MULTIPLE-SCLEROSIS AND THE HLA-D REGION - LINKAGE AND ASSOCIATION STUDIES

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically de termined components. The association between the HLA class II DR15, DQ 6, Dw2 haplotype and MS has been well documented in patients with ance stral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has gen erated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears cont radictory. We have collected and determined the HLA-DR and -DQ haploty pes of 115 sibling pairs with multiple sclerosis, and confirm a signif icant association with the Dw2-associated haplotype, both in index cas es and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing proba bilities to defined genetic models, we have not observed linkage of th is region to susceptibility in MS. We discuss the basis for associatio n and linkage and conclude that the DR15, DQ6, Dw2 haplotype does repr esent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibi lity genes, this haplotype is not necessary for disease expression.