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Background  Multiple sclerosis (MS) is a complex trait in which genes in the MHC class II region exert the single strongest effect on genetic susceptibility. The principal MHC class II haplotype that increases MS risk in individuals of Northern European descent are those that bear  HLA-DRB1*15 . However, several other  HLA-DRB1  alleles have been positively and negatively associated with MS and each of the main allelotypes is composed of many sub-allelotypes with slightly different sequence composition. Given the role of this locus in antigen presentation it has been suggested that variations in the peptide binding site of the allele may underlie allelic variation in disease risk.    Methods  In an investigation of 7,333 individuals from 1,352 MS families, we assessed the nucleotide sequence of  HLA-DRB1  for any effects on disease susceptibility extending a recently published method of statistical analysis for family-based association studies to the particular challenges of hyper-variable genetic regions.    Results  We found that amino acid 60 of the  HLA-DRB1  peptide sequence, which had previously been postulated based on structural features, is unlikely to play a major role. Instead, empirical evidence based on sequence information suggests that MS susceptibility arises primarily from amino acid 13.    Conclusion  Identifying a single amino acid as a major risk factor provides major practical implications for risk and for the exploration of mechanisms, although the mechanism of amino acid 13 in the  HLA-DRB1  sequence's involvement in MS as well as the identity of additional variants on MHC haplotypes that influence risk need to be uncovered.

bmc medical genetics

An extension to a statistical approach for family based association studies provides insights into genetic risk factors for multiple sclerosis in the HLA-DRB1gene