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Updated: Jul 4, 2025
Isolation and Quantification of Epstein-Barr Virus from the P3HR1 Cell Line
Published on: September 28, 2022
Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis
Amin Ziaei1, Olivia Solomon2, T Charles Casper3
1University of California San Francisco, San Francisco, CA, USA/Department of Pathology & Laboratory Medicine, University of California, Irvine Medical Center (UCIMC), Orange, CA, USA.
Insights
Epstein-Barr virus (EBV) infection interacts with specific genetic variants, increasing the risk of pediatric-onset multiple sclerosis (POMS). These findings highlight the role of antigen-presenting cells in EBV-associated POMS.
Area of Science:
- Neuroimmunology
- Genetics
- Infectious Disease Epidemiology
Background:
- Epstein-Barr virus (EBV) infection is a known risk factor for multiple sclerosis (MS), both in adults and children.
- Understanding the biological mechanisms linking EBV to MS, particularly pediatric-onset MS (POMS), remains a challenge.
Purpose of the Study:
- To investigate the interactions between human leukocyte antigen (HLA) and non-HLA genetic variants and childhood EBV infection.
- To gain mechanistic insights into the association between EBV and POMS.
Main Methods:
- Utilized data from the Environmental and Genetic Risk Factors for Pediatric MS study.
- Assessed EBV-viral capsid antigen (VCA) serostatus in 473 POMS cases and 702 controls.
- Employed logistic regression to evaluate associations and interactions between EBV serostatus, HLA, and non-HLA variants, adjusting for covariates.
Main Results:
- Higher anti-VCA seropositivity was observed in POMS cases (94.6%) compared to controls (60.7%).
- Evidence of additive interaction was found between childhood EBV infection and the HLA-DRB1*15 allele (RERI=10.25).
- Multiplicative interaction was detected between EBV infection and HLA-DRB1*15 alleles (OR=3.43).
- Additive interaction was also observed between EBV infection and the GG genotype of the CD86 risk variant (rs2255214) (AP=0.30).
Conclusions:
- Childhood EBV infection interacts with the HLA-DRB1*15 allele and the CD86 risk variant (GG genotype) in POMS.
- These interactions suggest a significant role for antigen-presenting cells in the pathogenesis of EBV-associated POMS.
Background And Objective:
Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS.
Methods:
Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs).
Results:
A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58).
Conclusion:
We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.
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