CTLA4基因多态性与炎症性肠病遗传易感性相关性研究

目的：系统评价细胞毒性T淋巴细胞相关抗原4（ CTLA-4）基因多态性与炎症性肠病发病风险的相关性。方法计算机检索PubMed、 EMbase、 WanFang Data、 CNKI、 CBM和VIP,查找关于CTLA4基因多态性与炎症性肠病发病风险的病例-对照研究,检索时限均从建库至今。2名评价员按照纳入与排除标准独立筛选文献、提取资料并评价纳入研究的方法学质量后,采用RevMan5．2和Stata12．0软件进行Meta分析。结果纳入2个CTLA?4基因位点： rs231775,及非转录区（ AT） n重复序列微卫星片段,共10个研究。 Meta分析结果显示： CTLA?4?rs231775基因非转录区（ AT） n重复序列多态性与炎症性肠病发病风险有相关性： rs231775多态性增加人群克罗恩病易感性[AG＋GG vs． AA： OR＝1．29,95％CI （1．05～1．59）, P＝0．02。 GG vs． AA： OR＝2．14,95％CI （1．14～4．04）, P＝0．02]; CTLA?4基因非转录区（AT）n重复序列≥118 bp片段人群组发生溃疡性结肠炎的可能性是非≥118 bp片段组的4．85倍（ P＜0．05）,前者发生克罗恩病的可能性是后者的3．82倍（P＜0．05）, CTLA?4基因非转录区（AT）n重复序列122 bp片段人群发生溃疡性结肠炎的可能性是非122 bp片段的15．5倍（ P＜0．05）。结论 CTLA?4?rs231775基因非转录区（ AT） n重复序列多态性会增加炎症性肠病发病风险。但鉴于纳入研究数量有限,尚需开展更多研究予以验证。     

SOD基因多态性与COPD易感性的Meta分析

目的 系统评价SOD中SOD1 +35A/C,SOD2 Val 16 Ala,SOD3 R213G基因多态性与慢性阻塞性肺疾病的相关性。方法 检索CBM、CNKI、万方、VIP、EmBase和PubMed等中英文数据库,收集上述基因多态性与COPD的关系。采用Stata 12.0软件进行统计分析,以病例组和对照组基因型分布比值比及其95%可信区间(95%CI)表示其关联强度。结果 共纳入研究11项,其中病例组5915例,对照组96831例。Meta分析结果显示,SOD1 +35A/C(CA vsAA:OR:1.31;95%CI:0.88~1.95)、SOD2 Val 16 Ala (TC vsTT: OR:1.31;95%CI:0.88~1.95;CC vsTT:OR:0.93;95%CI:0.68~1.28)、SOD3 R213G (CA vsAA:OR,0.98;95%CI:0.63~1.53)基因多态性可能与COPD易感性无关,SOD3 R213G相关研究异质性较大(I2=68.8%),分组分析结果显示异质性主要来自于吸烟人群中。结论 SOD1 +35A/C,SOD2 Val 16 Ala,SOD3 R213G基因多态性可能与COPD易感性无关,但在吸烟人群中SOD3 R213G多态性对COPD的影响需更多大样本的研究进一步证实。     

P73基因多态性与宫颈癌遗传易感性的关系及Meta分析

目的 探讨抑癌基因P73第2外显子的两个单核苷酸多态性(G4C14-A4T14,G4A)与宫颈癌遗传易感性的关系.方法 采用PCR-CTPP技术结合直接测序法检测皖南地区汉族人群218例宫颈癌患者和220例正常对照者P73基因多态性,分析P73基因多态性与宫颈癌发生的相关性,同时对世界不同群体的相关研究进行Meta分析.结果 在病例组和对照组中P73基因G4C14-A4T14多态位点基因型和等位基因分布差异无统计学意义.PCR-CT-PP技术检测结果与PCR-直接测序法一致.Meta分析结果显示,AT等位基因与亚洲人群宫颈癌发病显著相关(P＜0.05).结论 多个研究结果Meta分析显示P73基因G4C14-A4T14多态性可能与亚洲人群宫颈癌发病相关联,等位基因A4T14患宫颈癌的风险增加.     

炎症性肠病的MIF-173位点单核苷酸多态性研究

目的：探讨中国浙江地区汉族人群中巨噬细胞移动抑制因子（MIF）基因单核苷酸多态性（SNP）分布，分析其与炎症性肠病（IBD）的相关性。方法：分别应用四引物突变特异性扩增系统（ARMS）法和限制性片段长度多态性（RFLP）-PCR方法对142名健康个体和99例IBD患者MIF基因-173位点SNP多态性进行分型，并将PCR产物克隆及测序鉴定。结果：MIF基因-173位点检测到3种基因型，其基因型分布皆符合Hardy-Weinberg平衡定律。四引物ARMS法和RFLP-PCR两种方法结果完全一致。统计分析显示，溃疡性结肠炎（UC）患者MIF-173位点CC基因型频率15．5％显著高于正常人中的5．6％（P〈0．05）。MIF-173位点等位基因和基因型频率在IBD患者和正常人群中差异无统计学意义（P〉0．05）。进一步分析发现CC基因型与UC患者的临床特征无关。结论：四引物ARMS是一种准确、快速和经济的SNP测定方法。MIF-173位点CC基因型可能与UC的发生相关。     

肥大细胞与炎症性肠病

肥大细胞(MC)广泛分布于胃肠道,对胃肠粘膜分泌、吸收、粘膜血流、神经及平滑肌功能具有重要的调控作用.粘膜内MC数量及功能的改变、粘膜内IgE的作用、MC释放生物活性介质以及与神经、胃肠激素的相互作用等机制在炎症性肠病(IBD)的发生发展中有重要作用.MC稳定剂Ketotifen已应用于临床.     

肥大细胞与炎症性肠病

炎症性肠病（Inflammatoryboweldisease,IBD）包括溃疡性结肠炎（Ulcerativecolitis）和克罗恩病（Crohn’sdisease）,是一种原因不明的慢性非特异性肠道炎症,其发病机制主要和免疫、遗传、感染、应激等多种因素有关。近年来发现其发病与肥大细胞也密切相关。     

ADAM33基因遗传多态性与支气管哮喘易感性关系的Meta分析

目的:综合评价解整合素金属蛋白酶33 (ADAM33)基因Met764Thr和Pro774Ser位点多态性与哮喘易感性的关系.方法:按照统一的检索策略,检索Pubmed、Ovid-Medline、CNKI及维普数据库中有关ADAM33基因多态性与哮喘易感性关系的病例-对照研究,按照纳入和排除标准选择文献提取相关信息,应用Review Manager 5.0软件进行Meta分析.结果:本研究纳入国内外14篇合格文献,其中Met764Thr位点12篇,共3 418例哮喘病例和3 520例对照;Pro774Ser位点8篇,共2 793例哮喘病例和3 207例对照.Meta分析结果显示,携带764位点Met/Thr或Thr/Thr突变基因型患哮喘的危险性是野生型的1.56倍(OR=1.56,95％CI=1.09～2.22),Pro774Ser位点突变基因型也与哮喘危险性升高有关(OR=1.39,95％CI=1.00～ 1.93).将人群分层后,该两个位点多态性与哮喘的关联均仅见于中国人群(764位点:OR=2.73,95％CI=1.79 ～4.17,774位点:OR =2.32,95％CI=1.30 ～4.15).结论:ADAM33基因764和774位点的突变与哮喘的易感性升高有关.     

炎症性肠病相关肠纤维化模型的研究进展

肠纤维化是炎症性肠病（IBD）严重的并发症,至今尚无有效的药物治疗。肠纤维化是由反复发作的炎症和黏膜愈合导致细胞外基质沉积引起的,但是抑制炎症并不能阻止或逆转纤维化的形成。由于缺乏相关的动物模型目前关于肠纤维化和肠狭窄形成的潜在机制的认识是有限的。本文旨在综述已建立的和正在发展的肠道纤维化动物模型,着重阐述各种模型建立的方法、评价其优缺点、适用范围,为临床深入研究肠纤维化发病机制及治疗方法奠定基础。     

MMP-9 R279Q基因多态性与冠心病易感性的Meta分析

 目的 探讨MMP-9 R279Q基因多态性与冠心病易感性的关系。方法 检索PubMed,获取2012年1月1日以前发表的MMP-9 R279Q基因多态性与冠心病易感性的病例-对照研究。以冠心病组与对照组人群基因型分布的OR值及95%CI为效应指标,在纯合子比较模型、显性模型和隐性模型中采用固定效应方法进行合并分析, 并进行偏倚评估,应用STATA11.0软件进行统计学处理。结果 共纳入文献5篇,在MMP-9 R279Q多态性位点,基因型比较模型中合并OR值为0.925 (95% CI = 0.847-1.009),纯合子比较模型合并OR值为0.866 (95% CI = 0.713-1.052),显性模型合并OR值为0.909 (95% CI = 0.809-1.020),隐性模型合并OR值为0.902 (95% CI = 0.750-1.086)。结论 MMP-9 R279Q基因多态性可能与冠心病易感性无关。     

黄芪多糖对炎症性肠病模型大鼠NFATC4表达的影响

目的 观察黄芪多糖（APS）对炎症性肠病（IBD）模型大鼠结肠黏膜NFATC4表达及受损结肠黏膜的修复作用.方法 采用三硝基苯磺酸诱导IBD大鼠模型.45只大鼠随机分为假手术组、IBD模型组、APS低剂量组（100 mg·kg-1）、APS高剂量组（200 mg·kg-1）和地塞米松对照组（地塞米松0.3 mg·kg-1）.分别给予相应药物腹腔注射,每日1次.给药7 d后,乙醚麻醉下处死大鼠,取结肠组织进行形态学及病理组织学评分,实时PCR和ELISA法检测结肠组织NFATC4 mRNA和蛋白表达.结果 各组大鼠结肠组织形态学肉眼评分为：假手术组0分、IBD模型组（5.67 ± 0.87）分、APS低剂量组（3.56 ± 0.89）分、APS高剂量组（1.56 ± 0.53）分、地塞米松对照组（0.89 ± 0.78）分,组间差异总体上有统计学意义（F=69.195,P〈0.001）.病理学评分为：假手术组（0.11± 0.08）分,IBD模型组（5.67 ± 1.15）分、APS低剂量组（3.33 ± 0.58）分、APS高剂量组（1.33 ± 1.15）分、地塞米松对照组（1.67 ± 1.52）分,组间差异总体上有统计学意义（F=13.34,P〈0.01）.组织病理学检查显示APS可修复IBD模型大鼠受损结肠黏膜.NFATC4 mRNA表达APS高剂量组、APS低剂量组与地塞米松对照组均显著高于IBD模型组（P〈0.01）;仅APS高剂量组与地塞米松对照组NFATC4蛋白表达较IBD模型组显著增加（P〈0.001）.结论 APS可增加IBD模型大鼠NFATC4表达,对损伤结肠黏膜有修复作用,APS对NFATC4调控机制尚有待进一步研究.     

CTLA-4 polymorphisms and susceptibility to inflammatory bowel disease: A meta-analysis

Objective

The aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) polymorphisms are associated with susceptibility to ulcerative colitis (UC) and Crohn’s disease (CD).

Methods

The authors conducted a meta-analysis on associations between CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms, and (AT)n repeat in the 3′ untranslated region (UTR) and UC and CD susceptibility.

Results

A total of 15 comparison studies were considered in our meta-analysis. Meta-analysis revealed no association between UC and the CTLA-4 +49 G and CTLA-4 −318 T alleles in all subjects (OR = 0.982, 95% CI = 0.851–1.1339, p = 0.804; OR = 0.500, 95% CI = 0.223–1.124, p = 0.094). No association was found between UC and the CTLA-4 CT60 A/G polymorphism in Europeans. However, a significant association was observed between the longer allele (?118 bp) of the (AT)n and UC in Asian population (OR = 6.073, 95% CI = 4.246–8.684, p = 1.0 × 10⁻⁹). Meta-analysis of the CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms showed no association with CD.

Conclusions

This meta-analysis demonstrates that the CTLA-4 (AT)n repeat in 3′ UTR may be associated with susceptibility to UC in Asians, while no association was found between the CTLA-4 +49 A/G, −318 C/T, and CD60 A/G polymorphism and susceptibility to UC and CD.     

Correlations between TLR polymorphisms and inflammatory bowel disease: a meta-analysis of 49 case-control studies

Immunologic Research - Recently, the roles of toll-like receptor (TLR) polymorphisms in inflammatory bowel disease (IBD) were intensively explored, with conflicting results. Therefore, we performed...     

Association between toll-like receptors/CD14 gene polymorphisms and inflammatory bowel disease in Korean population

The innate immune response in patients who develop inflammatory bowel disease (IBD) may be abnormal. However, the exact role of Toll-like receptors (TLRs) / CD14 gene in the pathogenesis of IBD has not been fully elucidated. We aimed to investigate the association between polymorphisms of TLR1, 2, 4, 6, and CD14 gene and susceptibility to IBD in Korean population. A total 144 patients of IBD (99 patients with ulcerative colitis, 45 patients with Crohn's disease) and 178 healthy controls were enrolled. Using a PCR-RFLP, we evaluated mutations of TLR1 (Arg80Thr), TLR2 (Arg753Gln and Arg677Trp), TLR4 (Asp299Gly and Thr399Ile), TLR6 (Ser249Pro) genes and the -159 C/T promoter polymorphism of CD14 gene. No TLR polymorphisms were detected in Korean subjects. T allele and TT genotype frequencies of CD14 gene were significantly higher in IBD patients than in healthy controls. In subgroup analysis, T allelic frequency was higher in pancolitis phenotype of ulcerative colitis. In Korean population, the promoter polymorphism at -159 C/T of the CD14 gene is positively associated with IBD, both ulcerative colitis and Crohn's disease.     

Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease

Interleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL-1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1alpha, IL-1beta, IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1alpha and IL-1beta were not detected. IL-1sRII levels were marginally lower in CD (-10%) and UC (-9%), whereas IL-1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively (P < 0.01) with Crohn's disease activity index (r = 0.53), C-reactive protein (r = 0.46) and alpha1-acid glycoprotein (r = 0.42). In colonic explant cultures, IL-1alpha and IL-1Ra levels were elevated in non-lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non-lesional UC. IL-1beta was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL-1sRII levels were elevated in non-lesional CD (+65%), but remained unchanged in lesional CD, non-lesional and lesional UC. IL-1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL-1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL-1sRII may dampen colonic inflammation in CD, but not in UC.     

Association between intestinal microbiota and inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn''s disease (CD) and ulcerative colitis (UC), has emerged as a global disease with high incidence, long duration, devastating clinical symptoms, and low curability (relapsing immune response and barrier function defects). Mounting studies have been performed to investigate its pathogenesis to provide an ever‐expanding arsenal of therapeutic options, while the precise etiology of IBD is not completely understood yet. Recent advances in high‐throughput sequencing methods and animal models have provided new insights into the association between intestinal microbiota and IBD. In general, dysbiosis characterized by an imbalanced microbiota has been widely recognized as a pathology of IBD. However, intestinal microbiota alterations represent the cause or result of IBD process remains unclear. Therefore, more evidences are needed to identify the precise role of intestinal microbiota in the pathogenesis of IBD. Herein, this review aims to outline the current knowledge of commonly used, chemically induced, and infectious mouse models, gut microbiota alteration and how it contributes to IBD, and dysregulated metabolite production links to IBD pathogenesis.     

The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications

Inflammatory bowel disease (IBD) is associated with a hypercoagulable state and subsequently with an increased risk for venous thromboembolism (VTE). VTE in IBD is characterized by a high recurrence rate and is associated with the disease activity. Acquired endothelial dysfunction, abnormalities of platelets, activation of coagulation system and impaired fibrinolysis are the main changes in the coagulation state in IBD. The development of VTE in IBD has been considered to be the result of multiple interactions between acquired and inherited risk factors. The treatment of VTE in IBD patients is recommended to be similar and to follow the same protocols as for non-IBD patients. In the clinical practice, the management of IBD patients and especially the hospitalized patients should include thromboprophylaxis.     

Assessment of systemic genetic damage in pediatric inflammatory bowel disease

The etiology of distal site cancers in inflammatory bowel disease (IBD) is not well understood and requires further study. We investigated whether pediatric IBD patients' blood cells exhibit elevated levels of genomic damage by measuring the frequency of mutant phenotype (CD59-/CD55-) reticulocytes (MUT RET) as a reporter of PIG-A mutation, and the frequency of micronucleated reticulocytes (MN-RET) as an indicator of chromosomal damage. IBD patients (n = 18 new-onset disease, 46 established disease) were compared to age-matched controls (constipation or irritable bowel syndrome patients from the same clinic, n = 30) and young healthy adults age 19–24 (n = 25). IBD patients showed no indication of elevated MUT RET relative to controls (mean ± SD = 3.1 ± 2.3 × 10⁻⁶ vs. 3.6 ± 5.6 x 10⁻⁶, respectively). In contrast, 59 IBD patients where %MN-RET measurements were obtained, 10 exceeded the upper bound 90% tolerance interval derived from control subjects (i.e., 0.42%). Furthermore, each of the 10 IBD patients with elevated MN-RET had established disease (10/42), none were new-onset (0/17) (p = .049). Interestingly, each of the subjects with increased chromosomal damage was receiving anti-TNF based monotherapy at the time blood was collected (10/10, 100%), whereas this therapy was less common (20/32, 63%) among patients that exhibited ≤0.42% MN-RET (p = .040). The results clearly indicate the need for further work to understand whether the results presented herein are reproducible and if so, to elucidate the causative factor(s) responsible for elevated MN-RET frequencies in some IBD patients.     

Analysis of diamine oxidase gene polymorphisms in patients with inflammatory bowel disease

Inflammation Research -     

Breed-independent toll-like receptor 5 polymorphisms show association with canine inflammatory bowel disease

Inflammatory bowel disease (IBD) is thought to be the most common cause of vomiting and diarrhoea in dogs. Although IBD can occur in any canine breed, certain breeds are more susceptible. We have previously shown that polymorphisms in the TLR4 and TLR5 (toll-like receptor) genes are significantly associated with IBD in German Shepherd dogs (GSDs). In order to allow for the development of novel diagnostics and therapeutics suitable for all dogs suffering from IBD, it would be useful to determine if the described polymorphisms are also significantly associated with IBD in other breeds. Therefore, the aim of this study was to investigate whether polymorphisms in the canine TLR4 and TLR5 genes are associated with IBD in other non-GSD canine breeds. The significance of the previously identified non-synonymous single nucleotide polymorphisms (SNPs) in the TLR4 (T23C, G1039A, A1571T and G1807A) and TLR5 genes (G22A, C100T and T1844C) were evaluated in a case-control study using a SNaPSHOT multiplex reaction. Sequencing information from 85 unrelated dogs with IBD consisting of 38 different breeds was compared with a breed-matched control group consisting of 162 unrelated dogs. Indeed, as in the GSD IBD population, the two TLR5 SNPs (C100T and T1844C) were found to be significantly protective for IBD in other breeds (P = 0.023 and P = 0.0195 respectively). Our study suggests that the two TLR5 SNPs, C100T and T1844C could play a role in canine IBD as these were found to be protective factors for this disease in 38 different canine breeds. Thus, targeting TLR5 in the canine system may represent a suitable way to develop new treatment for IBD in dogs.