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Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis
A Ligers1, D A Dyment, C J Willer
1Division of Neurology, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.
Abstract:
The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (chi2=138.3; P<.0001). We obtained significant evidence of linkage throughout the whole data set (mlod=4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod=1.56; 62.7% sharing; P=.0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.
Insights
The human leukocyte antigen (HLA)-DRB1*15 allele is associated with multiple sclerosis (MS) susceptibility. However, this study found significant linkage even in families without HLA-DRB1*15, suggesting other factors may influence MS risk.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Human Genetics
Background:
- The HLA-DR locus is a key area of investigation for multiple sclerosis (MS) susceptibility.
- Previous research has established a strong association between MS and the HLA-DRB1*15 allele.
Purpose of the Study:
- To investigate the role of the HLA-DR locus in MS susceptibility within families.
- To determine if the HLA-DRB1*15 association is the sole determinant of MS risk in Northern European populations.
Main Methods:
- Genotyping of 1,978 individuals from 542 MS sib pairs and their families for HLA-DRB1 alleles.
- Utilizing the transmission/disequilibrium test (TDT) to assess allele association and linkage.
Main Results:
- Confirmed the strong association between MS and HLA-DRB1*15 (chi2=138.3; P<.0001).
- Observed significant evidence of linkage across the entire dataset (mlod=4.09; 59.9% sharing).
- Surprisingly, significant linkage was also found in families negative for the DRB1*15 allele (mlod=1.56; 62.7% sharing; P=.0081).
Conclusions:
- The findings challenge the idea that HLA-DRB1*15 is the exclusive major histocompatibility complex determinant for MS susceptibility in Northern European populations.
- The association of MS with HLA-DRB1*15 might be influenced by linkage disequilibrium with nearby loci or the presence of other risk alleles in DRB1*15-negative haplotypes.