Integrating risk factors

Jager, Philip L. De; Simon, Kelly Claire; Munger, Kassandra L.; Rioux, John D.; Hafler, David A.; Ascherio, Alberto

doi:10.1212/01.wnl.0000294325.63006.f8

Cited by 165 publications

(132 citation statements)

References 23 publications

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“…We report several additional meaningful interactions that modify the association between EBV and pediatric MS. First, in line with previous reports, we observed that prior EBV infection is a stronger risk factor in carriers of HLA ‐ DRB1 * 15:01 7, 22. Although, this synergistic effect suggests possible causality of EBV infection in MS development, there is also a possibility that carrying HLA ‐ DRB1 * 15:01 affects both the risk of MS and susceptibility to EBV infection.…”

Section: Discussionsupporting

confidence: 91%

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWhile prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.MethodsCases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status.ResultsA total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status.Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

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Section: Discussionsupporting

confidence: 91%

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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“…It was shown that presence of high EBNA1 IgG levels was associated with higher risk for MS among DRB1*15-positive individuals compared with DRB1*15 negative individuals. 12,13 But causal interaction, that is, departure from additivity was not tested in these studies as we have shown here. These interactions have been suggested by previous smaller studies but have not been formally tested.…”

Section: Discussionmentioning

confidence: 81%

Epstein-Barr virus and multiple sclerosis: interaction with HLA

et al. 2011

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Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM)and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR) ¼ 1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR ¼ 1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR ¼ 3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.

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“…For example, changes in the patterns of demyelination/regeneration or axonal loss in MS patients carrying different HLA haplotypes may lead to different accumulation of lesions and/or brain atrophy, with subsequent heterogeneity of MRI features. 15 Although we did not specifically look at haplotype analysis, it is reasonable to believe that other HLA allele combinations do exist and they may also explain the heterogeneity of MS clinical expressions, such as the responsiveness to treatment as previously reported by single HLA allele associations 17,[29][30][31] and the different clinical forms and disabilities.…”

Section: Hla Alleles and Mri In Ms M Liguori Et Almentioning

confidence: 88%

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

et al. 2010

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Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P ¼ 0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P ¼ 0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P ¼ 0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P ¼ 0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

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Integrating risk factors

Abstract: Anti-Epstein-Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS.

Cited by 165 publications

References 23 publications

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Epstein-Barr virus and multiple sclerosis: interaction with HLA

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

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