Abstract
BACKGROUND: Epstein-Barr Virus (EBV) and its clinical manifestation, infectious mononucleosis (IM), are strongly linked to MS risk. A recent in vitro study suggests that HLA-E*01:03, in contrast to HLA-E*01:01, may protect against MS through more effective immune responses against EBV-infected B cells. However, the role of HLA-E*01 in MS remains unclear. METHODS: We investigated if HLA-E*01:01 was significantly associated with higher MS risk in individuals with a history of IM diagnosis, using 487,144 individuals from the UK Biobank's cohort. We estimated the interaction between HLA-E*01:01 and IM using Cox proportional hazard models, adjusting for demographics, smoking, childhood body size, older siblings, and MS-related HLA alleles (e.g., HLA-DRB1*15:01). RESULTS: HLA-E*01:01 allele alone was not significantly associated with IM or MS (p > 0.05). However, a significant interaction between HLA-E*01:01 and IM history was observed in relation to MS risk (p < 0.001). Specifically, MS risk was significantly higher in both HLA-E*01:01 heterozygotes (HR = 1.74 [95% CI: 1.36, 1.97], p < 0.001) and homozygotes (HR = 3.01 [95% CI: 1.81, 3.88], p < 0.001) with IM history, compared to HLA-E*01:03 homozygotes. Conversely, these associations were non-significant in individuals without IM history (p > 0.05). The estimated proportion of the combined risk attributable to interaction effects was 40% in HLA-E*01:01 heterozygotes and 65% in HLA-E*01:01 homozygotes. CONCLUSIONS: HLA-E*01:01 carriers diagnosed with IM are at significantly increased risk of MS, independently from other MS-related HLA alleles. This supports the hypothesis that HLA-E*01:01 may contribute to MS susceptibility due to weaker immune control over EBV infection. Incorporating HLA-E*01:01 into existing MHC-based MS risk models could then enhance personalized risk assessments in individuals with IM history.