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Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-3994-2305
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2715Article in journal (Refereed) Published
Abstract [en]

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, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). 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 DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. 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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019. Vol. 10, article id 2715
Keywords [en]
Epstein-Barr virus, association, human herpesvirus 6A, human herpesvirus 6B, human leukocyte antigen, multiple sclerosis, risk, serology
National Category
Microbiology in the medical area Neurology
Identifiers
URN: urn:nbn:se:umu:diva-169073DOI: 10.3389/fimmu.2019.02715PubMedID: 32038605Scopus ID: 2-s2.0-85076683059OAI: oai:DiVA.org:umu-169073DiVA, id: diva2:1415734
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2020-03-24Bibliographically approved
In thesis
1. Environmental risk factors for the occurrence of multiple sclerosis
Open this publication in new window or tab >>Environmental risk factors for the occurrence of multiple sclerosis
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that typically debuts around age 30. About 2.3 million people are affected in the world today, and besides trauma it is the most common cause of neurological disability among young adults in the western world. The disease likely develops via a complex interplay of genetic vulnerability and environmental risk factors, and adolescence is assumed to be a critical time for disease initiation. The aim of this study was to investigate how MS risk in different age groups is influenced by vitamin D, infections with Epstein-Barr virus and Human herpesviruses 6A and B as well as the metabolic markers leptin and insulin.

Methods. In this nested case-control study we identified pre-symptomatically drawn blood samples from individuals below age 40, that later developed relapsing remitting MS. This was done through crosslinking of the Swedish MS registry, or a local database, with six Swedish biobanks containing remainders of samples used in microbiological analyses. For each case, one control matched for biobank, sex, date of sampling and age of sampling was selected. These samples were then analysed to determine antibody reactivity against Epstein-Barr virus and Human herpesvirus 6A and B, as well as measure concentrations of leptin, insulin and 25-hydroxyvitamin D. The effect of these variables on MS risk was estimated using conditional logistic regression, both in the entire case-control material as well as stratified into three groups by age at sampling (<20, 20-29 and 30-39) and by sex.

Results. Human herpesvirus 6A, but not B, was consistently associated with an increased risk of developing MS. In contrast, Epstein-Barr virus demonstrated an age dependent pattern indicating that early infection may be protective against MS while later infection increases the risk. As for the metabolic markers, insulin was not associated with MS while elevated levels of leptin showed an association with increased MS risk both among individuals below 20 years of age and among all men. For women there was instead an inverse association in the oldest group, aged 30-39, when adjusting the leptin analysis for insulin concentrations. Finally, having vitamin D concentrations in the top quintile was associated with decreased MS risk, without evidence of a stronger effect in young subjects.

Conclusion. These results implicate Human herpesvirus 6A and leptin as risk factors for MS development. They also further support a protective role for vitamin D in MS etiology and provide serological evidence of an age dependency of Epstein-Barr virus infection as it relates to MS risk.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2020. p. 61
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2076
Keywords
Multiple sclerosis, risk factors, epidemiology, case-control study, Human herpesvirus 6A, Human herpesvirus 6B, leptin, insulin, Epstein-Barr virus, vitamin D
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-169158 (URN)978-91-7855-225-2 (ISBN)978-91-7855-224-5 (ISBN)
Public defence
2020-04-17, Hörsal B, Målpunkt T, vån 9, NUS, Umeå, 09:00 (Swedish)
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Supervisors
Available from: 2020-03-27 Created: 2020-03-23 Last updated: 2020-03-24Bibliographically approved

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Biström, MartinSundström, Peter

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