THE COMPLEX INTERPLAY OF THE DQB1 AND DQA1 LOCI IN THE GENERATION OF THE SUSCEPTIBLE AND PROTECTIVE PHENOTYPE FOR INSULIN-DEPENDENT DIABETES-MELLITUS

IDDM patients of North East Italian region were molecularly typed for their HLA-DQB1 and DQA1 loci by using allele specific oligonudeotide p robes and PCR amplified genomic DNA. IDDM status strongly correlated w ith DQB1 alleles carrying a non-aspartic acid residue in position 57 o f DQ beta chain and DQA1 alleles with an arginine residue in position 52 of DQ alpha chain. Genotype analysis revealed that individuals with two DQB1 alleles having a non-aspartic residue in position 57 and two DQA1 alleles with an arginine residue in position 52 had the highest relative risk of disease: they constituted 41% of IDDM patients as com pared to 0% of controls. Heterozygosity either at residue 57 of DQB1 o r residue 52 of DQA1 was sufficient to abrogate statistical significan ce for disease association, although 43.6% of IDDM patients were inclu ded in these two groups as compared to 21.6% of normal controls. On th e other hand the presence of two DQB1 alleles with aspartic acid in po sition 57 was sufficient to confer resistance to disease irrespective of the DQA1 genotype. Based on the number of possible susceptible hete rodimers an individual can form, it was found that 85% of IDDM cases c ould form two or more heterodimers (two in cis and two in trans), but no IDDM case was found to form one susceptible heterodimer in cis. The se results demonstrate that the complete HLA-DQ genotype, more than si ngle DQB1 or DQA1 alleles or DQB1-DQA1 haplotypes, is associated with the highest risk of disease. Screening of the population for preventiv e purposes and/or early signs of IDDM should then take advantage of th is result and ''susceptible homozygous'' individuals should be followe d very closely and considered the first group of choice for possible n ew therapeutical trials.