HLA-DPB1 Gene Variants May Influence MS Onset and Relapse Risk

A variant of the HLA-DPB1 gene — called HLA-DPB1*04 — appears to protect people from developing multiple sclerosis (MS) either in childhood or as adults, a study from Greece suggests.

Findings also point to a protective role of one other variant of this gene, HLA-DPB1*02, in adult-onset MS patients.

The study, “HLA-DPB1*03 as Risk Allele and HLA-DPB1*04 as Protective Allele for Both Early- and Adult-Onset Multiple Sclerosis in a Hellenic Cohort,” was published in the journal Brain Sciences.

HLA genes provide instructions to make proteins that play a critical role in immune system activation. Specific HLA-related proteins are found on the surface of immune cells, and help the immune system distinguish invading microbes from the body’s own cells.

Given their role in immunity, variants of these genes, particularly HLA subtypes HLA-DR, HLA-DQ, HLA-DP, have been shown to influence MS risk. (A gene variant refers to any mutation in the DNA sequence of a gene, and can be disease-related or benign.)

One well-defined HLA-DR variant, known as HLA-DRB1*15:01, has been linked to a higher risk of early-onset MS (EOMS, pediatric and adolescent MS) and accounts for up to 5% of cases. In people of Greek origin, the HLA-DRB1*03 variant was recently found to predispose people to EOMS. A possible association between HLA-DPB1*03:01 and MS also has been suggested.

“The present study attempts to expand the existing data on HLA and MS by investigating the influence of HLA-DPB1* alleles on disease risk and resistance in a Hellenic sample of 100 patients of both EOMS and AOMS [adult-onset MS],” the researchers wrote.

The team, led by scientists at the National and Kapodistrian University of Athens, examined 100 MS patients of Greek origin, including 62 females and 38 males. Of these, 28 were 19 years old or younger (EOMS group), and 72 were older than 19 (AOMS group). 

Secondary progressive MS (SPMS) was identified in 48 patients, 42 had relapsing-remitting disease (RRMS), and the remaining 10 were primary progressive MS (PPMS) patients. 

Using blood samples from each patient and from healthy people as a comparison group, the team investigated the influence of HLA-DPB1 gene variants on disease risk. They also examined the potential association between the well-defined HLA-DRB1*15:01 variant and various HLA-DPB1 variants. 

Analyses found no differences in the frequency of HLA-DPB1 variants between patients with EOMS and those with AOMS. 

However, compared with controls, significantly fewer EOMS patients had the HLA-DPB1*04 variant — 92.7% in healthy controls vs. 64.3% in the pediatric MS group — suggesting that this variant may protect people from developing MS early in life.

In the AOMS group, the HLA-DPB1*03 variant was found to be significantly more common among patients than healthy controls — 23.6% vs. 13.4% — suggesting this variant may be an adult MS risk factor.

But the variants HLA-DPB1*02 and HLA-DPB1*04 were found to be significantly lesser in AOMS patients compared with controls, indicating a protective effect with MS. 

Overall, 21 out of 87 patients (24.1%) carried the well-known HLA-DRB1*15 variant, which was significantly higher than in controls (11.4%), confirming its role in MS risk. This variant was found in five of 24 EOMS patients (20.8%) and 16 of 63 AOMS patients (25.4%). 

The HLA-DRB1*15 variant was absent in all HLA-DPB1*03-positive patients, whereas it was significantly increased among all HLA-DPB1*04 and HLA-DPB1*14-positive patients, “suggesting that HLA-DPB1*04 exerts a protective effect only in the absence of HLA-DRB1*15,” the researchers wrote. 

This common variant was also lacking in HLA-DPB1*03-positive adult-onset MS patients, while present in two HLA-DPB1*14-positive early-onset MS patients.

Cerebrospinal fluid (CSF, found around the brain and spinal cord) was isolated from 60 patients, and showed higher levels of  immunoglobulin G (IgG, an antibody) in those with early-onset compared to adult-onset disease. High levels of IgG are indicative of an autoimmune disorder.

Regardless of the age of MS onset, higher CSF antibody levels were found in patients who carried the HLA-DPB1*02 variant compared with those who did not. 

AOMS patients who were positive for this HLA-DPB1*02 variant had significantly fewer relapses since disease onset than did HLA-DPB1*02-negative patients, suggesting a protective role. 

“In conclusion, our study supports the previously reported risk susceptibility role of the HLA-DPB1*03 [variant] in AOMS in many Caucasian populations,” the researchers wrote. 

“Additionally, we report, for the first time in the international literature, the protective role of the HLA-DPB1*04 [variant] for patients with both EOMS and AOMS, and the putative protective role of the HLA-DPB1*02 [variant] in patients with AOMS in our sample.”