血清IL-18水平及其基因多态性与脑胶质瘤的相关性研究
发布时间：2019-07-05 12:31
【摘要】：脑胶质瘤是一种源于神经外胚层间质细胞的肿瘤,约占脑部肿瘤的40%~50%,是最常见的脑部恶性肿瘤之一。其按照病理组织又可分为胶质母细胞瘤、室管膜瘤、星形细胞瘤、髓母细胞瘤、少枝胶质细胞瘤等。脑胶质瘤临床复发率很高,死亡率也很高,而且在临床治疗中经常会出现对化疗的耐药性以及对放疗的不敏感,导致脑胶质瘤的临床治疗效果不佳,预后较差。因此,脑胶质瘤一直是神经外科最难办的问题之一。然而,脑胶质瘤的具体发病机制尚未十分清晰。流行病学调查发现,高强度电磁辐射是增加脑胶质瘤患病的重要危险因素。除外界环境因素外,内在遗传易感基因在脑胶质瘤的发病及进展中也产生着一定的影响。白介素-18(interleukin-18,IL-18)是一种复杂的促炎性细胞因子,主要由巨噬细胞、单核细胞、成纤维细胞产生。IL-18不仅能促进T细胞和自然杀伤(natural killer cell,NK)细胞产生干扰素-γ(interferon-γ,IFN-γ)、白介素-2(interleukin-2,IL-2)、和粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony stimulating factor,GM-CSF)等细胞因子,而且能增强辅助性T1(T helper cells 1,Th1)细胞和NK细胞表达Fas配体,从而介导细胞毒性作用。此外,它还能够促进Th1细胞的发育,增强Th2细胞因子的分泌等。IL-18具有广泛的免疫调节功能,通过调控IFN-γ通路与CD134通路参与机体的固有免疫和获得性免疫调节,组成具体的免疫防御体系,尤其是在肿瘤的发病、发展过程中发挥着重要的作用。编码IL-18的基因位于人类第11号染色体(11q22.2-q22.3)上,其基因组呈高度多态性,以往研究表明IL-18基因多态性与多种肿瘤的发病风险存在关联。但国内外对于IL-18与脑胶质瘤的关联研究还很少。因此,本课题重点研究了血清IL-18水平及IL-18基因多态性与脑胶质瘤遗传易感性的关联。第一部分血清IL-18水平与脑胶质瘤的相关性目的:检测所有研究对象血清IL-18水平,探讨其与脑胶质瘤的关系。方法:运用酶联免疫吸附试验(Enzyme Linked Immunosorbent Assay,ELISA)法测定571例研究对象血清IL-18的浓度,并分析血清IL-18水平与脑胶质瘤的关系。结果:本研究共纳入182例脑胶质瘤患者和389例健康对照者。脑胶质瘤组中男性99例(54.4%),女性83例(45.6%),年龄46.34±16.72岁;健康对照组中男性200(51.4%),女性189例(48.6%),年龄45.56±13.76。两组人群在性别和年龄分布上无统计学差异(P分别为0.58和0.28)。脑胶质瘤组按照世界卫生组织(World Health Organization,WHO)脑胶质瘤Ⅰ-Ⅳ级的组织学分类,Ⅰ-Ⅱ级划分为低级别组,共71例(39.01%),Ⅲ-Ⅳ级划分为高级别组,共111例(60.99%)。脑胶质瘤组中血清IL-18水平为477.85±110.34pg/mL,健康对照组中血清IL-18水平为110.87±49.95 pg/mL,血清IL-18水平在两组间的分布差异具有统计学意义(P0.01)。低级别组中血清IL-18水平为456.61±106.95 pg/mL,高级别组中血清IL-18水平为511.07±107.27 pg/mL,血清IL-18水平在两组间的分布差异具有统计学意义(P0.01)。结论:血清IL-18水平与脑胶质瘤存在关联,对于脑胶质瘤的发生发展以及预后具有一定的临床指导意义。第二部分IL-18基因多态性与脑胶质瘤遗传易感性的关系目的:探讨IL-18基因多态性与脑胶质瘤遗传易感性的关系,为脑胶质瘤的个体化治疗提供科学依据。方法:运用Taqman-MGB技术检测182例脑胶质瘤患者和389例健康对照者的IL-18基因rs1946519、rs187238和rs549908三个位点的基因型分布。结果:研究对象的一般特征同第一部分;在健康对照组中,对IL-18基因三个位点(rs1946519、rs187238和rs549908)的三种基因型的频率进行Hardy--Weinberg平衡检验,结果显示,上述三位点的各基因型的实际频数与理论频数在对照组中的分布差别无统计学意义(χ12=0.67 P1=0.41,χ22=1.69 P2=0.19,χ32=0.46 P3=0.49);采用多因素logistic回归分析,rs1946519和rs187238位点结果显示,其杂合基因型、纯合基因型以及杂合基因型和纯合基因型合并的频率与各自野生基因型的频率相比差异均无统计学意义(P值均0.05);rs549908位点结果显示,其杂合基因型AC在脑胶质瘤组中分布显著低于健康对照组(调整OR=0.64,95%CI=0.42-0.98),提示该位点AC基因型可显著降低脑胶质瘤的发病风险,显性模型显示,与野生纯合型AA相比,rs549908位点AC+CC基因型亦可显著降低脑胶质瘤的发病风险(调整OR=0.59,95%CI=0.39-0.89);采用PHASE 2.0软件推断IL-18基因3个SNP位点(rs1946519、rs187238和rs549908)的单倍型及其频率。采用多因素Logistic回归方法进行分析结果显示:与TGA单倍型相比,携带GGC单倍型的个体脑胶质瘤发病风险较低(调整OR=0.51,95%CI=0.26-0.99);采用多因素logistic回归统计方法,分析IL-18基因SNPs位点多态性与不同级别脑胶质瘤的关系,结果未发现IL-18基因SNPs位点多态性与不同级别脑胶质瘤存在关联(P值均0.05);采用方差分析方法,分析IL-18基因rs549908位点基因型分布与血清IL-18水平的关系。结果显示,在脑胶质瘤组和健康对照组中,rs549908位点不同基因型分组中血清IL-18水平有统计学差异(F=163.42,P0.01)。结论:IL-18基因多态性与脑胶质瘤遗传易感性存在关联,且可能是通过影响IL-18水平来影响脑胶质瘤的发生、发展。
文内图片：
图片说明：TaqMan探针法进行等位基因鉴定的结果（蓝色代表野生纯合基因型，绿色代表杂合基因型，红色代表突变纯合基因型）
[Abstract]:Glioma is a tumor derived from neuroectodermal interstitial cells, accounting for 40 to 50% of brain tumors, one of the most common malignant tumors of the brain. It can be divided into glioblastoma, ependymoma, astrocytoma, medulloblastoma, oligodendroglioma, etc. according to the pathological tissue. The clinical recurrence rate of the glioma is high, the mortality rate is high, and the drug resistance to the chemotherapy and the insensitivity to the radiotherapy are often present in the clinical treatment, so that the clinical treatment effect of the brain glioma is poor and the prognosis is poor. Therefore, glioma has been one of the most difficult problems in neurosurgery. However, the specific pathogenesis of glioma has not been very clear. Epidemiological investigation has found that high-intensity electromagnetic radiation is an important risk factor to increase the risk of brain glioma. In addition to the external environmental factors, the internal genetic susceptibility gene has a certain effect in the pathogenesis and progression of the brain glioma. Interleukin-18 (IL-18) is a complex proinflammatory cytokine, mainly produced by macrophages, monocytes, and fibroblasts. IL-18 not only promotes T-cell and natural killer cell (NK) cells to produce cytokines such as interferon-2 (IFN-1), interleukin-2 (interleukin-2, IL-2), and granulocyte-macrophage colony stimulating factor (GM-CSF), But also can enhance the expression of Fas ligand in the helper T1 (T helper cells 1, Th1) cells and the NK cells, thereby mediating the cytotoxicity of the cells. In addition, it can promote the development of Th1 cells and enhance the secretion of Th2 cytokines. IL-18 plays an important role in the pathogenesis and development of the tumor, especially in the pathogenesis and development of the tumor. The gene encoding IL-18 is located on chromosome 11 of human chromosome 11 (11q22.2-q22.3), and its genome is highly polymorphic. Previous studies have shown that the polymorphism of IL-18 is associated with the risk of multiple tumors. However, there are few studies on the association between IL-18 and glioma at home and abroad. Therefore, this topic focuses on the association of the level of serum IL-18 and the polymorphism of IL-18 gene with the genetic susceptibility of brain glioma. Objective: To study the relationship between serum IL-18 level and glioma in the first part: to detect the level of IL-18 in the serum of all the subjects and to explore the relationship between the level of IL-18 and the glioma. Methods: The serum IL-18 concentration in 571 subjects was determined by enzyme-linked immunosorbent assay (ELISA) and the relationship between serum IL-18 level and glioma was analyzed. Results:182 patients with glioma and 389 healthy controls were included in this study. 99 (54.4%) males and 83 females (45.6%) in the glioma group, 46.34 and 16.72 years of age,200 (51.4%) in the healthy control group,189 (48.6%) females and 45.56 to 13.76. There was no statistical difference between the two groups in the distribution of sex and age (P was 0.58 and 0.28, respectively). According to the histological classification of the grade 鈪
本文编号：2510526
文内图片：
图片说明：TaqMan探针法进行等位基因鉴定的结果（蓝色代表野生纯合基因型，绿色代表杂合基因型，红色代表突变纯合基因型）
[Abstract]:Glioma is a tumor derived from neuroectodermal interstitial cells, accounting for 40 to 50% of brain tumors, one of the most common malignant tumors of the brain. It can be divided into glioblastoma, ependymoma, astrocytoma, medulloblastoma, oligodendroglioma, etc. according to the pathological tissue. The clinical recurrence rate of the glioma is high, the mortality rate is high, and the drug resistance to the chemotherapy and the insensitivity to the radiotherapy are often present in the clinical treatment, so that the clinical treatment effect of the brain glioma is poor and the prognosis is poor. Therefore, glioma has been one of the most difficult problems in neurosurgery. However, the specific pathogenesis of glioma has not been very clear. Epidemiological investigation has found that high-intensity electromagnetic radiation is an important risk factor to increase the risk of brain glioma. In addition to the external environmental factors, the internal genetic susceptibility gene has a certain effect in the pathogenesis and progression of the brain glioma. Interleukin-18 (IL-18) is a complex proinflammatory cytokine, mainly produced by macrophages, monocytes, and fibroblasts. IL-18 not only promotes T-cell and natural killer cell (NK) cells to produce cytokines such as interferon-2 (IFN-1), interleukin-2 (interleukin-2, IL-2), and granulocyte-macrophage colony stimulating factor (GM-CSF), But also can enhance the expression of Fas ligand in the helper T1 (T helper cells 1, Th1) cells and the NK cells, thereby mediating the cytotoxicity of the cells. In addition, it can promote the development of Th1 cells and enhance the secretion of Th2 cytokines. IL-18 plays an important role in the pathogenesis and development of the tumor, especially in the pathogenesis and development of the tumor. The gene encoding IL-18 is located on chromosome 11 of human chromosome 11 (11q22.2-q22.3), and its genome is highly polymorphic. Previous studies have shown that the polymorphism of IL-18 is associated with the risk of multiple tumors. However, there are few studies on the association between IL-18 and glioma at home and abroad. Therefore, this topic focuses on the association of the level of serum IL-18 and the polymorphism of IL-18 gene with the genetic susceptibility of brain glioma. Objective: To study the relationship between serum IL-18 level and glioma in the first part: to detect the level of IL-18 in the serum of all the subjects and to explore the relationship between the level of IL-18 and the glioma. Methods: The serum IL-18 concentration in 571 subjects was determined by enzyme-linked immunosorbent assay (ELISA) and the relationship between serum IL-18 level and glioma was analyzed. Results:182 patients with glioma and 389 healthy controls were included in this study. 99 (54.4%) males and 83 females (45.6%) in the glioma group, 46.34 and 16.72 years of age,200 (51.4%) in the healthy control group,189 (48.6%) females and 45.56 to 13.76. There was no statistical difference between the two groups in the distribution of sex and age (P was 0.58 and 0.28, respectively). According to the histological classification of the grade 鈪
本文编号：2510526
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