DR4 SUBTYPES AND THEIR MOLECULAR-PROPERTIES IN A POPULATION-BASED STUDY OF SWEDISH CHILDHOOD DIABETES

The aim of this study was to determine the association between childho od insulin-dependent diabetes mellitus (IDDM) and HLA-DR4 subtypes and to test in a population-based investigation whether the DR4 associati on has an effect independent to that of DQ. First, HLA genotyping iden tified DR4 in 337/425 (79%) patients and 148/367 (40%) controls (Odds Ratio 5.67; p<0.01). Second, a total of 14 DR4 subtypes were defected by PCR and sequence specific oligo probes. Only two DR4 subtypes, DRB1 0401 (62% patients and 25% controls; OR 4.95, p<0.01) and *0404 (16% patients and 10% controls; OR 1.67, p<0.05) were however positively as sociated with the disease. These two subtypes were positively associat ed only when linked to DQB10302-DQA1*0301 (DQ8) (56% patients and 14% controls; OR 7.69, p<0.01; 15% patients and 10% controls; OR 1.55, p< 0.05, respectively). When DRB10401 was linked to DQB1*0301-DQA1*0301 (DQ7) (6% patients and 11% controls; OR 0.52, p<0.05), this DR4 subtyp es was negatively associated with IDDM. Third, tests of strongest asso ciation allowed the following ranking of alleles or haplotypes: DQB10 302-DQA10301 (DQ8) > DQB1*0302 > DRB1*0401 > DRB1*10404 and the assoc iation of DRB10401 has a significant effect in DQ8 positive IDDM pati ents. We conclude that the DR4 association with IDDM is secondary to D Q by linkage disequilibrium, which support the role of HLA-DQ as a pri mary genetic risk factor for IDDM.