HLA and IDDM: facts and speculations on the disease gene and its mode of inheritance

1. The mode of inheritance of the DR3- and DR4-associated susceptibility genotype is essentially recessive, based on both the segregation data and the existence of Hardy-Weinberg equilibrium in Ashkenazi Jewish and possibly in patients of other populations. 2. Maternal effects may alter the expressivity of IDDM in some susceptible offspring, depending on the maternal DR genotype. Thus, the number of susceptible DR4 types inherited from the mothers may be decreased in certain population samples. Conceivably, these maternal effects also account for the smaller proportion of diabetic children born to diabetic women than to diabetic men. Conversely, maternal DRw6 may raise this risk. 3. The locus of the susceptibility gene is most likely in the DQ region. While specific DQA1 and DQB1 alleles are very closely associated with IDDM in some populations, neither is completely associated with it in DR4 haplotypes and neither accounts for the differences in IDDM susceptibility associated with DR3 haplotypes. 4. Linkage disequilibrium between DR and DP alleles in affected haplotypes indicates the existence of subsets of DR3 and DR7, which account for all or most of the risk to those haplotypes. The possibility of direct DP effects is less likely because the respective DP alleles are different and because DR4 does not maintain disequilibrium with DP alleles in either affected or unaffected haplotypes. 5. The DQA2-BglII-7.2Kb polymorphism in complete association with affected B8,DR3 haplotypes suggests the possible involvement of DQA2.(ABSTRACT TRUNCATED AT 250 WORDS)