TNF, TNF receptor type 1, and allograft inflammatory factor-1 gene polymorphisms in Japanese patients with type 1 diabetes.
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.
Nishimura
Masataka
M
Department of the Clinical Neuroscience, Tokushima University Hospital, Japan. m_nishim@clin.med.tokushima-u.ac.jp
Obayashi
Hiroshi
H
Mizuta
Ikuko
I
Hara
Hirokazu
H
Adachi
Tetsuo
T
Ohta
Mitsuhiro
M
Tegoshi
Hisataka
H
Fukui
Michiaki
M
Hasegawa
Goji
G
Shigeta
Hirofumi
H
Kitagawa
Yoshihiro
Y
Nakano
Koji
K
Kaji
Ryuji
R
Nakamura
Naoto
N
D000328:Adult; D017668:Age of Onset; D015703:Antigens, CD / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008233:Lymphotoxin-alpha / Q000235:genetics; D008840:Microfilament Proteins; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C112986:AIF1 protein, human; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008233:Lymphotoxin-alpha; D008840:Microfilament Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha