No independent association between a tumor necrosis factor-alpha promotor region polymorphism and insulin-dependent diabetes mellitus.
Several studies have implicated tumor necrosis factor (TNF)-alpha in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In the present study we analyzed the first reported TNF-alpha gene polymorphism in relation to IDDM. We have made frequence analysis and tested in vitro lipopolysaccharide (LPS)-induced TNF-alpha secretion. A significant difference in allele frequency was observed between patients and controls (p = 0.03). However, a very strong association of the uncommon TNF2 allele was observed with the HLA-B8, -DR3 alleles. The relative risk (RR) of TNF2 was 2.2 compared to a RR of 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, TNFa1, TNFb5, B18. Thus, the IDDM-associated TNF2 allele had no DR3-independent value as a disease marker. The LPS-induced TNF-alpha 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.
Pociot
F
F
Steno Diabetes Center, Gentofte, Denmark.
Wilson
A G
AG
Nerup
J
J
Duff
G W
GW
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D009000:Monocytes / Q000276:immunology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha