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Grut, V. (2024). Exposures associated with multiple sclerosis development: presymptomatic case-control studies. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Exposures associated with multiple sclerosis development: presymptomatic case-control studies
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Exponeringar associerade med multipel skleros : presymptomatiska fall-kontrollstudier
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
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:nbn:se:umu:diva-224589 (URN)9789180703109 (ISBN)9789180703116 (ISBN)
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
Grut, V., Biström, M., Salzer, J., Stridh, P., Jons, D., Gustafsson, R., . . . Sundström, P. (2024). Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis. Brain, 147(1), 177-185
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
Grut, V., Biström, M., Salzer, J., Stridh, P., Jons, D., Gustafsson, R., . . . Sundström, P. (2024). Interactions between high seroreactivity to human herpes virus 6A and Epstein–Barr virus in MS development: a presymptomatic case–control study. Annals of Neurology
Open this publication in new window or tab >>Interactions between high seroreactivity to human herpes virus 6A and Epstein–Barr virus in MS development: a presymptomatic case–control study
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2024 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249Article in journal (Refereed) Epub ahead of print
Abstract [en]

Synergistic interactions between human herpesvirus 6A (HHV-6A) and Epstein–Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV-6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV-6A and EBNA-1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV-6A and EBV infections interact in MS development. ANN NEUROL 2024.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
National Category
Microbiology in the medical area Neurology
Identifiers
urn:nbn:se:umu:diva-226943 (URN)10.1002/ana.27009 (DOI)001243851600001 ()38860471 (PubMedID)2-s2.0-85195543916 (Scopus ID)
Funder
Swedish Research Council, 2015-02419Visare NorrRegion Jämtland HärjedalenThe Swedish Brain FoundationEU, Horizon 2020, 733161
Available from: 2024-06-25 Created: 2024-06-25 Last updated: 2024-07-02
Jons, D., Grut, V., Bergström, T., Zetterberg, H., Biström, M., Gunnarsson, M., . . . Andersen, O. (2023). Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage. Journal of Neurology, Neurosurgery and Psychiatry, Article ID 331868.
Open this publication in new window or tab >>Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
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2023 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, article id 331868Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens.

Methods: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury.

Results: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001). With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026).

Conclusions: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-215746 (URN)10.1136/jnnp-2023-331868 (DOI)001085444600001 ()37802637 (PubMedID)2-s2.0-85174051593 (Scopus ID)
Funder
Visare NorrRegion Jämtland HärjedalenSwedish Research Council, 2018-02532EU, European Research Council, 681712EU, European Research Council, 101053962Familjen Erling-Perssons StiftelseStiftelsen Gamla TjänarinnorThe Swedish Brain Foundation, FO2019-0228EU, Horizon 2020Swedish Research Council, 2017-00915The Swedish Brain Foundation, FO2017-0243NIH (National Institutes of Health), 1R01AG068398-01Knut and Alice Wallenberg FoundationEU, Horizon 2020, 733161Swedish Research Council, 2020-01638
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2024-07-02
Grut, V., Biström, M., Salzer, J., Stridh, P., Lindam, A., Alonso-Magdalena, L., . . . Sundström, P. (2022). Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis: A presymptomatic case-control study. European Journal of Neurology, 29(8), 2335-2342
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
Grut, V., Biström, M., Salzer, J., Stridh, P., Lindam, A., Alonso-Magdalena, L., . . . Sundström, P. (2022). Systemic inflammation and risk of multiple sclerosis: a presymptomatic case-control study. Multiple Sclerosis Journal, Experimental, Translational and Clinical, 8(4), 1-4
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
Grut, V., Biström, M., Salzer, J., Stridh, P., Jons, D., Gustafsson, R., . . . Sundström, P. (2021). Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis: a presymptomatic case–control study. European Journal of Neurology, 28(9), 3072-3079
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
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5415-6567

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