HLA-DRβ, -DQα, and -DQβ restriction fragment length polymorphisms in multiple sclerosis

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Abstract
Restriction fragment length polymorphism (RFLP) studies were performed on DNA from unrelated Caucasian patients with multiple sclerosis (MS) using cDNA probes to the HLA class II genes DRβ, DQα, and DQβ. In a study of 34 patients and 34 controls who were not matched for DR type, we found that the DQβ allele‐specific RFLP or allogenotype, termed DQβlb, which corresponds at the molecular level to the DQwl serotype, is preferentially associated with MS. A significant disease association with DR2 was demonstrated by serology but this was not confirmed using DR2/Dw2‐specific RFLPs. We suggest that DQβlb is largely responsible for HLA‐associated susceptibility to MS and that the apparent MS‐DR2 serological association is due to the strong linkage disequilibrium between DR2 and DQβlb. Homozygosity of one of the two allelic bands of the DX α gene, usually termed the DXα lower (DXαL) band (which cross‐hybridizes with the DQα probe), correlated with reduced susceptibility to MS. Similarly a 5.3 kb band identified by the DQα probe in Mspl digests showed a negative correlation with MS. In an analysis of 27 DR2+ controls and 26 DR2+ patients it was found that these individuals all had DR2/Dw2‐specific RFLPs and all had identical DR2/Dw2‐associated DQβ (DQβlb) and DQα (DQαlb) allogenotypes. We detected no polymorphisms of DRβ, DQα, or DQβ genes among the DR2+ MS patients which distinguished them from normals. This suggests that the various HLA class II genes associated with MS are normal and not variant alleles. Because of strong linkage disequilibrium, a particular DRβ allogenotype in Caucasians is characteristically associated with specific DQα and DQβ allogenotypes. However, approximately 20% of all MS patients studied showed anomalous DR‐DQ associations including absence of anticipated allogenotypes or inappropriate allogenotypes. This result suggests that in at least some cases, aberrant DR‐DQ associations may be important in the pathogenesis of MS.