No abstract

We analyzed 11 markers in the IDDM1 region in 120 IDDM patients and 83 healthy control subjects who were fully matched for the highest risk HLA-DQA1*0301-DQB1 *0302/DQA1*0501-DQB1*0201 genotype. Our study provides strong evidence that two regions in the major histocompatibility complex contribute to IDDM susceptibility or protection. First, despite selection for highest IDDM-associated risk DQ genotypes, this region displays extensive linkage disequilibrium (LD) differences between IDDM patients and control subjects. A second critical region was mapped around the microsatellite locus D6S273 centromeric of TNF, and it is approximately 200 kb in size. LD analysis shows that "diabetogenic haplotypes" may have resulted from a recombination telomeric of D6S1014 in the region of D6S273 and TNFa. Haplotype analysis using HLA and microsatellite loci refines IDDM risk assessment in carriers of the HLA-DQ highest risk genotype.

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper-and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G4C and APOA5 À1131 T4C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (Po0.05). Furthermore, the frequencies of the APOA5 c.56 G4C polymorphism and LPL c.27 G4A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 À1131 T4C, c.56 G4C and/or LPL c.27 G4A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval ¼ 1.8 -7.5, Po0.0001). The HTG patients showed similar allele frequencies of the APOA5, APOC3 and LPL polymorphisms, whereas the NDCP showed similar allele frequencies as the normolipidemic APOE2/2. Patients with the APOC3 3238 G4C/APOA5 À1131 T4C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2.