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A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501

K Duvefelt1, M Anderson, A Fogdell-Hahn

  • 1Division of Neurology, Neurotec, Karolinska Institutet at Huddinge University hospital, Huddinge, Sweden. kristina.duvefelt@neurotec.ki.se

Tissue Antigens
|December 4, 2003
PubMed

Insights

This study investigated NOTCH4 and tumor necrosis factor-alpha (TNFalpha) gene associations with multiple sclerosis (MS). Neither gene showed a primary link to MS susceptibility, despite linkage disequilibrium with known HLA associations.

Area of Science:

  • Immunogenetics
  • Neuroimmunology
  • Human Genetics

Background:

  • Multiple sclerosis (MS) is a chronic central nervous system (CNS) inflammatory disease with suspected autoimmune components.
  • A specific human leukocyte antigen (HLA) DR-DQ haplotype (DR15, DQ6) is strongly associated with MS susceptibility.
  • Previous research indicated associations extending to HLA-B and independent associations with HLA-A alleles, but complex linkage disequilibrium (LD) obscured whether classical HLA genes or nearby genes were responsible.

Purpose of the Study:

  • To investigate the association of the NOTCH4 and tumor necrosis factor-alpha (TNFalpha) genes with multiple sclerosis (MS) susceptibility.
  • To determine if these genes, located between HLA-DRB1 and HLA-A, contribute independently to MS risk.
  • To clarify the role of non-HLA genes in the complex genetic landscape of MS.

Main Methods:

  • Genotyping of single nucleotide polymorphisms (SNPs) at positions -25 and a trinucleotide repeat in the NOTCH4 gene.
  • Genotyping of SNPs at positions -308 and -238 in the TNFalpha gene.
  • Analysis of 181 MS patients and 180 controls, with prior HLA-DRB and HLA-A typing.

Main Results:

  • A modest association (OR = 3.44) was observed between the NOTCH4 C-25 allele and MS.
  • However, two-locus analysis revealed this NOTCH4 association was secondary to the established HLA-DRB1 association.
  • No association was found between the studied TNFalpha gene polymorphisms and MS, despite observed LD with HLA-DRB1 and HLA-A.

Conclusions:

  • Alleles of the NOTCH4 and TNFalpha genes are unlikely to be primary determinants of MS susceptibility.
  • The observed modest association with NOTCH4 is likely due to its linkage disequilibrium with the strongly associated HLA-DRB1 locus.
  • Specific alleles of NOTCH4 and TNFalpha are frequently found on the same haplotype as the MS-associated DR15, DQ6 haplotype, but do not confer independent risk.

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