| 1. |
- Biström, Martin, et al.
(författare)
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Epstein-Barr virus infection after adolescence and Human herpesvirus 6A as risk factors for multiple sclerosis
- 2021
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Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 28:2, s. 579-586
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Infections with human herpesvirus 6A (HHV-6A) and Epstein–Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS.Methods: In this nested case–control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.Results: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6–2.7).Conclusions: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.
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| 2. |
- Biström, Martin, et al.
(författare)
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High serum concentration of vitamin D may protect against multiple sclerosis
- 2019
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Ingår i: Multiple Sclerosis Journal, Experimental, Translational and Clinical. - : Sage Publications. - 2055-2173. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals.Objective: Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent.Methods: Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry.Results: High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93).Conclusion: These findings further support a role for vitamin D in MS aetiology.
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| 3. |
- Biström, Martin, 1982-, et al.
(författare)
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Leptin levels are associated with multiple sclerosis risk
- 2021
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Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 27:1, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing-remitting multiple sclerosis (RRMS). Methods: In this nested case-control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1-1.9) and in all men (OR = 1.4, 95% CI = 1.0-2.0). In contrast, for women aged 30-39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54-1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.
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| 4. |
- Grut, Viktor, et al.
(författare)
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Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis : a presymptomatic case-control study
- 2021
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Ingår i: European Journal of Neurology. - : Blackwell Publishing. - 1351-5101 .- 1468-1331. ; 28:9, s. 3072-3079
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 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, we sought to increase the understanding of CMV in MS aetiology.METHODS: We performed a nested case-control study with presymptomatically collected blood samples identified through cross-linkage 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 intervals (CI) for CMV seropositivity as 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 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: CMV 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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| 5. |
- Grut, Viktor, et al.
(författare)
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Free vitamin D3 index and vitamin D-binding protein in multiple sclerosis : A presymptomatic case-control study
- 2022
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 29:8, s. 2335-2342
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Grut, Viktor, et al.
(författare)
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Systemic inflammation and risk of multiple sclerosis – A presymptomatic case-control study
- 2022
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Ingår i: Multiple Sclerosis Journal - Experimental, Translational and Clinical. - : SAGE Publications. - 2055-2173. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Jons, Daniel, 1974, et al.
(författare)
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Axonal injury in asymptomatic individuals preceding onset of multiple sclerosis
- 2022
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 9:6, s. 882-887
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Tidskriftsartikel (refereegranskat)abstract
- Axonal loss is the main cause of irreversible disability in multiple sclerosis (MS). Serum neurofilament light (sNfL) is a biomarker of axonal disintegration. In this nested case-control study, blood samples from 519 presymptomatic persons (age range 4-39 years) who later received an MS diagnosis showed higher sNfL concentrations than 519 matched controls (p < 0.0001), noticeable at least 10 years before clinical MS onset. Mean values for pre-MS and control groups were 9.6 pg/mL versus 7.4 pg/mL 0-5 years before onset, and 6.4 pg/mL versus 5.8 pg/mL 5-10 years before onset. These results support that axonal injury occurs early in MS pathogenesis.
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| 8. |
- Jons, Daniel, et al.
(författare)
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Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage
- 2023
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 1468-330X .- 0022-3050.
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Biström, Martin, 1982-
(författare)
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Environmental risk factors for the occurrence of multiple sclerosis
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 10. |
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