HLA-DRB1-ASTERISK-0401 IS ASSOCIATED WITH SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES-MELLITUS INDEPENDENTLY OF THE DQB1 LOCUS

The distribution of DRB104 alleles and DRB1/DQB1 haplotypes was analy sed in 57 DR4(+) caucasoid subjects with insulin-dependent diabetes me llitus (IDDM) and 96 DR4(+) healthy controls selected on the basis of DR serology, and the findings were analysed in relation to age at diag nosis of IDDM. DNA samples were amplified using specific DR and DQ pri mers and hybridized with sequence-specific oligonucleotide probes. A s ignificantly increased combined frequency of DRB10401 and 0402 was ob served in IDDM subjects aged less than or equal to 12 years at diagnos is (allele frequency 88.4% compared with 62.0% in controls, P < 0.025) . There was a non-significant increase in DRB10401 and 0402 in IDDM s ubjects less than or equal to 12 years when compared with IDDM subject s > 12 years (P < 0.1). DRB10404 was decreased in the total IDDM subj ect group compared with controls (4.8% vs. 19.0%, P < 0.025) but did n ot reach statistical significance in the individual age at diagnosis g roups. In contrast, the frequency of DQB10302 was increased uniformly across both ages at diagnosis groups. In controls DRB10401 occurred in haplotype. association with DQB10301 in a significantly greater fr equency than with DQB10302. However, 95.0% of DRB1*0401 IDDM subjects were DQB10302. DRB1*0404, which was decreased in frequency in IDDM s ubjects, occurred in association significantly more frequently with DQ B10302 in controls. These results imply that DRB1 and DQB1 have indep endent roles as HLA susceptibility genes in IDDM. DQB1 may have a perm issive role whereas DRB1 could influence the rate at which underlying disease progresses to clinical IDDM.