Human leukocyte antigens with special reference to association and linkage in multiple sclerosis

Abstract: The polymorphism of HLA (human leukocyte antigen) is extensive. Allelic variation has previously been detected by cellular and serological methods. Today a variety of genomic typing techniques have been developed, which give higher resolution and a possibility to detect single nucleotide variations. One such HLA typing technique, PCR-amplification with sequence-specific primers (PCR-SSP), has been developed in our laboratory. The application of PCR-SSP for typing of the DQA1 locus and its use in the study of linkage and association in disease, is described in this thesis. Better typing techniques have lead to identification of new alleles, of which one (DRB1'1415) is described here. The complexity of the HLA system is even more increased by the combination of alleles in different haplotypes. Tight linkage disequilibrium between the DR and DQ subregions ensures that specific DR and DQ alleles often are inherited together. The haplotype carrying the DQA1'0104 allele is described in this thesis. Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Its etiology is unknown, but probably MS is a multifactorial and polygenic disease with autoimmune characteristics. The only repeatedly verified genetic factor in MS is the HLA association with the class II haplotype DR2,DQ6,Dw2 ( specified here with genomic typing as DRB1'1501,DRB5'0101, DQA1'0102,DQB1'0602). This haplotype is present in 60% of MS patients and 30% of controls in North European populations. The importance of HLA genes in MS has been questioned since it has been difficult to establish linkage with markers in this region. In Swedish multiplex families we do find significant linkage (lod score >3) between HLA-DR,DQ and MS. Further analysis, with detailed PCR-SSP typing of all class I and class II loci (A, B, C, DR, DQ and DP) in 200 patients and 210 healthy controls, added to the complexity of HLA as part of the genetic susceptibility in MS. A'0301 was found to be positively associated with MS independently of DR2,DQ6,Dw2. In contrast, the A'0201 allele was underrepresented in the patient group and in DR2,DQ6,Dw2 positive individuals it decreased the relative risk from 3.6 to 1.8. In addition, the DPB1'0401 allele occurred in increased frequency together with DR2,DQ6,Dw2 in patients compared with controls. In conclusion, HLA is probably one of the major genetic factors determining MS susceptibility, although several additional events, both genetic and environmental, are required to develop MS.