Gene variant plus mono raises MS risk: Large-scale study
Interaction seen independent of other MS-related variants
The risk of multiple sclerosis (MS) is significantly higher in people who carry a variant of the HLA gene called HLA-E*01:01 and have a history of infectious mononucleosis (mono), the manifestation of an Epstein-Barr virus (EBV) infection, according to a study based on U.K. Biobank data.
The higher MS risk tied to HLA-E*01:01, which was not found among those without records of a mono diagnosis, was independent of other MS-related HLA gene variants.
“Understanding this interaction could offer new insights into the gene-environment mechanisms underlying MS development and help identify individuals at higher risk based on HLA genotypes [genetic profiles] and IM [infectious mononucleosis] history,” the researchers wrote.
The study, “Stratifying Multiple Sclerosis Susceptibility Risk: The Role of HLA-E*01 and Infectious Mononucleosis in a Population Cohort,” was published in the European Journal of Neurology.
MS is marked by inflammatory attacks against healthy parts of the brain and spinal cord. These attacks damage the myelin sheath, a fatty coating around nerve fibers, ultimately causing MS symptoms.
Focus on gene variant
EBV infection is “a key environmental trigger” of MS, “with infectious mononucleosis (IM), its symptomatic manifestation, being strongly associated with increased MS risk,” the researchers wrote.
It’s thought that certain EBV proteins have a similar shape to proteins within the myelin sheath. So when immune cells make antibodies to fight the virus, they mistakenly target the myelin sheath.
Because most people have been infected with EBV but only a few develop MS, unique genetics is likely to be involved in disease susceptibility.
HLA is a family of genes that help the immune system discern infectious agents from healthy tissues. In the context of MS, people carrying HLA-DRB1*15:01, a form, or allele, of an HLA gene, have a higher risk of the autoimmune disorder, while those with the HLA-A*02:01 allele appear to be protected.
MS research has recently focused on the HLA-E gene, which include two alleles: HLA-E*01:01 and HLA-E*01:03. Cell-based studies suggest that HLA-E*01:03, but not HLA-E*01:01, may protect against MS.
At the same time, no connection between HLA-E*01:01 and MS was found in genome-wide association studies (GWAS), which look for statistical links between genetic variants and a given feature or disease.
The team of researchers in Italy and France who performed the study said they “hypothesized that the association between HLA-E*01 and MS risk may be modified by the presence of a significant immune response triggered by EBV, such as the occurrence of IM.”
To test this, they analyzed data from 487,144 people from the U.K. Biobank, of whom 3,855 (0.8%) had records of a mono diagnosis and 2,491 (0.5%) had records of a diagnosis of MS.
Statistical analyses adjusted for potential influencing demographic and genetic factors, including HLA-DRB1*15:01, showed that carrying the HLA-E*01:01 allele alone was not significantly associated with mono or MS, which was consistent with GWAS data.
Still, people who carried HLA-E*01:01 and had a history of mono showed a significantly higher risk of MS. Among people with a history of mono, the risk of MS was increased by 1.74 times in those with one copy of the HLA-E*01:01 allele and by three times among those with two HLA-E*01:01 copies, compared with those carrying two HLA-E*01:03 copies.
On the other hand, HLA-E*01:01 was not significantly associated with MS risk in people without a history of mono.
Significant link
In line with previous findings, the researchers confirmed a significant link between the HLA-DRB1*15:01 MS risk allele and a mono diagnosis but not between the absence of the MS protective HLA-A*02:01 allele.
“This highlights how HLA-E*01:01 alleles further increase MS risk through their interaction with IM independently from the interaction already taking place between IM and HLA-DRB1*15:01 alleles,” the researchers wrote.
They found the risk of MS with a mono diagnosis increased further for those with HLA-E*01:01 and any combination of the HLA-DRB1*15:01 and HLA-A*02:01 alleles.
The overall findings remained the same when the team excluded 761 people with late-onset MS (older than 50) or 46,870 individuals born outside the U.K.
“These findings suggest that HLA-E*01 is associated with increased MS risk in EBV-infected individuals diagnosed with IM,” the researchers wrote. “If confirmed, HLA-E*01:01 screening, along with other MS-related alleles, could improve MS risk assessment and become a key tool for targeted monitoring and early detection strategies in EBV-exposed individuals, particularly those with a history of IM diagnosis.”
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