Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study.

BACKGROUND

Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method.

OBJECTIVE

To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping.

METHODS

Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study.

RESULTS

In addition to the known risk allele HLA-DRB11501, evidence of increased susceptibility to MS was found for three additional alleles, DRB10405, DRB11104 and DRB11303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB10701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB104 sub-allele HLA-DRB10407 and HLA-DRB10901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB11501/0801 heterozygotes and DRB11501 homozygotes and the lowest in HLA-DRB10701/0101 heterozygotes. There was no significant gender association with HLA-DRB11501 overall, but the HLA-DRB1*1501/1104 risk genotype was significantly associated with female gender. HLA-DRB11501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS.

CONCLUSION

Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB104 and DRB111 sub-alleles.