Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a German population

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered b y variations within MHC class II region on chromosome 6p as well as the CTL A4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA 1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR 3) in 130 families with a type 1 diabetic offspring in order to evaluate th eir role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. Th e presence or absence of DQLTR3 was defined by a nested PCR approach and CT LA4 microsatellite polymorphisms were detected with fluorescence-labeled pr imer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB 1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Wherea s the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not m odulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmis sion of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibi lity to type 1 diabetes mellitus.