An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at theHLA-DRB1locus

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of theHLA-DRB1locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed thatHLA-DRB1*01was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant forHLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying theHLA-DRB1*01allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion ofHLA-DRB1*04subtypes closely related toHLA-DRB1*01. The protective effect ofHLA-DRB1*01in sibling pairs may result from a specific epistatic interaction with the susceptibility alleleHLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting thatHLA-DRB1may itself be the disease-modifying locus. We conclude thatHLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.