【摘要】：腦膠質(zhì)瘤是一種源于神經(jīng)外胚層間質(zhì)細胞的腫瘤,約占腦部腫瘤的40%~50%,是最常見的腦部惡性腫瘤之一。其按照病理組織又可分為膠質(zhì)母細胞瘤、室管膜瘤、星形細胞瘤、髓母細胞瘤、少枝膠質(zhì)細胞瘤等。腦膠質(zhì)瘤臨床復(fù)發(fā)率很高,死亡率也很高,而且在臨床治療中經(jīng)常會出現(xiàn)對化療的耐藥性以及對放療的不敏感,導(dǎo)致腦膠質(zhì)瘤的臨床治療效果不佳,預(yù)后較差。因此,腦膠質(zhì)瘤一直是神經(jīng)外科最難辦的問題之一。然而,腦膠質(zhì)瘤的具體發(fā)病機制尚未十分清晰。流行病學(xué)調(diào)查發(fā)現(xiàn),高強度電磁輻射是增加腦膠質(zhì)瘤患病的重要危險因素。除外界環(huán)境因素外,內(nèi)在遺傳易感基因在腦膠質(zhì)瘤的發(fā)病及進展中也產(chǎn)生著一定的影響。白介素-18(interleukin-18,IL-18)是一種復(fù)雜的促炎性細胞因子,主要由巨噬細胞、單核細胞、成纖維細胞產(chǎn)生。IL-18不僅能促進T細胞和自然殺傷(natural killer cell,NK)細胞產(chǎn)生干擾素-γ(interferon-γ,IFN-γ)、白介素-2(interleukin-2,IL-2)、和粒細胞-巨噬細胞集落刺激因子(granulocyte-macrophage colony stimulating factor,GM-CSF)等細胞因子,而且能增強輔助性T1(T helper cells 1,Th1)細胞和NK細胞表達Fas配體,從而介導(dǎo)細胞毒性作用。此外,它還能夠促進Th1細胞的發(fā)育,增強Th2細胞因子的分泌等。IL-18具有廣泛的免疫調(diào)節(jié)功能,通過調(diào)控IFN-γ通路與CD134通路參與機體的固有免疫和獲得性免疫調(diào)節(jié),組成具體的免疫防御體系,尤其是在腫瘤的發(fā)病、發(fā)展過程中發(fā)揮著重要的作用。編碼IL-18的基因位于人類第11號染色體(11q22.2-q22.3)上,其基因組呈高度多態(tài)性,以往研究表明IL-18基因多態(tài)性與多種腫瘤的發(fā)病風(fēng)險存在關(guān)聯(lián)。但國內(nèi)外對于IL-18與腦膠質(zhì)瘤的關(guān)聯(lián)研究還很少。因此,本課題重點研究了血清IL-18水平及IL-18基因多態(tài)性與腦膠質(zhì)瘤遺傳易感性的關(guān)聯(lián)。第一部分血清IL-18水平與腦膠質(zhì)瘤的相關(guān)性目的:檢測所有研究對象血清IL-18水平,探討其與腦膠質(zhì)瘤的關(guān)系。方法:運用酶聯(lián)免疫吸附試驗(Enzyme Linked Immunosorbent Assay,ELISA)法測定571例研究對象血清IL-18的濃度,并分析血清IL-18水平與腦膠質(zhì)瘤的關(guān)系。結(jié)果:本研究共納入182例腦膠質(zhì)瘤患者和389例健康對照者。腦膠質(zhì)瘤組中男性99例(54.4%),女性83例(45.6%),年齡46.34±16.72歲;健康對照組中男性200(51.4%),女性189例(48.6%),年齡45.56±13.76。兩組人群在性別和年齡分布上無統(tǒng)計學(xué)差異(P分別為0.58和0.28)。腦膠質(zhì)瘤組按照世界衛(wèi)生組織(World Health Organization,WHO)腦膠質(zhì)瘤Ⅰ-Ⅳ級的組織學(xué)分類,Ⅰ-Ⅱ級劃分為低級別組,共71例(39.01%),Ⅲ-Ⅳ級劃分為高級別組,共111例(60.99%)。腦膠質(zhì)瘤組中血清IL-18水平為477.85±110.34pg/mL,健康對照組中血清IL-18水平為110.87±49.95 pg/mL,血清IL-18水平在兩組間的分布差異具有統(tǒng)計學(xué)意義(P0.01)。低級別組中血清IL-18水平為456.61±106.95 pg/mL,高級別組中血清IL-18水平為511.07±107.27 pg/mL,血清IL-18水平在兩組間的分布差異具有統(tǒng)計學(xué)意義(P0.01)。結(jié)論:血清IL-18水平與腦膠質(zhì)瘤存在關(guān)聯(lián),對于腦膠質(zhì)瘤的發(fā)生發(fā)展以及預(yù)后具有一定的臨床指導(dǎo)意義。第二部分IL-18基因多態(tài)性與腦膠質(zhì)瘤遺傳易感性的關(guān)系目的:探討IL-18基因多態(tài)性與腦膠質(zhì)瘤遺傳易感性的關(guān)系,為腦膠質(zhì)瘤的個體化治療提供科學(xué)依據(jù)。方法:運用Taqman-MGB技術(shù)檢測182例腦膠質(zhì)瘤患者和389例健康對照者的IL-18基因rs1946519、rs187238和rs549908三個位點的基因型分布。結(jié)果:研究對象的一般特征同第一部分;在健康對照組中,對IL-18基因三個位點(rs1946519、rs187238和rs549908)的三種基因型的頻率進行Hardy--Weinberg平衡檢驗,結(jié)果顯示,上述三位點的各基因型的實際頻數(shù)與理論頻數(shù)在對照組中的分布差別無統(tǒng)計學(xué)意義(χ12=0.67 P1=0.41,χ22=1.69 P2=0.19,χ32=0.46 P3=0.49);采用多因素logistic回歸分析,rs1946519和rs187238位點結(jié)果顯示,其雜合基因型、純合基因型以及雜合基因型和純合基因型合并的頻率與各自野生基因型的頻率相比差異均無統(tǒng)計學(xué)意義(P值均0.05);rs549908位點結(jié)果顯示,其雜合基因型AC在腦膠質(zhì)瘤組中分布顯著低于健康對照組(調(diào)整OR=0.64,95%CI=0.42-0.98),提示該位點AC基因型可顯著降低腦膠質(zhì)瘤的發(fā)病風(fēng)險,顯性模型顯示,與野生純合型AA相比,rs549908位點AC+CC基因型亦可顯著降低腦膠質(zhì)瘤的發(fā)病風(fēng)險(調(diào)整OR=0.59,95%CI=0.39-0.89);采用PHASE 2.0軟件推斷IL-18基因3個SNP位點(rs1946519、rs187238和rs549908)的單倍型及其頻率。采用多因素Logistic回歸方法進行分析結(jié)果顯示:與TGA單倍型相比,攜帶GGC單倍型的個體腦膠質(zhì)瘤發(fā)病風(fēng)險較低(調(diào)整OR=0.51,95%CI=0.26-0.99);采用多因素logistic回歸統(tǒng)計方法,分析IL-18基因SNPs位點多態(tài)性與不同級別腦膠質(zhì)瘤的關(guān)系,結(jié)果未發(fā)現(xiàn)IL-18基因SNPs位點多態(tài)性與不同級別腦膠質(zhì)瘤存在關(guān)聯(lián)(P值均0.05);采用方差分析方法,分析IL-18基因rs549908位點基因型分布與血清IL-18水平的關(guān)系。結(jié)果顯示,在腦膠質(zhì)瘤組和健康對照組中,rs549908位點不同基因型分組中血清IL-18水平有統(tǒng)計學(xué)差異(F=163.42,P0.01)。結(jié)論:IL-18基因多態(tài)性與腦膠質(zhì)瘤遺傳易感性存在關(guān)聯(lián),且可能是通過影響IL-18水平來影響腦膠質(zhì)瘤的發(fā)生、發(fā)展。
文內(nèi)圖片：
圖片說明：TaqMan探針法進行等位基因鑒定的結(jié)果（藍色代表野生純合基因型，綠色代表雜合基因型，紅色代表突變純合基因型）
[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

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