HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis

Abstract

Background: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. Objective: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. Methods: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. Results: HLA-DRB1*1501 -positive ( n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative ( n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference −0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference −0.22 mm2/year, p < 0.05). Interpretation: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

A role for HLA in mediating long-term multiple sclerosis outcomes?

“…The benefit of MS disease-modifying therapies is well established, 12 shown to be most effective if initiated within the first 3 years of disease onset. 13,14 In the present study, Brownlee 9 suggest that a more inflammatory phenotype, such as that seen in their HLA-DRB1*15:01 minor allele carriers, may respond better to disease-modifying therapy. This raises the possibility that the association of HLA with longitudinal MS outcomes may therefore have been masked in largely treated, recently reported, cohorts recruited and studied during equivalent periods, that failed to show associations between HLA and severity outcomes as measured using the EDSS.…”

“…This work by Brownlee 9 adds significantly to the literature that to date has struggled to demonstrate an association between MS risk variants and longitudinal MS outcomes. Although, associations with carriage of DRB1*15:01 and MRI metrics have previously been reported, these were cross-sectional in nature.…”

“…DRB1*15:01-positive individuals had, on average, a 0.06 point greater increase in EDSS score per year, or equivalently, a difference of 0.9 in EDSS score over the 15-year followup period. This work by Brownlee 9 adds significantly to the literature that to date has struggled to demonstrate an association between MS risk variants and longitudinal MS outcomes. Although, associations with carriage of DRB1*15:01 and MRI metrics have previously been reported, these were cross-sectional in nature.…”

“…In this issue of the Multiple Sclerosis Journal , Brownlee 9 report a first in the field of HLA and MS genetics, demonstrating an association between carriage of the main risk allele HLA-DRB1*15:01 and longitudinal disability outcomes. Using data from the Queen Square Clinically Isolated Syndrome (CIS) cohort, the authors report that individuals positive for HLA-DRB1*15:01 had a higher T2 lesion volume and a greater number of gadolinium-enhancing lesions at CIS onset relative to DRB1*15:01-negative individuals.…”

“…Furthermore, the cohort was largely untreated; only 25 individuals (23%) received treatment over the observation period. 9 This provides for a rare glimpse into the natural history of the disease in the modern day.…”