Multiple sclerosis and HLA: is the susceptibility gene really HLA-DR or -DQ?

Area of Science:

• Immunogenetics
• Neurology
• Human Genetics

Background:

• Multiple sclerosis (MS) is a complex neurological disorder with a suspected genetic component.
• Human Leukocyte Antigen (HLA) genes, particularly HLA-DR and HLA-DQ, are known to influence immune responses and are associated with various autoimmune diseases.

Purpose of the Study:

• To investigate the association between specific HLA-DR and HLA-DQ polymorphisms and multiple sclerosis in a patient cohort.
• To test proposed hypotheses regarding MS susceptibility genes within the HLA region and their relationship to clinical disease patterns.

Main Methods:

• Genotyping of HLA-DR and HLA-DQ polymorphisms using serological methods and DNA analysis (Taq1 digestion with DRB, DQA, DQB probes).
• Comparison of HLA allele frequencies between 71 MS patients (classified into four clinical subgroups) and 100 healthy controls.
• Analysis of specific DNA fragments (3.25-kb Mspl digest hybridizing to DQA) in both patient and control groups.

Main Results:

• A significant excess of HLA-DR2 (DRw15 subtype) and associated HLA-DQw6 was observed in MS patients compared to controls.
• No significant differences in DR or DQ allele distribution were found among the different clinical patterns of MS.
• The study did not find an excess of DQw8 and DQw9 alleles, challenging a specific hypothesis on shared DQB hypervariable regions.

Conclusions:

• The findings support the hypothesis that a primary MS susceptibility gene resides within the HLA region, strongly associated with DRw15 and DQw6 in Northern European populations.
• The results argue against hypotheses linking MS susceptibility to shared DQB hypervariable regions (DQw6, 8, 9).
• The study does not support the concept of immunogenetically distinct subtypes for chronic progressive and relapsing-remitting MS.