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November 2017; 4 (6) ArticleOpen Access

Elevated EBNA-1 IgG in MS is associated with genetic MS risk variants

Karim L. Kreft, Gijsbert P. Van Nierop, Sandra M.J. Scherbeijn, Malou Janssen, Georges M.G.M. Verjans, Rogier Q. Hintzen
First published October 13, 2017, DOI: https://doi.org/10.1212/NXI.0000000000000406
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Abstract

Objective: To assess whether MS genetic risk polymorphisms (single nucleotide polymorphism [SNP]) contribute to the enhanced humoral immune response against Epstein-Barr virus (EBV) infection in patients with MS.

Methods: Serum anti-EBV nuclear antigen 1 (EBNA-1) and early antigen D (EA-D) immunoglobulin γ (IgG) levels were quantitatively determined in 668 genotyped patients with MS and 147 healthy controls. Anti–varicella-zoster virus (VZV) IgG levels were used as a highly prevalent, non-MS–associated control herpesvirus. Associations between virus-specific IgG levels and MS risk SNPs were analyzed.

Results: IgG levels of EBNA-1, but not EA-D and VZV, were increased in patients with MS compared with healthy controls. Increased EBNA-1 IgG levels were significantly associated with risk alleles of SNP rs2744148 (SOX8), rs11154801 (MYB), rs1843938 (CARD11), and rs7200786 (CLEC16A/CIITA) in an interaction model and a trend toward significance for rs3135388 (HLA-DRB1*1501). In addition, risk alleles of rs694739 (PRDX5/BAD) and rs11581062 (VCAM1) were independently associated and interacted with normal EBNA-1 IgG levels. None of these interactions were associated with EA-D and VZV IgG titers.

Conclusions: Several MS-associated SNPs significantly correlated with differential IgG levels directed to a latent, but not a lytic EBV protein. The data suggest that the aforementioned immune-related genes orchestrate the aberrant EBNA-1 IgG levels.

GLOSSARY

CI=
confidence interval;
EA-D=
early antigen D;
EBNA-1=
Epstein-Barr nuclear antigen 1;
EBV=
Epstein-Barr virus;
HC=
healthy control;
HLA=
human leukocyte antigen;
IgG=
immunoglobulin γ;
IM=
infectious mononucleosis;
miR=
micro RNA;
NF-κB=
nuclear factor kappa B;
OR=
odds ratio;
SNP=
single nucleotide polymorphism;
VCA=
viral capsid antigen;
VLA-4=
very late antigen 4;
VZV=
varicella-zoster virus

Footnotes

  • ↵* These authors contributed equally to this study.

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by Neurology® Neuroimmunology & Neuroinflammation.

  • Supplemental data at Neurology.org/nn

  • Received December 20, 2016.
  • Accepted in final form July 31, 2017.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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