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.


METHODS
Retrospective multicenter cohort study.


METHODS
Six hundred seventy-three African American and 717 white patients with MS.


METHODS
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.
Cree
Bruce A C
BA
Department of Neurology, University of California-San Francisco, USA. bruce.cree@ucsf.edu
Reich
David E
DE
Khan
Omar
O
De Jager
Philip L
PL
Nakashima
Ichiro
I
Takahashi
Toshiyuki
T
Bar-Or
Amit
A
Tong
Christine
C
Hauser
Stephen L
SL
Oksenberg
Jorge R
JR
D000328:Adult; D017668:Age of Onset; D044383:Black People / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D009471:Neuromyelitis Optica / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult; D001741:Black or African American
D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains