An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the
G C DeLuca1, S V Ramagopalan, B M Herrera
1Department of Clinical Neurology, and Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Abstract:
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.
Insights
The HLA-DRB1*01 gene variant appears to protect against severe disability in multiple sclerosis (MS). This finding suggests a genetic link between MS susceptibility and long-term disease progression, highlighting the MHC region's role.
Area of Science:
- Immunogenetics
- Neurology
- Human Genetics
Background:
- Multiple sclerosis (MS) is a central nervous system inflammatory disease with highly variable outcomes.
- The genetic factors influencing MS disease severity and long-term progression remain incompletely understood.
Purpose of the Study:
- To investigate the role of the Human Leukocyte Antigen (HLA)-DRB1 locus in determining the long-term disease severity of multiple sclerosis.
- To identify specific HLA-DRB1 alleles associated with benign versus malignant MS progression.
Main Methods:
- Genotyping of HLA-DRB1 alleles in a cohort of 163 sporadic MS cases stratified by disease outcome (benign vs. malignant).
- Replication studies in Sardinian MS patients and affected sibling pairs discordant for HLA-DRB1*01.
- Analysis of single nucleotide polymorphisms (SNPs) in the Major Histocompatibility Complex (MHC) region.
Main Results:
- The HLA-DRB1*01 allele was significantly underrepresented in patients with severe (malignant) MS compared to those with benign MS.
- Replication studies confirmed a protective effect of HLA-DRB1*01, with lower disability progression in carriers.
- No significant differences in other MHC region SNPs were found, suggesting HLA-DRB1 itself is the key locus.
Conclusions:
- The HLA-DRB1*01 allele acts as an independent genetic modifier, attenuating progressive disability in multiple sclerosis.
- These findings link MS susceptibility to long-term outcome, implicating shared MHC-based mechanisms in pathogenesis.
- The study underscores the critical role of the HLA-DRB1 locus in modulating MS disease progression.
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