印度北部1型糖尿病患者中肿瘤坏死因子-α基因与其他促炎和抗炎细胞因子基因及人类白细胞抗原基因的关联与相互作用

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.

作者信息

Kumar R, Goswami R, Agarwal S, Israni N, Singh S K, Rani R

机构信息

Neuroimmunology Laboratory, National Institute of Immunology, Aruna Asafali Marg, New Delhi 110067, India.

出版信息

Tissue Antigens. 2007 Jun;69(6):557-67. doi: 10.1111/j.1399-0039.2007.00817.x.

DOI:10.1111/j.1399-0039.2007.00817.x

PMID:17498265

Abstract

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)-B0801-DRB10301 haplotype, while TNF-alpha-308 A allele was in LD with the HLA-B5001-DRB10301 and B5801-DRB10301 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.

摘要

1型糖尿病（T1D）是一种多因素自身免疫性疾病，主要组织相容性复合体（MHC）基因和胰岛素连锁多态性区域已被证明起主要作用。我们在此报告肿瘤坏死因子（TNF）α与其他细胞因子基因的综合作用。与对照组（n = 128）相比，T1D患者（n = 235）中TNF-α -308 GA和AA（高分泌型）多态性显著增加[P < 7×10⁻⁶，优势比（OR）= 3.04，95%置信区间（CI）= 1.8 - 5.3]。干扰素-γ（IFN-γ）（A(+874)T）、白细胞介素（IL）-6（G(-174)C）、IL-10（A(-1082)G、T(-819)C、C(-592)A）和转化生长因子（TGF）β1（T(cdn10)C、G(cdn25)C）的变体在患者和对照组之间未显示出显著差异。然而，TNF-α -308 GA + AA与IFN-γ高分泌型和低分泌型基因型同时存在时（P < 0.003），患者中显著增加。TNF-α -308 GA + AA与IL-6高分泌型基因型（P < 0.0001，OR = 2.61，95% CI = 1.5 - 4.56）、IL-10高分泌型基因型（P < 0.0001，OR = 4.26，95% CI = 1.9 - 10.1）和TGF-β1高分泌型基因型（P < 0.00004，OR = 2.8，95% CI = 1.6 - 4.86）同时存在时，T1D患者中也显著增加。TNF-α -308 GG低分泌型基因型与IFN-γ低分泌型基因型（P < 0.001，OR = 0.465，95% CI = 0.28 - 0.77）、IL-6高分泌型基因型（P < 0.000004，OR = 0.76，95% CI = 0.227 - 0.621）和TGF-β1高分泌型基因型（P < 0.000006，OR = 0.336，95% CI = 0.198 - 0.568）同时存在时具有保护作用。TNF-α -308 G等位基因与人类白细胞抗原（HLA）-B0801 - DRB10301单倍型处于连锁不平衡（LD）状态，而TNF-α -308 A等位基因与HLA - B5001 - DRB10301和B5801 - DRB10301单倍型处于LD状态，这表明TNF-α -308 A等位基因的作用并非因其与任何HLA等位基因处于LD状态，而是因其功能作用及其与其他细胞因子的综合作用。