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.