Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA

Background: In those with multiple sclerosis ( MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. Objective: To determine whether genetic variation influences clinical MS patterns. Design: Retrospective multicenter cohort study. Participants: Six hundred seventy-three African American and 717 white patients with MS. Main Outcome Measures: Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Results: Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P=.001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti-aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P=. 008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P<.001) and risk of cane dependency (hazard ratio, 1.36; P<.001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P<.001). Conclusions: These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.