CD24 is a genetic modifier for risk and progression of multiple sclerosis

Multiple sclerosis (MS) is a chronic neurological disease of unknown etiology, but a genetic basis for the disease is undisputed. We have reported that CD24 is required for the pathogenicity of autoreactive T cells in experimental autoimmune encephalomyelitis, the mouse model of MS. Here we investigate the contribution of CD24 to MS by studying single-nucleotide polymorphism in the ORF among 242 MS patients and 207 population controls. This single-nucleotide polymorphism results in replacement of alanine (CD24 ^a) with valine (CD24^v) in the mature protein. We found that the CD24^v/v renders a >2-fold increase in the relative risk of MS in the general population (P = 0.023). Among familial MS, the CD24 ^v allele is preferentially transmitted into affected individuals (P = 0.017). Furthermore, 50% of CD24^v/v patients with expanded disability status scale 6.0 reached the milestone in 5 years, whereas the CD24^a/v (P = 0.00037) and CD24^a/a (P = 0.0016) patients did so in 16 and 13 years, respectively. Moreover, our data suggest that the CD24^v/v patients expressed higher levels of CD24 on peripheral blood T cells than did the CD24^a/a patients. Transfection with CD24 ^a and CD24^v cDNA demonstrated that the CD24^v allele can be expressed at higher efficiency than the CD24^a alleles. Thus, CD24 polymorphism is a genetic modifier for susceptibility and progression of MS in the central Ohio cohort that we studied, perhaps by affecting the efficiency of CD24 expression on the cell surface.