GENETIC-POLYMORPHISM OF THE HUMAN TUMOR-NECROSIS-FACTOR REGION IN INSULIN-DEPENDENT DIABETES-MELLITUS - LINKAGE DISEQUILIBRIUM OF TNFAB MICROSATELLITE ALLELES WITH HLA HAPLOTYPES

The TNF region within the MHC includes a number of immunologically imp ortant genes. Microsatellites TNFa and TNFb adjacent to TNF exhibit ex tensive polymorphism. Employing a PCR-based technique, we identified T NFab haplotypes and defined their distribution in 97 controls and 48 d iabetics of Caucasoid origin in a search for other genes within the MH C potentially associated with IDDM. Twenty-five different TNFab haplot ypes were identified. A significant difference (p < 0.0005) in frequen cy between patients and controls was found for TNFa1b5 (relative risk 53). However, no other TNFab microsatellites demonstrated significantl y different frequencies. Among diabetics TNFa1b5 was found to be in li nkage disequilibrium with HLA-DR3-B18, a haplotype known to be associa ted with IDDM. Thus the increased frequency of TNFalb5 among diabetics could reflect a linkage disequilibrium with a gene within the TNF reg ion or with other genes, including the HLAs, which characterite this h aplotype. In both controls and diabetics TNFa2b3 and TNFa7b4 were in l inkage disequilibrium with DR3-B8 and DR7, respectively. Among diabeti cs, TNFa2b1 and TNFa6b5 were in linkage disequilibrium with DR4-B62 an d DR4-B44, respectively. It is intriguing that TNFab haplotypes, repre sented by a short piece of about 200 nucleotides in the untranslated r egion upstream of TNF beta gene, maintain strong linkage disequilibria with different HLA haplotypes extending over 1 million base pairs. Th e identification of TNFab microsatellites exhibiting a high polymorphi c index in a region lacking known polymorphic markers may provide pote ntially important information regarding the association of HLA haploty pes with autoimmune diseases, as they are in close proximity to other genes of immunologic importance.