Association and interaction of the TNF-alpha gene with other pro- and anti-inflammatory cytokine genes and HLA genes in patients with type 1 diabetes from North India.
Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where major histocompatibility complex (MHC) genes and the insulin-linked polymorphic region have been shown to play major roles. We report here an integrated effect of tumor necrosis factor (TNF) alpha with other cytokine genes. The TNF-alpha-308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n = 235) [P < 7 x 10(-6), odds ratio (OR) = 3.04, 95% confidence interval (CI) = 1.8-5.3] compared with the controls (n= 128). The variants of interferon-gamma (IFN-gamma) (A(+874)T), interleukin (IL)-6 (G(-174)C), IL-10 (A(-1082)G, T(-819)C, C(-592)A) and transforming growth factor (TGF) beta1 (T(cdn10)C, G(cdn25)C) did not show a significant difference between patients and controls. However, simultaneous presence of TNF-alpha-308 GA+AA along with both high and low secretor genotypes of IFN-gamma (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF-alpha-308 GA + AA along with high secretor genotypes of IL-6 (P < 0.0001, OR = 2.61, 95% CI = 1.5-4.56), IL-10 (P < 0.0001, OR = 4.26, 95% CI = 1.9-10.1) and TGF-beta1 (P < 0.00004, OR = 2.8, 95% CI = 1.6-4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF-alpha-308 GG along with low secretor genotypes of IFN-gamma (P < 0.001, OR = 0.465, 95% CI = 0.28-0.77), high secretor genotypes of IL-6 (P < 0.000004, OR = 0.76, 95% CI = 0.227-0.621) and TGF-beta1 (P < 0.000006, OR = 0.336, 95% CI = 0.198-0.568) was protective. The TNF-alpha-308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)-B*0801-DRB1*0301 haplotype, while TNF-alpha-308 A allele was in LD with the HLA-B*5001-DRB1*0301 and B*5801-DRB1*0301 haplotypes, suggesting that the effect of TNF-alpha -308 A allele is not because of its being in LD with any HLA alleles, but because of its functional role and its integrated effect with other cytokines.
Kumar
R
R
Neuroimmunology Laboratory, National Institute of Immunology, Aruna Asafali Marg, New Delhi 110067, India.
Goswami
R
R
Agarwal
S
S
Israni
N
N
Singh
S K
SK
Rani
R
R
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D007194:India; D018836:Inflammation Mediators / Q000276:immunology; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016207:Cytokines; D006680:HLA Antigens; D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D018836:Inflammation Mediators; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha