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Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis: a presymptomatic case–control study
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-5415-6567
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-3994-2305
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-9205-0771
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
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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. Vol. 28, no 9, p. 3072-3079
Keywords [en]
case–control studies, cytomegalovirus, herpesviruses, multiple sclerosis, serology
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-186837DOI: 10.1111/ene.14961ISI: 000666872100001PubMedID: 34107122Scopus ID: 2-s2.0-85112301681OAI: oai:DiVA.org:umu-186837DiVA, id: diva2:1588884
Available from: 2021-08-30 Created: 2021-08-30 Last updated: 2024-07-02Bibliographically approved
In thesis
1. Exposures associated with multiple sclerosis development: presymptomatic case-control studies
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)
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Supervisors
Available from: 2024-05-24 Created: 2024-05-20 Last updated: 2024-05-21Bibliographically approved

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Grut, ViktorBiström, MartinSalzer, JonatanLindam, AnnaSundström, Peter

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