Overweight/obese levels of BMI at age 20, paired with history of infectious mononucleosis (IM) or high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels, synergize in elevating the risk of multiple sclerosis (MS), and the effect strengthens with increasing antibody levels, according to study results published in Neurology: Neuroimmunology & Neuroinflammation. Results also indicated significant 3-way additive interactions between DRB1*15:01 allele, BMI at age 20 years, and each aspect of Epstein Barr virus (EBV) infection.
The study researchers sought to find out whether these MS risk factors had an additive interaction for the inflammatory disease, and to analyze 3-way interactions between BMI at age 20, EBV infection, and the human leukocyte antigen (HLA)-DRB1* 15:01 allele.
They used data from the Epidemiological Investigation of Multiple Sclerosis (EIMS) and Genes and Environment in Multiple Sclerosis (GEMS) studies, 2 Swedish population-based case-control studies on environmental and genetic risk factors for MS. In the former, newly diagnosed cases of MS were recruited from neurology clinics and matched with 2 randomly selected controls from the country’s national population register, frequency matched in 5-year age strata, sex, and residential area. GEMS presented prevalent cases of MS from the Swedish National MS Registry, each of whom was matched with 1 control in the same way as in EIMS.
The study researchers also included controls from the Epidemiological Investigation of Rheumatoid Arthritis, which was designed in the same manner and with a similar study population as EIMS. Participants provided blood samples for the genotyping and self-reported contraction of IM, body height, and weight.
The combination of two risk factors, overweight/obesity at age 20 years and a history of IM, synergistically increased the risk of MS 5-fold. In contrast, nonoverweight subjects with IM history had a 90% increased risk of MS and those with overweight/obesity at age 20 years (BMI I ≥25 kg/m2) without IM history had a 40% increased MS risk.
BMI at age 20 years and high EBNA-1 antibody levels, even without history of IM, had a similar interaction that increased with elevated EBNA-1 antibody levels.
2-way interactions were present between DRB1*15:01 and overweight/obesity at age 20 years, between DRB1*15:01 and each aspect of EBV infection, and between overweight/obesity at age 20 years and each aspect of EBV infection. DRB1*15:01, BMI at age 20 years, and each aspect of EBV infection (IM history and high EBNA-1 antibody levels, respectively) had significant 3-way interactions.
These findings held significant for both EIMS and GEMS when investigators restricted the analysis to subjects with complete data on HLA alleles and EBNA-1 antibody levels.
Limitations of the study included selection bias and recall bias in the studies and risk of misclassification when dichotomizing subjects into those with and without self-reported IM history.
The study researchers concluded, “The obese state both induces a chronic immune-mediated inflammation and affects the cellular immune response to infections, which may contribute to explain our findings.” They added that their “data reinforce the importance of intervention efforts against childhood and adolescent obesity to reduce MS incidence.”
Disclosure: Several authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Hedström AK, Brenner N, Butt J, et al. Overweight/obesity in young adulthood interacts with aspects of EBV infection in MS etiology. Neurol Neuroimmunol Neuroinflamm. Published online December 15, 2020. doi:10.1212/NXI.0000000000000912