.

Results: Low sun exposure increased MS risk directly as well as indirectly, by affecting vitamin D status. The direct effect, expressed as OR, was 1.26 (95% CI 1.04-1.45) and the indirect effect, mediated by vitamin D deficiency, was 1.10 (95% CI 1.02-1.23). Of the total effect, nearly 30% was mediated by vitamin D deficiency. There was a significant interaction between low sun exposure and vitamin D deficiency (attributable proportion due to interaction 0.3, 95% CI 0.04-0.5) accounting for about 12% of the total effect. Further, both factors interacted with HLA-DRB1*15:01 to increase MS risk.

Interpretation: Our findings indicate that low sun exposure acts both directly on MS risk as well as indirectly, by leading to low vitamin D levels. The protective effect of sun exposure thus seems to involve both vitamin D and non-vitamin D pathways, which is of relevance for prevention, in particular for those with a genetic susceptibility to MS.
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http://dx.doi.org/10.1007/s00415-019-09677-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109160PMC
April 2020

A Gene-Environment Interaction Between Smoking and Gene polymorphisms Provides a High Risk of Two Subgroups of Sarcoidosis.

Sci Rep 2019 12 9;9(1):18633. Epub 2019 Dec 9.

Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.

The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren's syndrome (LS) and patients without Löfgren's syndrome (non-LS). To quantify smoking effects in sarcoidosis, we performed a gene-environment interaction study in a Swedish population-based case-control study consisting of 3,713 individuals. Cases and controls were classified according to their cigarette smoking status and genotypes by Immunochip platform. Gene-smoking interactions were quantified by an additive interaction model using a logistic regression adjusted by sex, age and first two principal components. The estimated attributable proportion (AP) was used to quantify the interaction effect. Assessment of smoking effects with inclusion of genetic information revealed 53 (in LS) and 34 (in non-LS) SNP-smoking additive interactions at false discovery rate (FDR) below 5%. The lead signals interacting with smoking were rs12132140 (AP = 0.56, 95% CI = 0.22-0.90), p = 1.28e-03) in FCRL1 for LS and rs61780312 (AP = 0.62, 95% CI = 0.28-0.90), p = 3e-04) in IL23R for non-LS. We further identified 16 genomic loci (in LS) and 13 (in non-LS) that interact with cigarette smoking. These findings suggest that sarcoidosis risk is modulated by smoking due to genetic susceptibility. Therefore, patients having certain gene variants, are at a higher risk for the disease. Consideration of individual's genetic predisposition is crucial to quantify effects of smoking in sarcoidosis.
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http://dx.doi.org/10.1038/s41598-019-54612-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901455PMC
December 2019

C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation.

J Clin Invest 2020 02;130(2):838-852

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS.
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http://dx.doi.org/10.1172/JCI125857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994148PMC
February 2020

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression.

Mol Psychiatry 2021 Aug 11;26(8):4179-4190. Epub 2019 Nov 11.

Department of Psychology, Humboldt-University Berlin, Berlin, Germany.

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10  × 10). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
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http://dx.doi.org/10.1038/s41380-019-0590-2DOI Listing
August 2021
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