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。     

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.     

Association of CARD8 with inflammatory bowel disease in Koreans

Caspase recruitment domain (CARD)-containing protein 8 (CARD8) is a potential candidate risk gene for inflammatory bowel disease (IBD) because of its role as a component of the NALP3 inflammasome and as an inhibitor of nuclear factor-kappa B. Previous studies examining the association of a CARD8 single-nucleotide polymorphism (SNP) (rs2043211, p.Cys10X) with IBD yielded mixed results in Caucasians that may result from interaction with NALP3 or NOD2 (nucleotide-binding oligomerization domain 2) variants. To understand the genetic association between CARD8/NALP3 and IBD in Koreans, we investigated seven CARD8, four NALP3 and four NOD2 SNPs in 650 Crohn's disease (CD), 660 ulcerative colitis (UC) patients and 688 controls from the Korean population. rs2043211 of CARD8 showed significant association with UC (P = 0.011; odds ratio = 1.50, 95% confidence intervals = 1.12-2.00, P = 0.006 under recessive model). In contrast, an SNP in intron 1, rs1972619, was associated with CD only (P = 0.033). None of the NALP3 or NOD2 SNPs was significantly associated with CD or UC in the Korean populations. The stop allele of rs2043211 was associated with higher serum interleukin-1β levels only in female patients with UC (P = 0.027). Our data suggest that CARD8 variants might have roles in the pathogenesis of CD and UC in Koreans.     

Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients

Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.     

Association analysis of MYO9B gene polymorphisms and inflammatory bowel disease in a Norwegian cohort

Association between single nucleotide polymorphisms (SNPs) within the MYO9B gene and celiac disease was recently reported. The role of MYO9B in celiac disease was suggested to relate to an epithelial barrier defect. The region to which MYO9B localize is also linked with inflammatory bowel disease (IBD). For these reasons, we hypothesize that MYO9B could also be a susceptibility gene in IBD. To address this, we performed an association study of a Norwegian IBD cohort (149 patients with Crohn's disease, 308 patients with ulcerative colitis and 562 healthy controls) using SNPs, which tagged the celiac disease associated MYO9B haplotype. No association between these SNPs and IBD was observed. Our results failed to support the notion that MYO9B is a susceptibility gene in IBD.     

Association of DLG5 R30Q variant with inflammatory bowel disease

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies. We are, however, unable to replicate the other proposed association to the common haplotype described in Stoll et al and suggest that this other finding could conceivably have been partially a statistical fluctuation and partially a result of LD with the replicated R30Q association. This study provides support for the hypothesis that DLG5 constitutes a true IBD risk factor of modest effect.     

Association of interleukin-18 gene single-nucleotide polymorphisms with susceptibility to inflammatory bowel disease

Interleukin-18 (IL-18) is believed to be one of the most important cytokines in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to clarify the significance of single-nucleotide polymorphisms (SNPs) at the 5'-end of the IL-18 gene in the development of IBD. DNA was obtained from peripheral blood of 99 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 102 healthy controls. All participants were Japanese. SNPs at -656G/T, -607C/A, -137G/C, +113T/G, and +127C/T were determined by means of direct sequencing, and a genetic association with IBD was examined. The frequencies of the G allele at +113 and the T allele at +127 were significantly higher in patients with CD and UC compared with controls. The differences in allelic frequencies were more striking in patients with CD than in patients with UC, and at position +127 than at position +113. The haplotype estimation, according to the E-M algorithm, suggested that TACGT is closely associated with IBD, especially with CD. It was concluded that SNPs at the 5'-end of IL-18 gene might be closely related to the etiology of IBD.     

Association of CTLA-4 variants with susceptibility to inflammatory bowel disease: A meta-analysis

Objective

The aim of this study was to determine whether CTLA-4 gene variants were associated with susceptibility to inflammatory bowel disease (IBD).

Methods

Meta-analysis was conducted on the association between CTLA-4 variants and IBD using: (1) allelic contrast, (2) the recessive model, and (3) the dominant model.

Results

A total of 9 relevant studies including 1739 Crohn’s disease (CD) cases, 10 relevant studies containing 1017 ulcerative colitis (UC) cases and 2685 healthy controls were involved in this meta-analysis. Overall, CTLA-4+49A/G, −318C/T and CT60 variants were not associated with IBD susceptibility in all genetic models (P > 0.05). Stratification by ethnicity indicated a significant association between the CTLA-4+49A/G variant and CD in Caucasian group (GG vs. GA + AA: OR = 0.723, 95% CI = 0.564–0.926, P = 0.010). In Asian group, meta-analysis showed a significant association between the CTLA-4 CT60 variant and UC (AA vs. AG + GG: OR = 0.375, 95% CI = 0.163–0.861, P = 0.021).

Conclusions

Based on the published literature, this meta-analysis suggests that the CTLA-4+49A/G variant may be related to CD susceptibility in Caucasians, and the CTLA-4 CT60 variant may be associated with UC susceptibility in Asians.     

Probiotics and inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterised by a chronic dysregulation of the inflammatory response in the gastrointestinal tract. While the pathogenesis is unclear, studies have demonstrated that the gastrointestinal tracts of patients with IBD are populated with increased levels of adherent and pathogenic bacteria. This evidence, combined with growing data accumulated from genetic studies as well as animal models of IBD, indicates that an aberrant response to altered enteric flora plays a significant role in the disease process. Current therapies for IBD have been directed towards the development of anti-inflammatory agents and immunomodulators to attenuate the inflammatory response in the gastrointestinal tract. Antibiotics are also partially effective in the treatment of IBD, presumably by altering the bowel flora. However, it is clear from clinical trials that immunomodulators and antibiotics are not effective in a large proportion of patients with IBD and other therapeutic alternatives need to be pursued. Probiotics are microbial supplements capable of recolonising the bowel with non-pathogenic strains of bacteria or yeast. Probiotics have long been shown to be beneficial in both infectious and non-infectious digestive disorders. Growing evidence indicates that probiotics may be effective in the treatment of specific clinical IBD conditions. This article addresses the current evidence for the role of enteric flora in the pathogenesis of IBD and the clinical evidence supporting the use of probiotics in specific clinical IBD conditions.     

Association and linkage studies of immunoglobulin heavy chain allotypes in inflammatory bowel disease

Inflammatory bowel disease is a familial disorder of unknown etiology, characterized by a variety of immunological abnormalities for which there are no proven genetic markers. Studies of immunoglobulin heavy chain and light chain allotypes were undertaken in 89 patients with Crohn's disease and in 18 families with ulcerative colitis or Crohn's disease in at least two first-degree relatives, to search for association and/or linkage between a postulated disease susceptibility locus and an immunoglobulin allotype locus. No evidence of association or linkage with a specific immunoglobulin allotype was found.     

Neuroinflammation in inflammatory bowel disease

Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.     

Dysplasia in inflammatory bowel disease

The risk of neoplasia in ulcerative colitis and Crohns colitis increases with both the duration and the extent of disease. In patients with extensive or pancolitis, the cancer risk increases dramatically 8 to 10 years after the first onset of disease. Childhood onset of colitis and primary sclerosing cholangitis further increase the risk of developing colorectal carcinoma. The performance of surveillance endoscopy to identify dysplastic precursor lesions via endoscopic biopsy specimens has become the main management strategy to combat this risk. Biopsies should be classified as negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia according to standard criteria. A prophylactic colectomy is the procedure of choice when high-grade dysplasia or low-grade dysplasia associated with a lesion or mass is present. Some centers also recommend a colectomy for the presence of low-grade dysplasia in flat mucosa. Given these management recommendations, care should be taken not to overcall reactive epithelial changes in the face of active colitis. All diagnoses of dysplasia should be confirmed, preferably by a pathologist experienced in interpreting gastrointestinal biopsies.     

Primary intrahepatic sclerosing cholangitis with inflammatory bowel disease

A case of primary intrahepatic sclerosing cholangitis associated with inflammatory bowel disease, which is rare in Japan, is reported. A 16-year-old Japanese boy was admitted to our hospital because of abdominal pain and fever. He was diagnosed as having primary intrahepatic sclerosing cholangitis by endoscopic retrograde cholangiography and liver biopsy. Inflammatory bowel disease was diagnosed by colonoscopy and biopsy of the colonic mucosa. Human lymphocyte antigen typing showed HLA-A2, A-9, -B52 and -DR2.