THE ROLE OF HLA CLASS-II GENES IN INSULIN-DEPENDENT DIABETES-MELLITUS- MOLECULAR ANALYSIS OF 180 CAUCASIAN, MULTIPLEX FAMILIES

We report here our analysis of HLA class II alleles in 180 Caucasian n uclear families with at least two children with insulin-dependent diab etes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determ ined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families, Consistent with other studies, our dat a indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in p atients compared to controls. In addition, we found an increase in DR1 /DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB10302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB10302 and DQ B10301 more closely resembling those in control populations. The prot ective effect of DR2 is evident in this data set and is limited to the common DRB11501-DQB1*0602 haplotype. Most DR2(+) patients carry the less common DR2 haplotype DRB11601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB10301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB10101, found almost exclusively on DR3 haplotypes in p atients, is slightly increased, and maternal transmissions of DRB1030 1-DPB10101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associate d IDDM susceptibility is evident from these data.