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Exposures associated with multiple sclerosis development: presymptomatic case-control studies
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. (Peter Sundströms forskargrupp)ORCID iD: 0000-0002-5415-6567
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Exponeringar associerade med multipel skleros : presymptomatiska fall-kontrollstudier (Swedish)
Abstract [en]

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease affecting the central nervous system. The current view is that MS is caused by a complex interplay of several environmental factors, eliciting an immune reaction in genetically susceptible individuals. Most previous studies of MS aetiology were retrospective, conferring the risk of reverse causation or recall bias. Few studies have been performed on data collected before the onset of the disease. The objective of this project was to identify risk factors for MS by analysing markers of exposure in samples collected before the clinical onset of MS.

Method: A series of nested case-control studies were performed by cross-linking Swedish MS registries with Swedish biobanks, thereby identifying serum or plasma samples from up to 837 cases who later developed MS. For each case, up to two matched controls were selected. The following environmental risk factors were assessed: Antibodies against herpesviruses Epstein-Barr virus (EBV), Human herpesvirus 6A (HHV-6A) and Cytomegalovirus (CMV); Free Vitamin D3 Index and Vitamin D Binding Protein (DBP); and C-reactive Protein (CRP). Early signs of neural injury were assessed by measuring the concentration of neurofilament light chain in serum (sNfL). The associations between the environmental factors and future development of MS were analysed with conditional logistic regression, calculating odds ratios (OR) with 95% confidence intervals (CI). Interactions were analysed on the multiplicative and additive scales. The temporal relation of HHV-6A serostatus and axonal injury was analysed with locally estimated scatterplot smoothing regression.

Results: Serological evidence of CMV infection was associated with a lower risk of MS development (OR = 0.70, 95% CI 0.56–0.88). Antagonistic interactions were observed between serological signs of CMV, HHV-6A, and EBV infection. Antibodies against HHV-6A were associated with a higher level of sNfL. In MS cases, increasing levels of HHV-6A antibodies were detected several years before increasing sNfL. Among young individuals, high levels of Free Vitamin D3 Index were associated with a lower MS risk (OR = 0.37, 95% CI 0.15–0.91). In older individuals, high levels of DBP were associated with a lower risk of developing MS (OR = 0.36, 95% CI 0.15–0.85). Elevated levels of CRP were not associated with MS risk.

Conclusions: These results strengthen the evidence for HHV-6A and EBV in MS aetiology. They also support the hypothesis that CMV infection and a high level of free Vitamin D3 during childhood and adolescence are associated with a lower risk of MS later in life. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 86
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2289
Keywords [en]
multiple sclerosis, risk factors, epidemiology, nested case-control study, Cytomegalovirus, Human herpesvirus 6A, Epstein-Barr virus, systemic inflammation, vitamin D, Vitamin D binding protein
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-224589ISBN: 9789180703109 (print)ISBN: 9789180703116 (electronic)OAI: oai:DiVA.org:umu-224589DiVA, id: diva2:1859104
Public defence
2024-06-14, Hörsal B, våning 9, byggnad 1D, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-05-24 Created: 2024-05-20 Last updated: 2024-05-21Bibliographically approved
List of papers
1. Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis: a presymptomatic case–control study
Open this publication in new window or tab >>Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis: a presymptomatic case–control study
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2021 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 28, no 9, p. 3072-3079Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
case–control studies, cytomegalovirus, herpesviruses, multiple sclerosis, serology
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-186837 (URN)10.1111/ene.14961 (DOI)000666872100001 ()34107122 (PubMedID)2-s2.0-85112301681 (Scopus ID)
Available from: 2021-08-30 Created: 2021-08-30 Last updated: 2024-07-02Bibliographically approved
2. Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: A presymptomatic case-control study
Open this publication in new window or tab >>Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: A presymptomatic case-control study
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2022 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 8, p. 2335-2342Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: High levels of 25-hydroxyvitamin D3 (25[OH]D3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D3 and DBP as risk factors for MS.

METHODS: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D3 was approximated as free vitamin D3 index: (25[OH]D3 /DBP) × 103 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: Serum samples from 660 pairs of matched cases and controls were included. At <20 years of age, high levels of free vitamin D3 index were associated with a lower risk of MS (highest vs. lowest quintile: OR = 0.37, 95% CI = 0.15-0.91, p for trend across quintiles = 0.04). At age 30-39 years, high levels of DBP were associated with a lower MS risk (highest vs. lowest quintile: OR = 0.36, 95% CI = 0.15-0.85, p for trend = 0.02).

CONCLUSIONS: These findings support the hypothesis that high levels of free 25(OH)D3 at a young age reduce the risk of MS later in life. They also implicate a role for DBP in MS etiology.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
case-control studies, multiple sclerosis, vitamin D, vitamin D-binding protein
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-202379 (URN)10.1111/ene.15407 (DOI)000805801300001 ()35582958 (PubMedID)2-s2.0-85131168703 (Scopus ID)
Funder
Region Jämtland Härjedalen, JLL-939768Visare NorrSwedish Research Council, 2015-02419
Available from: 2023-01-09 Created: 2023-01-09 Last updated: 2024-07-02Bibliographically approved
3. Systemic inflammation and risk of multiple sclerosis: a presymptomatic case-control study
Open this publication in new window or tab >>Systemic inflammation and risk of multiple sclerosis: a presymptomatic case-control study
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2022 (English)In: Multiple Sclerosis Journal, Experimental, Translational and Clinical, E-ISSN 2055-2173, Vol. 8, no 4, p. 1-4Article in journal (Refereed) Published
Abstract [en]

Background: C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS).

Objectives: To assess CRP as a risk factor for MS.

Methods: Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z-scored CRP values.

Results: Levels of CRP were not associated with MS risk.

Conclusions: We found no association between CRP levels and risk of MS development.

Place, publisher, year, edition, pages
Sage Publications, 2022
Keywords
C-reactive protein, Case-control studies, multiple sclerosis, systemic inflammation
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-201466 (URN)10.1177/20552173221139768 (DOI)000927944400001 ()2-s2.0-85142702455 (Scopus ID)
Funder
Swedish Research Council, 2015-02419Visare Norr, 940405Region Jämtland Härjedalen, JLL-939768
Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2024-07-02Bibliographically approved
4. Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
Open this publication in new window or tab >>Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
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2024 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 147, no 1, p. 177-185Article in journal (Refereed) Published
Abstract [en]

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A.

A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI).

Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis).

In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
axonal injury, Epstein-Barr virus, human herpesvirus 6-A, multiple sclerosis, neurofilament light chain
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-219831 (URN)10.1093/brain/awad374 (DOI)001129461500001 ()37930324 (PubMedID)2-s2.0-85181761078 (Scopus ID)
Funder
Swedish Research Council, 2015-02419Visare NorrRegion Jämtland Härjedalen, JLL-967380The Swedish Brain FoundationEU, Horizon 2020, 733161Swedish Research Council, 2017-00915Swedish Research Council, 2022-00732
Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-07-02Bibliographically approved

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Grut, Viktor

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