DRB1-DQA1-DQB1 LOCI AND MULTIPLE-SCLEROSIS PREDISPOSITION IN THE SARDINIAN POPULATION

Multiple sclerosis (MS) is a common neurological disease caused by gen etic and environmental factors, Previous genetic analyses have suggest ed that the MHC/HLA region on chromosome 6p21 contains an MS-predispos ing component. Which of the many genes present in this region is prima rily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the M editerranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition, Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian-specific DQB10405(DR4)- DQA10501-DQB1*0301 haplotype and the DRB1*0301(DR3)-DQA1*0501-DQB1*02 01 haplotype, Detailed comparative analysis of the DRB1-DQA1-DQB1 hapl otypes present in this data set did not identify an individual locus t hat could explain MS susceptibility. The predisposing effect is haplot ype specific, in that it is confined to specific combinations of allel es at the DRB1, DQA1 and DQB1 loci. Cross-ethnic comparison between th e two HLA haplotypes associated with MS in Sardinians and the DRB1150 1 (DR2)-DQA10102-DQB1* 0602 haplotype, associated with MS in other Ca ucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These re sults suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsib le for genetic susceptibility to MS. Alternatively, the presence of co mplex interactions between different HLA haplotypes, other non-HLA pre disposing genes and environmental factors may explain different associ ations in different populations.