HLA-DRB1 Gene Variants Seen to Influence Risk, Activity of Pediatric-onset MS

A variant of the HLA-DRB1 gene — called HLA-DRB1*03 — appears to predispose people to developing multiple sclerosis (MS) in childhood, and to correlate with greater disease activity among those who do, a study in Greek patients suggests.

The research also points to a protective role of one other variant of this gene, HLA-DRB1*11, which was significantly less common in pediatric-onset MS patients than in the general population.

These findings were detailed in “HLA-DRB1 allele impact on pediatric multiple sclerosis in a Hellenic cohort,” a study published in the Multiple Sclerosis Journal – Experimental, Translational and Clinical.

The HLA-DRB1 gene provides instructions for making a protein with a critical role in immune system activation. It is essentially found at the surface of certain immune cells, where it tells other immune system cells what their targets are, helping them to distinguish invaders from the body’s own cells.

Given its role in immunity, variants of this gene have been shown to influence the risk of MS in adults, with the HLA-DRB1*15:01 variant increasing nearly three times this risk, and variants like HLA-DRB1*16 protecting people from the disease. (A gene variant describes any change — benign or disease-causing — in the DNA sequences that compose a gene.)

Studies in pediatric-onset MS (POMS) patients are more scarce, but also point to associations between HLA-DRB1 gene variants and disease risk. But whether these variants also influence disease course and age at onset remains unknown.

A team led by researchers at the National and Kapodistrian University of Athens examined a group of 50 patients of Greek origin with pediatric-onset MS (mean age at onset, 15.3). Most had relapsing-remitting disease (39 patients), and the remaining 11 had secondary progressive MS.

Using blood samples from each patient, the team assessed which HLA-DRB1 gene variants were present. Because every person has two copies of the HLA-DRB1 gene (one inherited from the mother, and one from the father), patients could either have two copies of same variant, or one copy of two distinct variants.

A group of 144 adult-onset MS patients, as well as 246 healthy subjects, also of Greek origin, served as controls.

As expected, POMS patients were younger at the time of blood collection than adult-onset patients (mean age, 26.7 for the pediatric-onset group and 42.3 in adult-onset). They had lesser disability, and were more likely to have had clinically isolated syndrome onset — when symptoms of inflammatory demyelination are already evident.

When HLA-DRB1 gene variants were compared across all three groups, researchers found that HLA-DRB1*03 variant was significantly more frequent in POMS (present in 26% of these patients) than adult-onset patients (12.5%), or people of the general population (12.6%).

Compared to healthy subjects, the HLA-DRB1*11 variant was significantly less common in pediatric-onset patients (38% vs. 52% in healthy subjects), suggesting that this variant may protect people from developing MS early in life.

Also, confirming prior observations, the HLA-DRB1*15 variant was more common in MS patients than the general population (28% vs. 16.7% in healthy subjects), regardless of the timing of disease onset.

Given the association of the HLA-DRB1*03 variant with a higher risk of pediatric-onset MS, researchers next examined if the presence of this genetic variant had any impact on disease symptoms. They found that it does, putting patients at a significantly higher risk of relapse and of lesions in the thoracic spinal cord compared to those without this variant.

These findings remained significant after adjusting for factors like gender, disease type, and disease duration. In this analysis, patients with the HLA-DRB1*03 variant were nearly six times more likely to have thoracic spinal cord lesions than those without the variant.

Overall, this study’s results “suggest that the HLA-DRB1*03 allele not only predisposes to POMS, but is also correlated with increased disease activity,” the researchers wrote.

This may indicate that pediatric-onset MS is more dependent on antibodies that wrongly attack the protective myelin coating of nerve fibers (a hallmark of MS) than is adult-onset disease.

“The higher frequency of HLA-DRB1*03 in POMS than AOMS [adult onset MS] patients … could indicate a probably enhanced role of humoral immunity [through antibodies produced by immune B-cells] in POMS, which, if confirmed, could shift our therapeutic strategies to B-cell-directed therapies in the future,” the researchers wrote.

“To our knowledge, such a finding concerning the HLA-DRB1*03 allele risk in POMS has not been reported in other populations,” they added.

Studies in larger groups of patients, and in different ethnic groups, are needed to confirm these observations and validate this hypothesis.