An extension to a statistical approach for family based association studies provides insights into genetic risk factors for multiple sclerosis in the HLA-DRB1 gene.
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.


CONCLUSIONS
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.
Ramagopalan
Sreeram V
SV
1Department of Clinical Neurology, University of Oxford, The West Wing, The John Radcliffe Hospital, Oxford, OX3 9DU, UK. sramagopalan@gmail.com
McMahon
Roisin
R
Dyment
David A
DA
Sadovnick
A Dessa
AD
Ebers
George C
GC
Wittkowski
Knut M
KM
D000328:Adult; D000483:Alleles; D002648:Child; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D015233:Models, Statistical; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020539:Sequence Analysis, Protein
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains