TNF, TNF receptor type 1, and allograft inflammatory factor-1 gene polymorphisms in Japanese patients with type 1 diabetes

Abstract

The human leukocyte antigen (HLA) class III region, located on chromosome 6p21, has been regarded as one of the susceptible loci for type 1 diabetes. Because it contains many genes related to inflammatory and immune responses, including tumor necrosis factor (TNF), lymphotoxin-α (LT-α), and allograft inflammatory factor 1 (AIF-1) genes, it is unclear which gene within the class III region is responsible for the susceptibility to the disease. We sequenced the AIF-1 gene region and detected three novel polymorphisms, all of which were diallelic and localized at introns. Then, we investigated AIF-1, TNF, and LT-α gene polymorphisms in 165 patients with type 1 diabetes, consisting of 90 patients with young-onset type 1 diabetes, 75 patients with adult-onset type 1 diabetes, and 200 control patients. We also analyzed TNF receptors type 1 (TNFR1) and type 2 (TNFR2) gene polymorphisms, located on chromosome 12p13 and 1p36, respectively. Although there were significant differences between type 1 diabetes patients and controls in the distributions of TNF promoter polymorphisms at position −1031 and −857, and LT-α gene NcoI polymorphism, none of them was independently associated with the disease after two-locus analysis with HLA class II alleles. We detected the significantly increased frequency of the −383C allele, located in the TNFR-1 promoter region, in both young-onset and adult-onset diabetes patients compared with controls. In addition, the −383C allele was found to be associated with higher expression of the TNFR1 gene than that of −383A allele in in vitro expression. These results suggest that the TNFR1 gene region might be a susceptible locus to type 1 diabetes in Japanese.