Genetic Variants May Explain High Levels of Antibodies Against Epstein-Barr Virus in MS, Study Suggests

Genetic variants may contribute to increased levels of antibodies against proteins of the Epstein-Barr virus — a known environmental risk factor for multiple sclerosis (MS) — in MS patients and their siblings, a study suggests.

The study, “EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution,” was published in the journal Neurology, Neuroimmunology and Neuroinflammation.

The risk of developing MS is influenced by genetic and environmental factors. A meta-analysis with twins revealed that environmental factors can influence 21% of the risk for MS, with the major factor being infection with the Epstein-Barr virus (EBV, a common form of the herpes virus).

Moreover, heritable genetic traits influence the production of antibodies (also called immunoglobulins or Ig) against antigens (proteins that trigger an immune response) of EBV.

One such antibody type, called IgG, is directed against the EBV nuclear antigen 1 or EBNA-1.

In the new study, researchers at Erasmus University Medical Center, in the Netherlands, measured IgG levels against EBNA-1 in blood samples of MS patients, their healthy siblings, and biologically unrelated healthy spouses who served as controls.

The team also quantified the antibody levels against the varicella zoster virus (VZV) as an additional control. VZV is an herpes virus not associated with the development of MS.

In total, researchers analyzed 301 patients with MS (mean age 46.9 years), their 198 unaffected siblings (mean age 51.7 years), and 174 unrelated healthy spouses (mean age 51.1 years).

Among MS patients, the majority (207 patients, corresponding to 68.8%) were diagnosed with relapsing-remitting MS (RRMS), followed by secondary progressive MS (SPMS, 41 patients, 13.6%), primary progressive MS (PPMS, 38 patients, 12.6%), and clinically isolated syndrome (CIS, 15 patients, 5.0%).

Results showed that MS patients had higher levels of EBNA-1 IgG compared to their spouses and siblings. No differences were seen in IgG levels against VZV across the three groups.

Since patients with MS were significantly younger than their siblings and spouses, the researchers assessed whether age influenced the results, and they found higher levels of EBNA-1 IgG in younger patients (mean age 48.3 years) and lower levels in older participants (mean age 50.6 years).

When stratifying MS patients by age — patients younger than 50 years and patients 50 or older — researchers saw that young MS patients had higher EBNA-1 IgG titers.

Young MS patients were 2.7 times more likely to have high EBNA-1 IgG titers compared with their siblings. Patients older than 50 also had an increased risk for high EBNA-1 titers compared with their spouses and older siblings.

No link was found between EBNA-1 levels and gender, clinical disease course, or disease duration. Also, no changes were seen across the different age groups for VZV antibody titers.

The HLA-DRB1 gene provides instructions for making a protein with a critical role in immune system activation. Previous research has shown that variants of this gene can influence the risk of MS in adults, with the HLA-DRB1*15:01 variant increasing nearly three times this risk.

The researchers therefore analyzed the HLA-DRB1*15:01 variant and saw that it was more frequent in MS patients (39%) and their siblings (28%) when compared to spouses (17%). The genetic variant was associated with a 4.2 times higher risk of MS and also with elevated EBNA-1 IgG levels in patients and their siblings.

The VZV antibody titers showed no association with the HLA-DRB1*15:01 variant.

The risk for high EBNA-1 IgG levels was higher in younger MS patients compared to their spouses, independently of the HLA-DRB1*15:01 variant; while in older patients, high EBNA-1 IgG levels were seen in patients positive for the HLA-DRB1*15:01 variant.

Another genetic variant, named HLA-A*02, showed no association with MS or EBNA-1 IgG titers, even when accounting for age.

Based on the results, the team suggested that an MS diagnosis is an independent risk factor for high EBNA-1 IgG titers, regardless of whether the patient had an HLA-DRB1*15:01 variant.

Nonetheless, young (under 50 years of age) relatives of MS patients had an increased risk for elevated EBNA-1 IgG, which highlights how heritable genetic factors may influence the immune system’s response against EBV.

“In summary, our study showed that EBNA-1 IgG titers were highest in patients with MS, intermediate in siblings, and low in spouses, which suggests a strong genetic contribution on the EBNA-1 response that is partially associated with HLA-DRB1*1501,” the researchers wrote.

Further genetic studies are required to assess how genetics impacts the levels of EBNA-1 IgG response in MS, the team noted.