CONTRIBUTION OF DRB1-ASTERISK-04 VARIANTS TO PREDISPOSITION TO OR PROTECTION FROM INSULIN-DEPENDENT DIABETES-MELLITUS IS INDEPENDENT OF DQ

Certain DQ alpha/beta dimeric molecules have been shown to play a majo r role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB10302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB104 subtypes on the suscepti bility encoded by DQ alleles is possible, since not all DRB104-DQB1*0 302 haplotypes are associated with the disease. The distribution of DR B104 subtypes was analysed in 240 DR4-positive Caucasian IDDM patient s and 110 DR4-positive healthy controls using allele-specific hybridiz ation after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB10302 allele which was f ound in the majority of patients (94.2% vs 64.7% in controls, Odd's ra tio OR=8.8, P<0.0001), differences between DRB104 variants persisted after the effect of the DQB1 locus was removed by matching patients an d controls for DQB10302. Thus, the DRB1*0402 allele conferred a stron g IDDM-predisposing effect (OR=3.1, P<0.02) which was highly significa nt in the absence of DR3 on the second haplotype (OR=5.6, P<0.0001) bu t was not visible among DR3/4 heterozygote individuals. Conversely, th e DRB10404 allele conferred a strong protective effect (OR=0.26, P<0. 0001) which was dominant even in the presence of the associated high r isk DR3 haplotype (OR=0.21, P<0.03). These data indicate that DQ molec ules are not the sole contributors to the DR4-associated IDDM predispo sition, and that peculiar DR4 subtypes play a significant role in susc eptibility to or protection from the disease. DRB10402 differs from D RB10404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate wit h the genetic linkage of IDDM predisposition. (C) 1996 Academic Press Limited