HLA CLASS-II-ASSOCIATED GENETIC SUSCEPTIBILITY IN MULTIPLE-SCLEROSIS - A CRITICAL-EVALUATION

Multiple sclerosis (MS) has, since the 1970s, been known to be associated with the HLA-Dw2 and -DR2 specificities in Caucasian Europeans and North Americans. By the use of genomic typing techniques, the association has been specified to be with the DRw15,DQw6,Dw2, i.e. the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A significant DPw4 association in Scandinavian MS patients has been described in one report. However, this association has not been confirmed in several subsequent studies with patients from the same and other ethnic groups. During the last few years several reports, based on serological, RFLP and PCR-SSO data, have suggested that the HLA class II-associated MS susceptibility gene(s) may be more closely associated with the DQ than with the DR subregion. The observations that the HLA-DQB1 genes of MS patients share long stretches of sequence motifs and also carry DQA1 alleles encoding glutamine at position 34 of the DQ alpha-chain have received considerable attention. It has been suggested that the susceptibility to develop MS might be determined by the corresponding DQ alpha-beta-heterodimers either encoded in cis or in trans. We have investigated these issues in a large group of Swedish MS patients (n = 179). We found that the associations with the suggested DQB1 sequences and position 34 of the DQ alpha-chain were due to linkage disequilibrium and secondary to the association with the DRw15,DQw6,Dw2 haplotype (p < 10(-9) and p < 10(-8), respectively). No overrepresentation of the implicated DQ alpha-beta-heterodimers was observed in DRw15,DQw6,Dw2-negative patients. We conclude that available data does not allow the localization of the HLA class II-associated MS susceptibility genes within the DRw15,DQw6,Dw2 haplotype. We have previously described immunogenetic differences between different clinical forms of MS. In the present study of a new group of MS patients compared with a new control panel, these differences were partly confirmed. The DRw17,DQw2 association in relapsing/remitting MS was affirmed. However, in patients with primarily chronic progressive MS a negative association with the DQw7 allele was not substantiated and a positive association with the DR4,DQw8 haplotype could neither be confirmed nor rejected.