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

Hum Immunol. 2003 Feb;64(2):302-9. doi: 10.1016/s0198-8859(02)00799-1.

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-alpha (LT-alpha), 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-alpha 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-alpha 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.

MeSH terms

  • Adult
  • Age of Onset
  • Antigens, CD / genetics*
  • Autoimmune Diseases / genetics*
  • Calcium-Binding Proteins / genetics*
  • Child
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 6 / genetics*
  • DNA-Binding Proteins
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genotype
  • HeLa Cells
  • Humans
  • Japan / epidemiology
  • Lymphotoxin-alpha / genetics
  • Microfilament Proteins
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • AIF1 protein, human
  • Antigens, CD
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Lymphotoxin-alpha
  • Microfilament Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha