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Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster

R J Allcock1, E G de la Concha, M Fernandez-Arquero

  • 1Department of Biochemistry, University of Western Australia, Nedlands. rallock@dci.uwa.edu.au

Human Immunology
|January 8, 2000
PubMed

Insights

Human leukocyte antigen (HLA)-DRB1*1501 is linked to multiple sclerosis (MS) susceptibility. Other genes, like those near the tumor necrosis factor (TNF) cluster, may modify this risk, suggesting potential resistance alleles.

Area of Science:

  • Immunogenetics
  • Human Leukocyte Antigen (HLA) complex
  • Multiple Sclerosis (MS) genetics

Background:

  • Multiple Sclerosis (MS) susceptibility is strongly associated with the Human Leukocyte Antigen (HLA)-DRB1*1501 allele.
  • Previous studies suggest potential associations with HLA-B7 and HLA-B18, often found on specific ancestral haplotypes (AH) co-expressed with HLA-DRB1*1501.
  • The genetic architecture of MS risk, particularly within the Major Histocompatibility Complex (MHC) region, requires further elucidation.

Purpose of the Study:

  • To systematically investigate the association of specific HLA and tumor necrosis factor (TNF) alleles and a novel polymorphism in the inhibitor of kappa B-like protein (IKBL) gene with MS susceptibility.
  • To identify genetic factors that may modify the risk conferred by HLA-DRB1*1501.
  • To explore potential resistance alleles located telomeric to the IKBL gene.

Main Methods:

  • Genotyping of 218 MS patients and 274 controls at standard class II and TNF microsatellite loci.
  • Typing for a novel non-synonymous polymorphism (IKBL+738) in the central MHC region.
  • Statistical analysis to assess associations between specific alleles, haplotypes, and MS status, including stratified analysis for HLA-DRB1*1501 carriers.

Main Results:

  • HLA-DRB1*1501 was confirmed as a significant susceptibility factor for MS.
  • The IKBL+738C allele, found exclusively on the 7.1 ancestral haplotype, and the TNFa11b4 allele were less frequent in MS patients, suggesting a protective effect.
  • Alleles TNFa10b4 and TNFa1b5, associated with the 18.1 and 18.2 ancestral haplotypes, were more common in HLA-DRB1*1501 positive MS patients, indicating a modifying role in disease risk.

Conclusions:

  • While HLA-DRB1*1501 is a primary risk factor for MS, other genes within the MHC region, particularly telomeric to the TNF cluster, significantly modulate this susceptibility.
  • The identified resistance alleles (IKBL+738C and TNFa11b4) and potential risk-modifying alleles (TNFa10b4 and TNFa1b5) highlight the complex genetic landscape of MS.
  • Further investigation into candidate genes telomeric to the TNF locus is warranted to fully understand their role in MS pathogenesis.

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