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。     

溃疡性结肠炎的IL-1β、IL-1RA、LMP2基因多态性研究

目的研究溃疡性结肠炎(UC)病人的R-1β、IL-1RA、LMP2基因多态性,并分析其与抗中性粒细胞胞浆抗体(AN-CA)及临床分型的关系.方法用PCR-限制性片段多态性(PCR-FLP)方法和序列特异性引物-PCR(PCR-SSP)方法分别对81例UC病人和114名健康者进行IL-1β、LMP2和IL-1RA基因多态性分析.结果UC病人和健康者之间IL-1β、IL-1RA和LMP2各基因型和基因频率比较均无显著性差异(P＞0.05);当UC病人分为ANCA(+)组和ANCA(-)组后,发现ANCA(+)组IL-1RA等位基因2频率高于ANCA(-)组(13.7%对3.3%,P＜0.05),其它各基因型及基因频率比较,统计学上均无显著性差异(P＞0.05).结论中国汉族UC病人与IL-1β、IL-1RA、LMP2基因多态性无关联,但ANCA(+)UC病人IL-1RA等位基因2频率明显增加.     

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。     

IL-2基因多态性与中国汉族人群特发性扩张型心肌病的相关性研究

目的 研究中国西南地区汉族特发性扩张型心肌病(idiopathic dilated cardiomyopathy,IDCM)患者白细胞介素-2(interleukin-2,IL-2)基因启动子区-384T/G、-475A/T、-631G/A多态性与IDCM的相关性.方法 采用聚合酶链反应-限制性片段长度多态性技术分析中国西南地区无血缘关系的109例汉族IDCM患者和210名正常对照者IL-2基因启动子区-384、-475、-631位点的单核苷酸多态性.结果 IL-2基因启动子区-384位点TT+TG基因型频率和T等位基因频率在IDCM患者中升高,与正常对照组相比差异有统计学意义(分别为95.41%vs.87.62%,P=0.042和72.94%vs.64.52%,P=0.039);而IL-2基因-631位点与-475位点基因型和等位基因频率在IDCM组与正常对照组之间无差异.结论 IL-2基因启动子区单核苷酸多态性与人类IDCM相关,IL-2基因启动子区-384位点T等位基因可能会增加发生IDCM的危险性.     

PTPN2基因单核苷酸多态性与中国东北地区人群溃疡性结肠炎的关系

目的探讨我国东北地区人群PTPN2 rs2542151基因多态性与溃疡性结肠炎(ulcerative colitis,UC)遗传易感性、疾病活动性和严重性的关系。方法收集115例UC患者和99例健康对照者全血,应用TAQMAN探针,Realtime-PCR检测PTPN2 rs2542151位点等位基因多态性。结果 UC组PTPN2 rs2542151 T等位基因频率,G等位基因频率分别为79.13%,20.87%;对照组分别为85.35%,14.65%,差异无统计学意义(0.05)。GG纯合子相对于TT纯合子和TG杂合子UC易感性较健康对照组有显著差异(=0.042)。基因型是TG的患者病情为重度的可能性是GG的11.553倍(0.05)。PTPN2 rs2542151位点基因多态性与UC患者的发病年龄、性别、血红蛋白、血沉、C反应蛋白、血小板、临床分型及发病部位无关(0.05)。结论 PTPN2 rs2542151单核苷酸多态性与中国东北地区人群UC易感性相关,PTPN2 rs2542151基因突变可影响UC的病情严重程度。     

甲状腺球蛋白基因外显子33单核苷酸多态性与Graves病停药后复发的相关性分析

目的:探究甲状腺球蛋白基因外显子33单核苷酸多态性(E33SNP)与Graves病(GD)复发的相关性,为临床预测GD抗甲状腺药物(ATD)治疗后的复发提供合理性依据。方法:选取健康对照者232例以及GD治疗后停药的患者243例,且根据GD停药患者的复发情况将观察组分为A、B、C 3个亚组:77例治疗后1年内复发者为A组,86例治疗后1~2年内复发者为B组,80例治疗后2年内未复发者为C组。利用RT-PCR检测对照组和观察组的E33SNP进行分型,对比分析对照组和观察组不同基因型的比率及观察组不同甲状腺球蛋白基因型患者的游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)和促甲状腺激素受体抗体(TRAb)水平,以及眼征、甲状腺肿大程度等临床资料,且对观察组不同基因型患者在治疗后2年内的累积有效率进行对比分析。结果:观察组与对照组E33SNP的基因型差异无统计学显著性,但观察组各个亚组间E33SNP基因型差异具有统计学显著性(P0.05)。对观察组的A、B、C 3个亚组间不同基因型患者各项甲状腺功能相关指标进行对比分析表明,不同基因型患者的TSH、FT3、FT4水平及甲状腺肿大程度的差异无统计学显著性,而TRAb水平和眼征发生率的差异具有统计学显著性(P0.05)。此外,E33SNP T/T型GD患者ATD治疗后2年内的累积有效率为61.8%,E33SNP T/C型患者为42.6%,E33SNP C/C型患者为21.3%,差异具有统计学显著性(P0.05)。结论:E33SNP C/C型GD患者停药后的TRAb水平以及眼征发生率明显偏高,在ATD治疗后更加容易复发,E33SNP T/T型患者则呈现相反的趋势,复发率明显偏低,因此E33SNP C/C型GD患者采用其它治疗方式或者联合治疗方式可能更加合理。     

IL-1Ra，IL-1Ra基因多态性与溃疡性结肠炎

IL - 1Ra,IL - 1Ra基因多态性与溃疡性结肠炎 (U C)的相关性研究是从遗传基因角度探讨了 UC的发病。通过对该方面深入研究可望进一步认识到 U C发病机制 ,为其诊断及治疗开辟新途径     

IL-6基因单核苷酸多态性与腰椎间盘疾病的关联研究

目的： 研究汉族人白细胞介素6（IL-6）基因启动子G-597-A、G-572-C和G-174-C、5号外显子T15-A和C132-T单核苷酸多态性与腰椎间盘疾病关系。 方法： 采用聚合酶链反应技术，扩增81例腰椎间盘疾病患者和101例正常对照者中分别包含启动子G-597-A、G-572-C、G-174-C和5号外显子T15-A、C132-T位点的片段，直接测序法检测其中的单核苷酸多态性情况，并比较两组中单核苷酸多态性与腰椎间盘疾病的关系。同时，利用MRI检测两组的椎间盘退变情况，并分析其中小于45岁者单核苷酸多态性与椎间盘退变的关系。 结果： 腰椎间盘疾病病例组及对照组中均未检测到启动子G-597-A和G-174-C、5号外显子T15-A和C132-T单核苷酸多态性情况，仅启动子G-572-C位点存在GG、CG和CC 3种表型。但启动子G-572-C单核苷酸多态性与腰椎间盘疾病及椎间盘退变严重程度无关。 结论： 在汉族人中，IL-6基因仅存在G-572-C单核苷酸多态性，但G-572-C单核苷酸多态性与椎间盘病变及其发病基础椎间盘退变并无关联。     

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。     

Genetic variants in the HLA-G region are associated with Kawasaki disease

Kawasaki disease is an acute, self-limited vasculitis of infants and children, manifest as fever and signs of mucocutaneous inflammation. Treatment with high-dose immunoglobulin reduces systemic inflammation and prevents coronary artery lesions in Kawasaki disease. In this study, we investigated the possible association of the major histocompatibililty complex (MHC) region for the susceptibility to Kawasaki disease using an MHC panel of 2360 single nucleotide polymorphism (SNP) markers. Analysis of data obtained from screening MHC-specific SNP chips with 48 case and 90 control subjects revealed five candidate loci with significance levels of uncorrected p < 0.01. However, only one candidate locus (HLA-G) was confirmed to have a significant association with Kawasaki disease (rs2523790, odds ratio [OR] = 3.00, 95% confidence interval [95% CI] = 1.14–7.91, uncorrected p = 0.0263) in the replication study using 44 new case subjects and the previous 90 controls. In the fine mapping of the HLA-G locus, in particular, a nonsynonymous SNP (C/A) of the HLA-G gene (rs12722477, Leu134Ile) was significantly associated with Kawasaki disease (OR = 3.23, 95% CI = 1.12–9.32). A subgroup analysis showed that this association was more apparent in patients with coronary artery aneurysms (OR = 4.02, 95% CI = 1.23–13.19). Therefore, our results indicate that HLA-G may play a crucial role for the susceptibility to Kawasaki disease.     

杀菌/通透性增加蛋白基因Glu216Lys多态性与中国汉族人群炎症性肠病无关

 目的：探讨杀菌/通透性增加蛋白（BPI）基因Glu216Lys多态性与中国汉族人群炎症性肠病（IBD）发病及各种临床特征的相关性。方法：纳入286例确诊的汉族IBD患者［173例克罗恩病（CD）和113例溃疡性结肠炎（UC）］及年龄、性别匹配的332名健康人进行病例对照研究。采用引物介导的限制性分析PCR方法检测基因分型;应用单因素分析和Logistic回归模型分析该位点多态性对IBD发病及临床特征的影响。结果：CD和UC病例组与正常对照组间Glu216Lys基因型和等位基因频率差异均无统计学意义（均P>0.05）;进一步分析Glu216Lys与CD和UC的临床特征关系,差异均无统计学意义（P>0.05）。结论：BPI基因 Glu216Lys多态性与中国汉族人群IBD发病和临床特征无明显相关。IBD的遗传易感性具有种族差异性。     

Escherichia coli isolates from patients with inflammatory bowel disease: ExPEC virulence- and colicin-determinants are more frequent compared to healthy controls

A set of 178 Escherichia coli isolates taken from patients with inflammatory bowel disease (IBD) was analyzed for bacteriocin production and tested for the prevalence of 30 bacteriocin and 22 virulence factor determinants. Additionally, E. coli phylogenetic groups were also determined. Pulsed-field gel electrophoresis (PFGE) was used for exclusion of clonal character of isolates. Results were compared to data from a previously published analysis of 1283 fecal commensal E. coli isolates.The frequency of bacteriocinogenic isolates (66.9%) was significantly higher in IBD E. coli compared to fecal commensal E. coli isolates (54.2%, p < 0.01). In the group of IBD E. coli isolates, a higher prevalence of determinants for group B colicins (i.e., colicins B, D, Ia, Ib, M, and 5/10) (p < 0.01), including a higher prevalence of the colicin B determinant (p < 0.01) was found. Virulence factor determinants encoding fimbriae (fimA, 91.0%; pap, 27.5%), cytotoxic necrotizing factor (cnf1, 11.2%), aerobactin synthesis (aer, 43.3%), and the locus associated with invasivity (ial, 9.0%) were more prevalent in IBD E. coli (p < 0.05 for all five determinants). E. coli isolates from IBD mucosal biopsies were more frequently bacteriocinogenic (84.6%, p < 0.01) compared to fecal IBD isolates and fecal commensal E. coli. PFGE analysis revealed clusters specific for IBD E. coli isolates (n = 11), for fecal isolates (n = 13), and clusters containing both IBD and fecal isolates (n = 10).ExPEC (Extraintestinal Pathogenic E. coli) virulence and colicin determinants appear to be important characteristics of IBD E. coli isolates, especially the E. coli isolates obtained directly from biopsy samples.     

Genetic association between CARD9 variants and inflammatory bowel disease was not replicated in a Chinese Han population

Objective: In order to investigate whether CARD9 gene is associated with IBD in Chinese Han population, we replicated 2 SNPs of CARD9 which have been reported to be significantly associated with IBD. Methods: Two SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients (232 CD patients, 56 UC patients) and 274 controls. Results: The frequencies and distributions of alleles and genotypes of the tested SNPs were analyzed, and no significant differences were found between patients and controls. Conclusions: We observed no significant association between the investigated CARD9 SNPs and the susceptibility of either CD or UC. Further studies with larger sample size focusing on different ethnicities are required to elucidate the correlation between CARD9 and IBD.     

<Emphasis Type="Italic">ADAM33 </Emphasis>polymorphisms are associated with aspirin-intolerant asthma in the Japanese population

Multiple single nucleotide polymorphisms (SNPs) within ADAM33 have been reported to be associated with asthma and bronchial hyper-responsiveness in Caucasian populations. We examined whether these SNPs contribute to a predisposition to asthma, especially aspirin-intolerant asthma (AIA), in the Japanese population. Ten polymorphic sites (ST+4, ST+7, T1, T2, T+1, V-3, V-2, V-1, V4, V5) were genotyped in 102 AIA patients, 282 aspirin-tolerant asthma (ATA) patients and 120 control (CTR) subjects by direct sequencing. Haplotype frequencies were estimated by the expectation-maximization method. Differences in allele and haplotype frequencies among phenotypes were analyzed by the chi-square and permutation tests. ST+7, V-1 and V5 sites in the AIA group were significantly different from those in the ATA group (P=0.034–0.004) and from those in the CTR group (P=0.019–0.002). Haplotypes at three sites (ST+7, V-1, and V5) were significantly different in frequency between the AIA and ATA (P=0.008) or CTR (P=0.001) groups. Sequence variations in ADAM33 are likely to correlate with susceptibility to AIA in the Japanese population. The authors declare that they have no conflict of interest.     

IL-33及其受体ST2在炎症性肠病中免疫调节作用的研究新进展

IL-33是近年来发现的一种IL-1家族的细胞因子,其受体为ST2.IL-33具有双重作用,既能作为分泌性细胞因子,参与调节Th2型免疫应答,诱导前炎性因子的表达,又能作为核因子,定位于细胞核内,起抑制转录作用,阻遏前炎性基因表达.在慢性炎症性肠病(IBD)患者的肠道组织中可查到该细胞因子的表达.研究IL-33及ST2受体有助于进一步了解IBD发病机制,寻找治疗IBD的新靶点.     

Genetic polymorphisms of interleukin-6 gene and susceptibility to coronary artery disease in Chinese population: Evidence based on 4582 subjects

The aim of this study was to explore whether interleukin-6 (IL-6) gene (−174 G/C and −572 C/G) polymorphisms are associated with susceptibility to coronary artery disease (CAD) risk in Chinese population. All the statistical tests were performed using Stata version 11.0. Twelve articles involving 16 studies were included in this meta-analysis, covering a total of 2309 CAD cases and 2273 controls. For IL-6 gene −572 C/G polymorphism, the results showed evidence for significant association between IL-6 gene −572 C/G polymorphism and CAD risk (for G allele vs. C allele: OR = 1.48, 95% CI = 1.26–1.74, p < 0.001; for G/G vs. C/C: OR = 2.60, 95% CI = 1.54–4.39, p < 0.001; for G/G vs. G/C + C/C: OR = 2.15, 95% CI = 1.35–3.42, p = 0.001; for G/G + G/C vs. C/C: OR = 1.55, 95% CI = 1.29–1.85, p < 0.001). However, for IL-6 gene −174 G/C polymorphism, no significant association was found between this variation and CAD risk. In summary, our meta-analysis showed evidence that IL-6 gene −572 C/G polymorphism may be a risk factor for CAD susceptibility. For IL-6 gene −174 G/C polymorphism, no significant association was found between this variation and CAD risk.     

Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn’s disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21^st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn’s disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBL-dependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.