【摘要】：目的： 炎癥性腸病(inflammatory bowel diseases, IBD)是一組病因不明的慢性腸道非特異性炎癥性疾病,主要包括潰瘍性結腸炎(ulcerative colitis, UC)和克羅恩病(Crohn's disease, CD)。目前研究證實腸道菌群失調在IBD的發(fā)病機制中起關鍵作用。組織血型抗原是某些腸道菌群的粘附受體,這些抗原的表達主要是由巖藻糖基轉移酶(FUT)2和FUT3基因編碼產生的巖藻糖基轉移酶調控的。研究表明FUT2基因多態(tài)性不僅與腸道菌群的構成相關,還與1型糖尿病、原發(fā)性硬化性膽管炎等自身免疫性疾病的易感性有關。至今針對FUT2與IBD相關性的研究證實FUT2基因是CD的易感基因,但與UC的關系尚不明確。此外,目前罕見FUT3基因多態(tài)性與UC的易感性研究。鑒于FUT2和FUT3基因在調控組織血型抗原的表達過程中具有協(xié)同作用,本研究擬在中國浙江漢族人群中同時探討FUT2和FUT3基因多態(tài)性及單倍型與UC的關系,旨在為闡明UC的遺傳學發(fā)病機制提供依據。 方法： 于2008年5月-2013年5月間,從包括溫州醫(yī)科大學附屬第二醫(yī)院、溫州醫(yī)科大學附屬第一醫(yī)院及溫州市中心醫(yī)院等在內的溫州市各大中型醫(yī)院的消化內科門診和住院部,收集確診的UC患者233例,UC的診斷標準和疾病評估標準根據中華醫(yī)學會消化病學分會2012年制定的“炎癥性腸病診斷與治療的共識意見”。同期在溫州醫(yī)科大學附屬第二醫(yī)院體檢中心收集292例性別、年齡匹配的健康對照組。從每個受試對象抽取約5ml外周靜脈血至EDTA抗凝管中。提取全基因組DNA后經多重PCR擴增目的基因,再采用SNaPshot法檢測FUT2(C357T、A385T、G428A)和FUT3(T59G、G508A、T1067A)基因多態(tài)性。用χ2檢驗分析上述各位點的基因型分布是否符合Hardy-Weinberg平衡定律,并分析UC組和正常對照組之間,各位點的等位基因和基因型的頻率差別。采用Haploview4.2軟件進行連鎖平衡和單倍型分析。多因子降維法分析基因-基因交互作用(FUT2和FUT3基因)和基因-環(huán)境(吸煙)交互作用。 結果： 經重復檢測和直接測序法驗證,SNaPshot法基因分型的準確率為100%。各位點的基因型分布均符合Hardy-Weinberg平衡定律。在UC組和對照組之間,FUT2(C357T、A385T、G428A)和FUT3(T59G, G508A、T1067A)六個位點的等位基因與基因型頻率分布均無統(tǒng)計學差異(均P0.05)。經非條件Logistic回歸分析發(fā)現在廣泛結腸炎患者中,FUT3(T59G)的突變等位基因(G)和基因型(TG+GG)的頻率低于直腸型和左半結腸型UC患者[17.5%(35/200)比25.9%(69/266)，，P=0.022, OR=0.530,95%CI:0.308-0.914和31.0%(31/100)比45.9%(61/133), P=0.030, OR=0.606,95%CI:0.384-0.956]。進一步連鎖不平衡分析發(fā)現,FUT2和FUT3兩基因之間不存在連鎖不平衡,但發(fā)現FUT2基因(C357T)和(A385T)兩個位點存在連鎖不平衡(D'=1.00,r2=0.102)；FUT3基因(T59G)和(G508A)兩個位點也存在連鎖不平衡(D'=0.95,r2=0.508)。采用Haploview4.2軟件構建單倍型后,結果表明各單倍型在UC組和對照組之間的分布無統(tǒng)計學差異(均P0.05)。多因子降維法分析這表明FUT2和FUT3基因,以及基因-環(huán)境(吸煙)之間不存在交互作用。 結論： FUT2基因多態(tài)性及單倍型與UC的易感性無關；FUT3(T59G)基因突變可能影響UC患者的病變部位。
[Abstract]:Purpose: Inflammatory bowel disease (IBD) is a group of non-specific inflammatory diseases of chronic intestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD).). At present, it is proved that the intestinal flora imbalance plays a key role in the pathogenesis of IBD The expression of these antigens is mainly regulated by the glycosyltransferase (FUT) 2 and the encoding of the FUT3 gene, and the expression of these antigens is mainly regulated by the encoding of the glycosyltransferase (FUT) 2 and the FUT3 gene. The research shows that the polymorphism of the FUT2 gene is not only related to the composition of the intestinal flora, but also the susceptibility of autoimmune diseases such as type 1 diabetes, primary sclerosing cholangitis and the like. The relationship between FU2 and IBD has confirmed that the FU2 gene is an easy-to-sense gene of the CD, but the relationship with the UC is unknown. in addition, it is rare that that polymorphism of the Fut3 gene and the susceptibility to UC are rare. In view of the synergistic effect of FU2 and FUT3 gene in regulating the expression of blood group antigen of tissue, this study is to study the relationship between FU2 and Fut3 gene polymorphism and single-fold and UC in the Han population of Zhejiang, China, aiming at providing the basis for elucidating the genetic pathogenesis of UC. It was reported. Methods: From May 2008 to May, 2013, the patients with UC were collected from the Department of Internal Medicine and the Hospitalization Department, including the Second Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of Wenzhou Medical University and the Central Hospital of Wenzhou. In 233 cases, the criteria for the diagnosis of UC and the criteria for the assessment of the disease are based on the criteria for the diagnosis of digestive diseases of the Chinese Medical Association, which will be formulated in 2012./ trunk>. In the same period, 292 cases of sex and age were collected in the second hospital in Wenzhou Medical University. Healthy control group. Approximately 5ml of peripheral venous blood was extracted from each subject to the EDT A anti-coagulation tube. After the whole genome DNA is extracted, the target gene is amplified by multiple PCR, and the FUT2 (C357T, A385T, G428A) and FUT3 (T59G, G508A, T1067A) are detected by the SNaPshot method. The genotype distribution of the above-mentioned points was analyzed by means of a two-step method to determine whether the Hardy-Weinberg equilibrium law was in line with the Hardy-Weinberg equilibrium law, and the alleles and genotypes of each point were analyzed between the UC group and the normal control group. the frequency difference of the system is different, and the linkage balance is carried out by using the Hapaloview4. 2 software. Single-fold analysis. Analysis of gene-gene interaction (FU2 and FUT3 genes) and gene-environment (smoking) Interaction Action. Results: The gene typing of the SNaPshot method was verified by repeated detection and direct sequencing. The accuracy rate is 100%. The genotype distribution of all points is in accordance with Hardy-Wei. The law of nberg equilibrium. There was no statistical difference between the alleles of FU2 (C357T, A385T, G428A) and FUT3 (T59G, G508A, T1067A) and the distribution of genotype frequencies between the UC and the control group. The frequency of mutant allele (G) and genotype (TG + GG) of FUT3 (T59G) in patients with extensive colitis was found to be lower than that of the patients with colorectal and left-and semi-colon UC[170.5% (35/ 200), 25.9% (69/ 266), P = 0.022, OR = 0.530, 95% CI: 0.308-0.914 and 31.0% (31/ 100) than 40.9% (61/ 133), P = 0.030, OR = 0.606, 95% CI: 0.3 The further linkage disequilibrium analysis found that there was no linkage disequilibrium between the two genes of FU2 and Fut3, but the linkage disequilibrium (D '= 1.00, r2 = 0.102) was found between the two sites of the FUT2 gene (C357T) and (A385T), and the linkage disequilibrium (D' = 0.95, r2 = 0. 508) The results showed that the distribution of the single-fold type in the UC group and the control group was not statistically significant after the single-fold type was constructed using the Hapaloview4. 2 software. Isomorphism (all P0.05). The multi-factor descending method analysis showed that the FU2 and FUT3 genes, as well as the gene-environment (smoking) No, no, no. Conclusion: The polymorphism of FU2 gene and the susceptibility of single-fold to UC are not related to the susceptibility to UC, and the gene mutation of FUT3 (T59G)
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R574.62

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