Analysis of tumor necrosis factor-alpha promoter polymorphism in type 1 diabetes: HLA-B and -DRB1 alleles are primarily associated with the disease in Japanese.
Polymorphisms in the 5'-flanking region of the tumor necrosis factor (TNF)-alpha gene were examined to study the genetic background of type 1 diabetes in Japanese. Five different biallelic polymorphisms were examined in 136 type 1 diabetic patients and 300 control subjects. The frequencies of individuals carrying TNF-alpha-857T allele (designated as TNFP-D allele) or -863A/-1,031C allele (designated as TNFP-B allele) were significantly increased in the patients as compared with the controls. Since these TNF-alpha alleles are in linkage disequilibria with certain DRB1 and HLA-B alleles, two-locus analyses were carried out. The TNFP-D allele did not increase the risk in either the presence or absence of the DRB1*0405 or HLA-B54 allele, while the DRB1*0405 and HLA-B54 alleles per se could confer susceptibility in both the TNFP-D allele-positive and -negative populations. Moreover, an odds ratio was remarkably elevated in the population carrying both DRB1*0405 and HLA-B54. Similarly, the TNFP-B allele did not show significant association with the disease in either the HLA-B61-positive or -negative population, while the HLA-B61 allele could significantly increase the risk in the TNFP-B allele-positive population. These data suggest that the associations of TNFP-D and -B alleles may be secondary to their linkage disequilibria with the susceptible HLA class I and class II alleles. Because HLA-B and DRB1 genes were independently associated, both of these genes may be contributed primarily to the pathogenesis of type 1 diabetes in Japanese.
Hamaguchi
K
K
Department of Internal Medicine I, Oita Medical University School of Medicine, Japan. khamaguc@oita-med.ac.jp
Kimura
A
A
Seki
N
N
Higuchi
T
T
Yasunaga
S
S
Takahashi
M
M
Sasazuki
T
T
Kusuda
Y
Y
Okeda
T
T
Itoh
K
K
Sakata
T
T
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000208:ethnology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha; D004247:DNA