HLA and susceptibility to multiple sclerosis

The study of the joint segregation of multiple sclerosis and HLA, using affected sib pairs as well as whole pedigrees, shows that these two traits are not independently transmitted. The hypothesis of a single susceptibility locus inside HLA region could explain all the observed data, only if a high gene frequency, a very low penetrance, and some environmental correlation between relatives are assumed. Linkage analysis performed on the basis of this hypothesis for 58 multiple sclerosis families concludes to a strict linkage. We obtained a maximum score of 3.11 at theta = 0.00 for a dominant gene of frequency 0.18 and penetrance of 0.02. This result contrasts with the large recombination fraction obtained by other authors and the discrepancy is explained by the very low gene frequency used in their analysis. Some environmental correlation, in addition to the genetic determinant in HLA region, may explain the overall familial aggregation, but an alternative is the existence of additional genetic determinants.