TUMOR NECROSIS FACTOR-BETA GENE RFLP ALLELES IN FINNISH IDDM HAPLOTYPES

The genes located between class II and class I HLA genes including polymorphic tumour necrosis factor (TNF) genes may contribute to the disease susceptibility in IDDM. Restriction fragment polymorphisms of the TNF-beta gene have been found to be fixed in the major IDDM susceptibility haplotypes, the B62,DR4 haplotype being associated with the 10.5-kb fragment and the B8,DR3 haplotype with a 5.5-kb fragment. We studied this TNF polymorphism in a sample of diabetic families. In all IDDM-associated haplotypes (n = 129) the 5.5-kb allele was more frequent than in haplotypes found only in healthy family members (n = 112) (58.1% versus 40.2 %, P < 0.01). Among IDDM haplotypes the B62,DR4 haplotype was characterized by the 10.5-kb TNF fragment, whereas two other common Finnish IDDM-associated DR4 haplotypes-A24,B39,DR4 and A2,B56,DR4-had the 5.5-kb TNF fragment. Both IDDM-associated and non-associated DR3 positive haplotypes were linked to the 5.5-kb fragment. The distribution of various combinations of TNF alleles in IDDM probands (n = 63) did not differ from that expected according to the Hardy-Weinberg distribution. Our results indicate that the 10.5-kb allele of TNF-beta gene as such is not a risk factor contributing to DR4/DQ8-associated susceptibility. Alternatively, there may be heterogeneity in pathogenetic effector mechanisms.