DOSE EFFECT OF CIS-ENCODED AND TRANS-ENCODED HLA-DQ-ALPHA-BETA HETERODIMERS IN IDDM SUSCEPTIBILITY

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ-alpha-beta heterodimers composed of a DQ-alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ-beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM Patients and 108 unrelated healthy nondiabetic control subjects were studied. With Polymerase chain reaction and sequence-specific oligonucleotide probes, both Patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ-alpha/Asp57- DQ-beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P < 10(-7)). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DO heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DO heterodimers were significantly increased in patients , conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, Cl 12.88-96.78, p < 10(-7)). 4) The simultaneous expression of four different susceptibility heterodimers explains the highest risk of DR3-DQw2/DR4-DQw8 heterozygotes. In conclusion, there is a dose effect of cis- and trans-encoded HLA-DQ-alpha-beta heterodimers in IDDM susceptibility influenced by the diversity of these molecules.