No independent association between a tumor necrosis factor‐α promotor region polymorphism and insulin‐dependent diabetes mellitus

Several studies have implicated tumor necrosis factor (TNF)‐α in the pathogenesis of insulin‐dependent diabetes mellitus (IDDM). In the present study we analyzed the first reported TNF‐α gene polymorphism in relation to IDDM. We have made frequence analysis and tested in vitro lipopolysaccharide (LPS)‐induced TNF‐α secretion. A significant difference in allele frequency was observed between patients and controls (p = 0.03). However, a very strong association of the uncommonTNF2 allele was observed with the HLA‐B8, –DR3 alleles. The relative risk (RR) of TNF2 was 2.2 compared to a RRof 3.1 for DR3. One reason for this difference was the identification of the TNF1 allele on the otherwise strongly IDDM‐associated HLA‐DR3 haplotype: DQB1*0201, DQA1*0501, DRB1*0301, TNFc2, TNFB*2, TNFal, TNFb5, B18. Thus, the IDDM‐associated TNF2 allele had no DR3‐independent value as a disease marker. The LPS‐induced TNF‐α production by human monocytes in relation to genotypes demonstrated that TNF1/2 heterozygous individuals had higher, though not statistically significantly (p = 0.08) levels than TNF1‐homozygous subjects. However, this difference was rather small, unlikely to be of biological significance and based on the present material we cannot establish the functional importance of this polymorphism.