溶質相關載體26A3基因多態性和潰瘍性結腸炎的相關性(碩士)

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溶質相關載體26A3基因多態性和潰瘍性結腸炎的相關性(碩士)(論文25000字)
中文摘要
研究背景和目的 炎癥性腸病(IBD)包括潰瘍性結腸炎(UC)和克羅恩病(CD),是病因尚不完全明確的腸道慢性非特異性炎癥性疾病。目前的研究表明遺傳易感人群在環境因素作用下,腸道細菌引起不恰當并且難以控制的炎癥反應從而導致疾病的發生發展。UC作為IBD的一種表現形式,以慢性復發性腸道炎癥為特點,主要臨床表現為腹痛、腹瀉及粘液膿血便。大量研究顯示遺傳因素和UC密切相關,分子生物學領域的不斷發展為研究UC相關基因的多態性檢測提供了強大的技術支持。腹瀉是UC最常見的癥狀,近年有學者提出腸道溶質載體的功能受損所導致水和電解質的吸收分泌失衡與UC相關性腹瀉關系密切,故溶質載體可能成為治療UC的靶點。SLC26A3是一種腸道Cl-/HCO3-轉運體,主要在結腸和 Na+ /H+交換體亞型3(NHE3)共同調節NaCl的吸收。學者們發現在UC的發展過程中,SLC26A3與炎癥因子和腸黏膜免疫系統相互作用,并且SLC26A3的轉運功能障礙與腸黏膜的屏障損害平行。故而提出改善SLC26A3的功能有利于控制UC疾病的發生和發展。來自亞洲人群的研究結果顯示rs7810937, rs7785539和 rs2108225是SLC26A3基因上最常見的SNP位點,均位于SLC26A3基因啟動子上游區域。目前研究表明這3個SNP發生基因突變后可能會影響SLC26A3的轉錄和表達,造成腸黏膜細胞中Cl-的重吸收和HCO3-的分泌功能障礙,從而導致腹瀉的發生。本研究擬在浙江籍漢族人群中探討SLC26A3基因中3個位點(rs2108225,rs7810937和rs7785539)的多態性與 UC 易感性的關系,為進一步闡明 UC 的遺傳學發病機制提供線索。
方法收集291例 UC 患者和380名年齡、性別相匹配的健康對照者,采用多重 Snapshot 技術檢測SLC26A3(rs7810937, rs7785539和rs2108225) 3種單核苷酸多態性(SNP),并進行連鎖不平衡和單倍型分析。在UC組和對照組中采用χ2檢驗分析SLC26A3(rs7810937, rs7785539和rs2108225) 3個SNP的基因型分布是否符合Hardy-Weinberg平衡定律。UC組和對照組的性別、年齡比較分別采用χ2檢驗和兩獨立樣本t檢驗。在UC組和對照組之間采用非條件Logistic回歸分析比較SLC26A3基因多態性的分布差異及其對UC患者臨床病理特征的影響。采用Haploview 4.2軟件進行連鎖不平衡及單倍型分析,并在UC組和對照組之間采用χ2檢驗比較各單倍型頻率差異。P<0.05認為有差異有統計學意義。以上數據均輸入SPSS 17.0統計軟件處理。
結果 UC組中rs2108225突變等位基因(G)和基因型(AG+GG)的頻率均高于對照組(65.46%比58.68%,P=0.011;87.29%比81.58%,P=0.045)。與輕中度UC患者相比,重度UC患者中rs7785539突變等位基因(C)和基因型(GC+CC)的頻率均顯著增高(15.79%比6.13%,P=0.003;26.32%比12.25%,P=0.020)。(rs7810937,rs7785539和rs2108225) 3個SNP位點彼此連鎖,但UC和對照組中各單倍型無顯著差異(P>0.05) 。
結論SLC26A3 (rs2108225) 基因突變可能增加UC發病風險,rs7785539基因多態性與UC疾病嚴重程度相關,(rs7810937,rs7785539和rs2108225) 構建的單倍型與UC發病風險無關。
關鍵詞:溶質相關載體26A3;潰瘍性結腸炎;單核苷酸;多態性;單倍型

A Study on the Associations of Ulcerative Colitis with    Solute-linked Carrier Family 26 Member A3 Gene Polymorphisms

Abstract
Background and Aims  Inflammatory bowel diseases (IBD) is a chronic inflammatory condition of the gastrointestinal tract consists of two main clinical entities whichare ulcerative colitis (UC) and Crohn’s disease (CD). Although the exact etiology andpathogenesis of IBD still remain unknown, most of the viewspresume that combinedgenetic and environmental factors that cause dysregulated mucosalimmune responses to the gut flora in genetically susceptible individuals. As oneoftheprincipalformsofIBD,the main symptomsof UC include abdominal pain and diarrhea mixed withblood.In recent years, some scholars have proposed that the impaired function of the intestinal ion transporters and channels caused the imbalance of the absorption and secretion withUC. These studies have shown that the predominant mechanismof diarrhea in UC involves impairment of water and electrolyte absorption, with very little role if any played by anion secretion. An understanding of the mechanisms of solute-linked carrier family (SLC) dysregulation isimportant for identification of novel therapeutic targets for thetreatment of IBD-associated diarrhea. Thetransport properties of solute-linked carrier family 26 member A3 (SLC26A3)have been studied in detail, revealing that it is a Cl-/HCO3-exchangerthat is functionally coupled to NHE3 (Na+/H+exchanger isoform 3) in the ileum and colon.During the development of UC, SLC26A3, inflammatory cytokines and intestinal mucosal immune system interact with each other, and the transport dysfunction of SLC26A3 is parallel to the intestinal mucosal barrier damage. Therefore, improving the function of SLC26A3 is beneficial to control the occurrence and development of UC.The results of the study from Asian populations showed that rs7810937, rs7785539 and rs2108225 are all located in the upstream region of SLC26A3 gene promoter, and are the most common SNP sites on SLC26A3 genes. The present study shows that the mutation of these three SNPsmay affect thetranscription and expression of SLC26A3, resulting in Cl- reabsorption and HCO3- secretion dysfunction in intestinal mucosal cells, leading to the occurrence of diarrhea.In this study, we aimed to find the association of ulcerative colitis (UC) with the polymorphisms of SLC26A3 gene of Han nationalitypatients in Zhejiang province and to provide clues to further elucidate the genetic pathogenesis of UC.
Methods  A total of 291 UC patients and 380 healthy subjects matched for age and sex were enrolled.The genetic polymorphisms of SLC26A3 (rs7810937, rs7785539 and rs2108225) were detected by Snapshot technique.The analyses of linkage disequilibrium (LD) and haplotype were performed in all study subjects.Theχ2 test was used to analyze whether the genotype distribution of the 3 SNP(rs7810937, rs7785539 and rs2108225) conform to the Hardy-Weinberg equilibrium rulein the UC group and control. The sex and age of these twogroups were compared with theχ2 test and the independent sample test. The unconditional Logistic regression analysis was used to compare the distribution difference of SLC26A3 gene polymorphism and its effect on the clinicopathological features of UC patients.The Haploview 4.2 software was used for linkage disequilibrium and haplotype analysis, and the frequency differences of haplotypes were compared between these two groups by theχ2 test.P<0.05 was considered significant.All the data were treated with SPSS 17.0 statistical software.
Results  The mutant allele (G) and genotype (AG+GG) of SLC26A3 (rs2108225)  were more frequent in UC patients than in the controls (65.46% vs 58.68%, P=0.010; 87.29% vs 81.58%, P=0.045, respectively). The mutant allele (C) and genotype (GC+CC) of SLC26A3 (rs7785539) were more prevalent in severe UC patients than in the other patients (15.79% vs 6.13%, P=0.003; 26.32% vs 12.25%, P=0.020). Moreover, the three SNPs (rs781093,rs7785539 and rs2108225) of SLC26A3 gene were found to be in a strong LD. However, there were no significant difference of haplotypes between UC and controls.
Conclusions The mutation ofSLC26A3 (rs2108225) might contribute to enhancing the risk of UC.SLC26A3 (rs7785539) gene polymorphisms were correlated with the severity of UC.The haplotypes formed by (rs7810937,rs7785539 and rs2108225)  were not significantly associated with the susceptibility of UC.
[Key Words] SLC26A3; Ulcerative colitis; Single nucleotide polymorphism; Haplotype

目錄
英文縮略詞表   
中文摘要   
英文摘要   
前言   
材料與方法   
結果   
分析與討論   
參考文獻   
附錄   
致謝   
綜述及參考文獻   

中英文縮寫對照表
英文縮寫    英文名稱    中文名稱
3’UTR    3’Untranslated Region    3’非翻譯區
5’UTR    5’Untranslated Region    5’非翻譯區
ABI    Applied Biosystems    美國應用生物系統公司
CD    Crohn’s disease    克羅恩病
cDNA    complementary DNA    互補脫氧核糖核酸
CFTR    Cystic Fibrosis Transmembrane  Conductance Regulator    囊性纖維跨膜轉導調控因子
CLD    Congenital chloridediarrhea    先天性失氯性腹瀉
CI    Confidence interval    可信區間
dNTP    deoxyribonucleoside triphosphate    三磷酸脫氧核糖核苷
ddNTP    dideoxyribonucleoside triphosphate    雙脫氧核苷三磷酸
DSS    Dextransulfatesodium    葡聚糖硫酸鈉
EDTA    Ethylene Diamine Tetraacetic Acid    乙二胺四乙酸二鈉
ENaC    Na+Channel    鈉離子通道
EPEC    enteropathogenic E. coli    腸致病型大腸埃希菌
GWAS    genome-wide association study    全基因組關聯研究
HNF4A    Hepatocyte Nuclear Factor 4A    肝細胞核因子4A
Hi-Di    Highly deionized-formamide    高度去離子甲酰胺
IBD    Inflammatory bowel diseases    炎癥性腸病
IFN    Interferon    干擾素
IL-1β    interleukin-1β    白細胞介素1β
LA    Lacticacid bacteria    乳酸桿菌
LD    linkage disequilibrium    連鎖不平衡
LPA    lysophosphatidic acid    溶血磷脂酸
MIF    macrophage migration inhibitory factor    巨噬細胞遷移抑制因子
MAPK    mitogen-activated protein kinase    有絲分裂原活化蛋白激酶
NHE3    Na+/H+exchanger-isoform3        Na+/H+交換體亞型3
NHERF    Na + /H + exchanger regulating factor    鈉氫交換子調節因子
PDZ    PDZ-domain proteins    盤狀同源區域(PDZ結構蛋白) 
RAGE    receptor for advanced glycation   endproduct    晚期糖基化終末產物受體
SAP    Shrimp Alkaline Phosphatase    蝦堿性磷酸酶
SLC        solute-linked carrier family    溶質相關載體
SLC26A3    solute-linked carrier family 26 member A3        溶質相關載體26A3
SNP    single nucleotide polymorphism    單核苷酸多態性
STAS    sulfate transporter anti-sigma domain    硫酸鹽轉運及抗δ因子
TNF    tumor necrosis factor    腫瘤壞死因子
UC    ulcerative colitis    潰瘍性結腸炎

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