Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA

Arch Neurol. 2009 Feb;66(2):226-33. doi: 10.1001/archneurol.2008.541.

Abstract

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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • African Continental Ancestry Group / genetics*
  • Age of Onset
  • Cohort Studies
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • HLA Antigens / genetics*
  • HLA-DQ Antigens / genetics
  • HLA-DQ beta-Chains
  • HLA-DR Antigens / genetics
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Multiple Sclerosis / epidemiology
  • Multiple Sclerosis / ethnology*
  • Multiple Sclerosis / genetics*
  • Neuromyelitis Optica / ethnology
  • Neuromyelitis Optica / genetics
  • Neuromyelitis Optica / physiopathology
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Retrospective Studies
  • Young Adult

Substances

  • HLA Antigens
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains