Abstract

HLA-DRB1*1501 is the strongest known genetic risk factor for developing multiple sclerosis (MS), but effects on clinical phenotype and outcome are unclear. We have investigated the association of HLA-DRB1*1501 with time to fixed disability milestones in large well-defined patient cohort with extensive prospective disability data.

1025 patients with mean follow-up of 17.1 years were included. DNA was typed externally for rs3135388, a single nucleotide polymorphism tagging HLA-DRB1*1501. Association with demographic features and clinical aspects of disease onset was analysed using chi-squared and Student's t-tests. Association with time to EDSS 4.0, 6.0, 8.0 and secondary progression (SPMS) was tested using Cox proportional hazards regression.

HLA-DRB1*1501 was associated with younger age at onset (31.1 y versus 32.4 y, p=0.04), but with no other demographic variable. Although there was a trend towards longer time to EDSS 4.0 and 6.0 in individuals homozygous for HLA-DRB1*1501 (EDSS 4.0: 17.3 y versus 13.3 y, EDSS 6.0: 20.5 y versus 18.0 y) this effect was not seen for EDSS 8.0 or SPMS, and did not remain significant following correction for age at onset.

Our findings suggest the main role of HLA DRB1*1501 is in determining susceptibility to MS, but that alternative mechanisms are responsible for the subsequent evolution of disability and long-term prognosis.