- Email: [email protected]
M1183 Microsatellite Polymorphisms in FOXP3 Gene in Patients with Ulcerative Colitis
if there are differences in socioeconomic factors and disease characteristics of CD between Caucasians and AA. METHODS: A database of patients seen for CD at Drexel University College of Medicine was generated. 75 patients were randomly surveyed via a telephone questionnaire. Four patients were excluded because they belonged to a race other than Caucasian or AA. Patient data collected included age, race, income, employment status, education level, age of diagnosis, duration of disease, family history, disease manifestations and complications, medications, and frequency of primary, specialist, and hospital visits. T-test and chi-square analyses with Microsoft Excel were performed to determine statistical significance. RESULTS: 43 Caucasian and 28 AA patients were surveyed. There were no significant differences in age (47.2 years for Caucasians and 50.3 years for AA), gender (22 male, 49 female) or duration of disease (17.6 years in Caucasians, 12.8 years in AA). Significant differences in age of diagnosis (Caucasians 29.7 years versus AA 37.5years, p= 0.023), family history (7% AA versus 30% Caucasians, p=0.040), and income (AA income <$40,000 versus Caucasians > $40,000, p=0.017) were found. No differences were found with regard to disease manifestations and complications, medications, employment status, education level, or access to health care as measured by visits to primary care providers, specialists, and hospitals. CONCLUSION: AA were diagnosed with CD later in life, were less likely to have a family history of CD, and had a lower median income than Caucasians. There were no differences in disease manifestations, complications or visits to healthcare professionals. Despite differences in socioeconomic factors between AA and Caucasians, there was no correlation with disease characteristics in our cohort. Future studies should attempt to demonstrate a lack of discrepancy in disease characteristics among the races while controlling for socioeconomic and demographic factors.
M1179 Fat Halo Sign in Small Bowel Crohn's Disease: Histologic, Radiographic, and Clinical Correlates Jacob E. Kurlander, Jeremy Adler, Barbara J. McKenna, Jonathan R. Dillman, Mahmoud M. Al-Hawary, Paul L. Sonda, Ellen M. Zimmermann The fat halo sign (FHS) is a common CT enterography (CTE) finding in Crohn's disease (CD) patients characterized by a circumferential band in the bowel wall with the density of fat. Grossly, fat is often seen on the serosal surface (fat wrapping) but rarely within the bowel wall. Little is known about the significance of FHS. Our aim was to correlate FHS with histologic findings and clinical history to determine its significance. Methods: CD patients who underwent ileal resection within 6 months of CTE from 2003-2008 were identified. Medical records were reviewed for gender, age, disease duration, and medical treatment, including steroids in the previous year. Instances of small bowel obstruction, fistula, and abscess were recorded. Two independent radiologists evaluated each CTE for FHS (threshold < -20 Hounsfield units). A GI pathologist reviewed histologic specimens for the presence of fat in the bowel wall. Specimens with the finding were scored for extent of the fat and degree of inflammation and fibrosis. A submucosal adipose lesion (SAL) was defined as a pathologic increase in fat accumulation in the deep submucosa of the small intestine remote from the ileocecal valve. Bivariate associations between SAL and clinical characteristics were tested for using chi-square and t-tests. Results: Nineteen patients underwent ileal resection for proven Crohn's disease and had CTE, histologic specimens, and clinical data available. Five patients had FHS on CTE; 7 had SAL histologically. Every instance of FHS was confirmed as SAL. The two patients with SAL that was not identified as FHS on CTE had less extensive fat lesions compared to all other specimens with SAL. All patients with SAL had inflammation and fibrosis adjacent to the lesion. Age (p=0.01) and treatment with aminosalicylates (p=0.05) were positively associated with SAL. Patients with SAL had a trend toward higher BMI (27.4 vs. 22.1 kg/m2; p=0.08) and greater likelihood of fistula than those without (p=0.06). Use of purine synthesis inhibitors (p=0.76), steroids (p=0.76), and biologics (p=0.09) were not associated with SAL. Conclusions: The common finding of FHS on CTE is associated with pathologic accumulation of submucosal fat in the bowel wall. CTE may be insufficiently sensitive to identify more subtle histologic cases. SAL is more common in patients with older age but not longer duration of disease, and may be associated with use of aminosalicylates. Increased inflammation and fibrosis in the region of the fat suggest that adipokines or growth factors such as IGF-1 that are expressed in chronic inflammation may play a role in intestinal adipocyte differentiation or proliferation.
M1182 Association of IL-27 and TBX21 Gene Polymorphisms in a Korean Population with Inflammatory Bowel Diseases Chun Shi Li, Suck Chei Choi, Ki Baik Hahm, Hyung Bae Moon, Ki Jung Yun, Geom Seog Seo, Yong Sung Kim, Ki Hoon Kim, Ji Hye Kwon, Soo Cheon Chae Backgrounds: The cytokine interleukin 27 (IL-27) is composed of two subunits, EpsteinBarr virus induced gene 3 (EBI3) and p28, is a novel IL-12 family member that mediates the innate and adaptive immune system. Macrophages and dendritic cells produce IL-27 within hours after stimulation by pathogens. This cytokine is mediated by one of the receptor chain (WSX-1) of IL-27 receptor that is highly expressed on CD4 + T lymphocytes and NK cells. IL-27p28 transcripts are significantly elevated in active Crohn's disease (CD) but not in ulcerative colitis (UC). TBX21 (T-bet) is a member of the T-box family of transcriptional factors that contain a conserved DNA binding domain. TBX21 is a critical regulator of IFNγ production in Th1 of CD4+ lymphocytes. We previously identified several polymorphisms in the human IL-27p28 and TBX21 gene. Aim: Our purpose of this study was to determine whether these TBX21 and IL-27p28 SNPs are associated with susceptibility of inflammatory bowel disease (IBD). Methods: The genotype and allele frequencies of TBX21 and IL-27p28 polymorphisms were analyzed between the IBD patients and the healthy controls. Genotype analysis in the TBX21 and IL-27p28 SNPs was performed by single-base extension (SBE) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: The genotype and allele frequencies of the g.-964A>G polymorphism of IL-27p28 gene in the IBD patients were significantly different from those of the controls group (P = 0.001). We also showed that the c.99C>G polymorphisms of TBX21 gene are suggestively associated with IBD susceptibility (P = 0.004). The frequencies of major haplotype by SNPs of TBX21 were significantly different between the healthy controls and IBD patients group. Conclusion: Our results suggest that the polymorphism of IL-27p28 gene located on IBD1 locus and TBX21 gene might be associated with susceptibility to IBD.
M1180 Epidemiology of Inflammatory Bowel Diseases in Northwestern Greece for the Years 1981-2007 Christos Zois, Konstantinos Katsanos, Dimitrios K. Christodoulou, Gerasimos Baltayiannis, Nikos Tzampouras, Athanasios Papathanasopoulos, Vasileios Theopistos, Kostas Masalas, Antonis Kogevinas, Epameinondas Tsianos
M1183 Microsatellite Polymorphisms in FOXP3 Gene in Patients with Ulcerative Colitis Katsuhito Arai, Yoshiaki Takeuchi, Chitose Ohishi, Reiko Makino, Michio Imawari
AIM: The estimation of Inflammatory Bowel Diseases (IBD) epidemiology in Northwestern Greece for the years 1981-2007. METHODS: Northwestern Greece (NW) has 6 Hospitals and 18 Registrars in Gastroenterology. An epidemiologic questionnaire was filled for each patient with IBD. RESULTS: 910 patients (558 men, 352 women) with IBD [654 patients with ulcerative colitis (UC) and 154 patients with Crohn's Disease (CD)] along with 102 patients with unspecified colitis (USC), were examined. The highest frequency of IBD patients was detected from the prefectures of Ioannina and Corfu. 11 deaths (1,2%) and 7 cases (0,77%) with total colectomy were reported. The UC/CD ratio was 4,2/1. Ages between 4060 years showed the highest prevalence in IBD. The most common distribution in UC was: left colitis 67,3%, total colitis 17,2%, proctitis 15,5%. In CD, respectively: terminal ileus 40,3%, terminal ileus and large bowel 35,8%, only large bowel 23,9%. 24 patients with dysplasia (2,63%) and 20 patients with neoplasia (2,2%) were also detected. From the latter, 7 had intestinal neoplasia (1 patient with 2 cancers) and 13 extraintestinal. CONCLUSIONS: The increase of IBD incidence in NW Greece can be attributed to the high rate of all IBD types (CD, UC, USC), in combination with the low mortality. The gap between UC-CD is continuously lowering and male sex predominates. Left colitis predominates in UC and involvement of terminal ileus is most common in CD.
Introduction: It is now known that both genetic and environmental factors are important for the pathogenesis of inflammatory bowel diseases. A number of candidate genes contributing to disease susceptibility have been identified up to date. They include genes associated with innate immunity, autophagy, epithelial barrier functions, and proinflammatory cytokines and their cognate receptors. Since abrogation of regulatory cells causes colitis experimentally, genes participating in the regulatory mechanisms may also be a potent susceptibility gene. FOXP3-expressing regulatory T cells are important for the immune tolerance and the association of polymorphisms of the FOXP3 gene and certain autoimmune diseases has recently been reported. Aim: The aim of this study is to investigate whether the microsatellite polymorphisms of FOXP3 gene are associated with susceptibility in ulcerative colitis. Method: This study was conducted in single institution. Eighty eight patients with ulcerative colitis participated in this study and the control group was 151 healthy subjects. All participants comprised of Japanese. The genomic DNA was obtained from white blood cells using a Magtration System 6GC (Precision System Science, Japan). The DNA fragments containing the GT-repeat in the first intron and TC-repeat in the 6th intron of FOXP3 gene were amplified by PCR by primers labeled with a fluorescent dye because variations of repeatnumber of these regions were shown to be functional. The amplified DNA fragments were then analyzed with a 3100 Genetic Analyzer (Applied Biosystems). The numbers of repeated units of each polymorphism were calculated from the length of the DNA fragments. Association studies between each of the polymorphism with ulcerative colitis were performed by chi-square test. P value less than 0.05 was considered to be significant. Results: Comparison of the whole allele distribution of the intron zero polymorphisms between control and UC patients demonstrated no significant difference. Since FOXP3 gene is located on Xchromosomes, the analysis of each allele frequency was done by dividing female and male groups. There were no difference in comparison between control and UC patients for the (GT)15 and (GT)16 allele in both gender. However, the frequency of the (GT)15 allele in male UC patients was higher than control. No significant difference was observed in comparison of genotype frequencies in intron 6 polymorphism. Conclusions: We did not find the association
M1181 Disparities Between Caucasians and African Americans in Crohn's Disease Xiaoyu Yang, Sveta Shah, Eva H. Alsheik, Asyia S. Ahmad, Radha Menon, Frank Pandolfe, David E. Stein The incidence of Crohn's Disease (CD) is 3.1 to 14.6 cases per 100,000 person-years. CD has a 30-fold higher incidence in Caucasians versus African Americans (AA). Over the past 30 years, incidence in AA has been increasing. Furthermore, several studies have noted differences in disease characteristics among the races, though findings are variable in nature and have not been consistently associated with socioeconomic factors. AIM: To determine
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respectively). The alterations of fetus and aminosalicilates, corticosteroids or no drugs administrated during pregnancy are shown in table 1. Conclusion: The administration of aminosalicilates or corticosteroids during pregnancy in patients with IBD did not worsen fetus outcome. Table 1. Fetus outcome and drug administration during pregnancy.
of microsatellite polymorphisms of FOXP3 gene with ulcerative colitis. The larger scale investigation of other polymorphisms of this gene will be needed to conclude susceptibility.
(Arg753Gln and Arg677Trp), TLR6 (Ser249Pro) genes and the -159C/T promoter polymorphism of CD14 gene in 99 patients with ulcerative colitis (UC), 45 patients with Crohn disease (CD) and 178 healthy controls. Results: No TLR polymorphism was detected in any patients or healthy controls in Korean population. T allele and TT genotype frequencies were significantly higher in IBD patients than in healthy controls (57% vs 37%, P<0.001; 33% vs 15%, P<0.005, respectively). In subgroup analysis, both CD and UC patients also had significantly higher T allele and TT genotype frequencies compared to health controls (P<0.05). There was no association between CD14 polymorphism and disease phenotype patient's age, disease location, activity, response to therapy and history of surgery. In patients with UC, however, T allele frequency was significantly higher in pancolitis groups compared to [proctitis + Lt. sided colitis] group (67% vs 51%, P=0.02). Conclusion: There is no TLR 1, 2, 4, 6 polymorphism in Korean population. The promoter polymorphism of the CD14 gene at -159C/T is positively associated with UC and CD. In UC, CD14 polymorphism has positive association with pancolitis. These findings support the role of an abnormal immune response in the pathogenesis of IBD.
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M1184 A Pilot Study for Genetic Mutations in African American Patients with Crohn's Disease Kristin Braun, Sidney Cohen, Anthony J. DiMarino, Paolo Fortina BACKGROUND: Crohn's disease(CD) is a chronic, idiopathic inflammatory disorder thought to be caused by an interplay of environmental and genetic factors. To date a number of candidate genes have been identified in Caucasians through genome wide association studies, the first and most widely studied is the CARD 15 gene in the IBD 1 locus. Single nucleotide polymorphisms (SNPs) have been identified in the coding regions of the IBD 1 loci and are considered to confer susceptibility to CD. Carriage of these polymorphisms has an OR of 2.20 up to 17.1 for carriage of more than one allele. Despite these recent genetic discoveries in Caucasians, little is known about the genetics of CD in the African American population. Several clinical studies have suggested that there are racial differences in CD family history, disease location, disease severity and extra-intestinal manifestations and recent pediatric data indicates that African Americans rarely have the same IBD 1 risk haplotypes as Caucasians. AIM: To identify genotypic differences in minorities compared to Caucasians with CD in our institution. METHODS: DNA was extracted from whole blood and 25ul PCR reactions were performed using primers for detecting SNPs R702W, G908R, L1007fsinsC. PCR reactions were set up on a ABI 9700 thermo cycler with subsequent sequencing and analysis of the PCR products. Patient clinical information was obtained through a computer database search. RESULTS: The DNA of 18 African American patients with crohn's disease was sequenced. Sixty-six percent of the patients were female, 55% had perianal disease evidenced by fistulas, 33% had stricturing disease, 50% had at least one prior surgery and 33% of the patients had at least one prior small bowel obstruction. DNA sequencing revealed that only 1/18 patients had an insertion at the L1007fsinsC loci, the remainder were all deletions. 1/ 18 patients was a heterozygote at the R702W loci, the remainder were all homozygotes. There were no polymorphisms detected in G908R loci, all of the patients were homozygotes. CONCLUSION: DNA sequencing data indicates that carriage of IBD1 risk associated polymorphisms is rare in African American patients with CD, despite these patients having complicated disease with intestinal strictures and fistulas.
M1187 The Endoscopic Spectrum of Segmental Colitis Associated with Diverticulosis Antonio Tursi, Giovanni Brandimarte, Walter Elisei, GianMarco Giorgetti, Alfredo Papa Introduction: Although recognition of “segmental colitis associated with diverticulosis” (SCAD) is increasing in clinical practice, the information about endoscopic appearance of this disease are lacking. Aims & Methods: To assess the endoscopic spectrum of SCAD, comparing them with the histological findings and with clinical features of the disease. A prospective study from January 2004 to October 2007 was performed after agreement between endoscopists participating at this study on the endoscopic classification. Diagnosis of SCAD was performed by specific endoscopic and histological patterns. Results: 6230 consecutive colonoscopies were performed in these Units. SCAD was diagnosed in 92 patients (14.76%, 42 Males and 50 Females, mean age 62.3 years, range 52-73 years). We recognized four endoscopic patterns: pattern A, a typical SCAD pattern as “crescentic fold disease” (48 patients, 52.20%); pattern B, a “Mild-to moderate ulcerative colitis-like” pattern (28 patients, 30.40%); pattern C, a “Crohn's disease colitis-like” pattern (10 patients, 10.90%); pattern D, a “Severe ulcerative colitis-like” pattern (6 patients, 6.50%). Most of patients showing pattern A (28 patients, 58.33%, p<0.018) and pattern B (25 patients, 89.29%, p<0.00001) showed histological alteration resembling moderate ulcerative colitis (UC); patients showing pattern C showed larger variability of histological damage (p<0.01); all patients showing pattern D showed the typical histological alteration similar of severe UC (p<0.0001). Patients showing pattern A (29 patients, 60.42%, p=n.s.) and pattern B (13 patients, 46.43%, p= n.s.), experienced more frequently diarrhea; whilst abdominal pain was the most experienced symptom in pattern C (50%, p=n.s.) and pattern D (83.33%, p=n.s.) patients. Conclusions: Endoscopic pattern of SCAD may range from milder to severe damage. The histopathological findings but not clinical features showed a statistically significant association with the degree of endoscopic damage.
M1185 Gender-Specificity and Genotypic Interaction of Common Genetic Variants in the p53/MDM2-Network in Crohn Disease Vincent Zimmer, Gunter Assmann, Thomas Widmann, Monika B. Mueller, Mei Fang Ong, Klaus Römer, Frank Lammert Background & Aim: Defective p53-mediated apoptosis and cell cycle control has been implicated in the immunopathogenesis of Crohn disease (CD), promoting intestinal inflammation by activation and expansion of mucosal T cells (1+2). Common functional sequence variants of p53 (SNP72 G/C) and its key negative regulator mdm2 (SNP309 T/G) are considered to modulate cellular apoptotic capacity and cell cycling by a low apoptotic potential of the SNP72 C variant and enhanced mdm2 transcription of the SNP309 G allele (3+4). From this perspective, we aimed to elucidate the effects of these polymorphic variants on CD susceptibility. Methods: The variants p53/SNP72 G/C (rs1042522) and mdm2/ SNP309 T/G (rs2279744) were genotyped in 149 European CD patients and 478 healthy controls. Subgroup analysis was performed in relation to NOD2/CARD15 status, designated as, at least, heterozygosity in either CD-associated SNP (Arg702Trp, Gyl908Arg, Leu1007finsC), and to demographic/clinical characteristics. Results: The SNP72 CC genotype tended to be less frequent in CD, which reached significance in males (0 vs. 7.3%; p=0.037). By contrast, SNP309 genotypes and allele frequencies of both SNPs demonstrated no significant difference. Of note in SNP309 TT carriers, genotype SNP72 CC was significantly less frequent (0 vs. 9.7%; p=0.034). No association was observed between NOD2/CARD15 and the respective SNPs. Conclusions: In this association study, we report on a gender-specific protective effect of the low-apoptotic SNP72 CC genotype, and a genotypic interaction between SNP309 TT and SNP72 CC, which links common genetic variation of the p53/ mdm2 network to CD independent of NOD2/CARD15. Since the G allele of SNP309 increases cellular mdm2 availability, it might abrogate the attenuation of p53-mediated apoptosis conferred by the SNP72 CC genotype. Our findings do not support a primary genetic T cell apoptosis defect at the level of p53. However, with increased epithelial cell death impacting on mucosal barrier integrity (5), apoptosis seems to have a dual role in CD, and, if replicated in larger cohorts, it remains to be determined how SNP72 CC might affect distinct pathogenetic steps. References: 1. Sturm A, JCI, 2002 2. Sturm A, Gut, 2004 3. Dumont P, Nat Genet, 2003 4. Bond GL, Cell, 2004 5. Zeissig S, Gut, 2004
M1188 Overall and Cause-Specific Mortality in Crohn's Disease: A Meta-Analysis of Population-Based Studies Dana Duricova, Natalia Pedersen, Margarita Elkjaer, Pia S. Munkholm, Tine Jess Background and Aim: An overview of mortality risk in Crohn's disease (CD) in unselected population is lacking. We therefore performed a meta-analysis of population-based studies on overall and cause specific mortality in CD. Methods: MEDLINE (January 1965-February 2008) abstracts from international conferences (DDW, UEGW, 2004-2007) and reference lists of selected articles were searched systematically. All papers fulfilling the predefined inclusion criteria were scrutinized for data on population size, time of follow-up, gender, age and observed to expected deaths. STATA meta-analysis software was used to calculate overall and cause specific pooled risk estimates (SMR, observed/expected). Results: Nine studies were included with overall SMRs ranging from 0.72 to 3.2 resulting in a significantly increased pooled SMR of 1.39 (95%CI: 1.30-1.50). Regarding cause-specific mortality, a significantly increased risk of death from cancer (in particular of the digestive system and lung), chronic obstructive pulmonary disease (COPD), gastrointestinal diseases and genitourinary diseases was observed (Table 1). Conclusion: Among unselected patients with CD, the overall mortality is slightly but significantly higher compared to the general population and primarily explained by death from gastrointestinal, respiratory and genitourinary diseases. It is notable that death from colorectal cancer is not increased. Table 1. Cause -Specific Mortality in Patients with Crohn's Disease
M1186 A Polymorphism of CD14 Is Associated with Inflammatory Bowel Disease in Korean Population Kang-Moon Lee, Woo Chul Chung, Chang Nyol Paik, Bo-In Lee, Jeong Rok Lee, Sung Hoon Jung, Min Kyoung Lee, Kyu Yong Choi Background: Inappropriate and exaggerated immune response to luminal bacteria is implicated in the pathogenesis of inflammatory bowel disease (IBD). Evidence is accumulating that mutations in the genes for pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NODs, are associated with IBD in Western populations. However, lack of NOD2 or TLR4 genetic polymorphisms in Japanese and Chinese population suggests the difference in genetic background between Asian and Western population. We analyzed the frequencies of TLR1, 2, 4, 6 and CD14 mutations in Korean patients to investigate the association between those polymorphisms and the susceptibility to IBD in Korean population. Methods: Using a polymerase chain reaction based restriction fragment length polymorphism, we evaluated mutations of TLR4 (Asp299Gly and Thr399Ile), TLR1 (Arg80Thr), TLR2
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M1179 Fat Halo Sign in Small Bowel Crohn's Disease: Histologic, Radiographic, and Clinical Correlates Jacob E. Kurlander, Jeremy Adler, Barbara J. McKenna, Jonathan R. Dillman, Mahmoud M. Al-Hawary, Paul L. Sonda, Ellen M. Zimmermann The fat halo sign (FHS) is a common CT enterography (CTE) finding in Crohn's disease (CD) patients characterized by a circumferential band in the bowel wall with the density of fat. Grossly, fat is often seen on the serosal surface (fat wrapping) but rarely within the bowel wall. Little is known about the significance of FHS. Our aim was to correlate FHS with histologic findings and clinical history to determine its significance. Methods: CD patients who underwent ileal resection within 6 months of CTE from 2003-2008 were identified. Medical records were reviewed for gender, age, disease duration, and medical treatment, including steroids in the previous year. Instances of small bowel obstruction, fistula, and abscess were recorded. Two independent radiologists evaluated each CTE for FHS (threshold < -20 Hounsfield units). A GI pathologist reviewed histologic specimens for the presence of fat in the bowel wall. Specimens with the finding were scored for extent of the fat and degree of inflammation and fibrosis. A submucosal adipose lesion (SAL) was defined as a pathologic increase in fat accumulation in the deep submucosa of the small intestine remote from the ileocecal valve. Bivariate associations between SAL and clinical characteristics were tested for using chi-square and t-tests. Results: Nineteen patients underwent ileal resection for proven Crohn's disease and had CTE, histologic specimens, and clinical data available. Five patients had FHS on CTE; 7 had SAL histologically. Every instance of FHS was confirmed as SAL. The two patients with SAL that was not identified as FHS on CTE had less extensive fat lesions compared to all other specimens with SAL. All patients with SAL had inflammation and fibrosis adjacent to the lesion. Age (p=0.01) and treatment with aminosalicylates (p=0.05) were positively associated with SAL. Patients with SAL had a trend toward higher BMI (27.4 vs. 22.1 kg/m2; p=0.08) and greater likelihood of fistula than those without (p=0.06). Use of purine synthesis inhibitors (p=0.76), steroids (p=0.76), and biologics (p=0.09) were not associated with SAL. Conclusions: The common finding of FHS on CTE is associated with pathologic accumulation of submucosal fat in the bowel wall. CTE may be insufficiently sensitive to identify more subtle histologic cases. SAL is more common in patients with older age but not longer duration of disease, and may be associated with use of aminosalicylates. Increased inflammation and fibrosis in the region of the fat suggest that adipokines or growth factors such as IGF-1 that are expressed in chronic inflammation may play a role in intestinal adipocyte differentiation or proliferation.
M1182 Association of IL-27 and TBX21 Gene Polymorphisms in a Korean Population with Inflammatory Bowel Diseases Chun Shi Li, Suck Chei Choi, Ki Baik Hahm, Hyung Bae Moon, Ki Jung Yun, Geom Seog Seo, Yong Sung Kim, Ki Hoon Kim, Ji Hye Kwon, Soo Cheon Chae Backgrounds: The cytokine interleukin 27 (IL-27) is composed of two subunits, EpsteinBarr virus induced gene 3 (EBI3) and p28, is a novel IL-12 family member that mediates the innate and adaptive immune system. Macrophages and dendritic cells produce IL-27 within hours after stimulation by pathogens. This cytokine is mediated by one of the receptor chain (WSX-1) of IL-27 receptor that is highly expressed on CD4 + T lymphocytes and NK cells. IL-27p28 transcripts are significantly elevated in active Crohn's disease (CD) but not in ulcerative colitis (UC). TBX21 (T-bet) is a member of the T-box family of transcriptional factors that contain a conserved DNA binding domain. TBX21 is a critical regulator of IFNγ production in Th1 of CD4+ lymphocytes. We previously identified several polymorphisms in the human IL-27p28 and TBX21 gene. Aim: Our purpose of this study was to determine whether these TBX21 and IL-27p28 SNPs are associated with susceptibility of inflammatory bowel disease (IBD). Methods: The genotype and allele frequencies of TBX21 and IL-27p28 polymorphisms were analyzed between the IBD patients and the healthy controls. Genotype analysis in the TBX21 and IL-27p28 SNPs was performed by single-base extension (SBE) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: The genotype and allele frequencies of the g.-964A>G polymorphism of IL-27p28 gene in the IBD patients were significantly different from those of the controls group (P = 0.001). We also showed that the c.99C>G polymorphisms of TBX21 gene are suggestively associated with IBD susceptibility (P = 0.004). The frequencies of major haplotype by SNPs of TBX21 were significantly different between the healthy controls and IBD patients group. Conclusion: Our results suggest that the polymorphism of IL-27p28 gene located on IBD1 locus and TBX21 gene might be associated with susceptibility to IBD.
M1180 Epidemiology of Inflammatory Bowel Diseases in Northwestern Greece for the Years 1981-2007 Christos Zois, Konstantinos Katsanos, Dimitrios K. Christodoulou, Gerasimos Baltayiannis, Nikos Tzampouras, Athanasios Papathanasopoulos, Vasileios Theopistos, Kostas Masalas, Antonis Kogevinas, Epameinondas Tsianos
M1183 Microsatellite Polymorphisms in FOXP3 Gene in Patients with Ulcerative Colitis Katsuhito Arai, Yoshiaki Takeuchi, Chitose Ohishi, Reiko Makino, Michio Imawari
AIM: The estimation of Inflammatory Bowel Diseases (IBD) epidemiology in Northwestern Greece for the years 1981-2007. METHODS: Northwestern Greece (NW) has 6 Hospitals and 18 Registrars in Gastroenterology. An epidemiologic questionnaire was filled for each patient with IBD. RESULTS: 910 patients (558 men, 352 women) with IBD [654 patients with ulcerative colitis (UC) and 154 patients with Crohn's Disease (CD)] along with 102 patients with unspecified colitis (USC), were examined. The highest frequency of IBD patients was detected from the prefectures of Ioannina and Corfu. 11 deaths (1,2%) and 7 cases (0,77%) with total colectomy were reported. The UC/CD ratio was 4,2/1. Ages between 4060 years showed the highest prevalence in IBD. The most common distribution in UC was: left colitis 67,3%, total colitis 17,2%, proctitis 15,5%. In CD, respectively: terminal ileus 40,3%, terminal ileus and large bowel 35,8%, only large bowel 23,9%. 24 patients with dysplasia (2,63%) and 20 patients with neoplasia (2,2%) were also detected. From the latter, 7 had intestinal neoplasia (1 patient with 2 cancers) and 13 extraintestinal. CONCLUSIONS: The increase of IBD incidence in NW Greece can be attributed to the high rate of all IBD types (CD, UC, USC), in combination with the low mortality. The gap between UC-CD is continuously lowering and male sex predominates. Left colitis predominates in UC and involvement of terminal ileus is most common in CD.
Introduction: It is now known that both genetic and environmental factors are important for the pathogenesis of inflammatory bowel diseases. A number of candidate genes contributing to disease susceptibility have been identified up to date. They include genes associated with innate immunity, autophagy, epithelial barrier functions, and proinflammatory cytokines and their cognate receptors. Since abrogation of regulatory cells causes colitis experimentally, genes participating in the regulatory mechanisms may also be a potent susceptibility gene. FOXP3-expressing regulatory T cells are important for the immune tolerance and the association of polymorphisms of the FOXP3 gene and certain autoimmune diseases has recently been reported. Aim: The aim of this study is to investigate whether the microsatellite polymorphisms of FOXP3 gene are associated with susceptibility in ulcerative colitis. Method: This study was conducted in single institution. Eighty eight patients with ulcerative colitis participated in this study and the control group was 151 healthy subjects. All participants comprised of Japanese. The genomic DNA was obtained from white blood cells using a Magtration System 6GC (Precision System Science, Japan). The DNA fragments containing the GT-repeat in the first intron and TC-repeat in the 6th intron of FOXP3 gene were amplified by PCR by primers labeled with a fluorescent dye because variations of repeatnumber of these regions were shown to be functional. The amplified DNA fragments were then analyzed with a 3100 Genetic Analyzer (Applied Biosystems). The numbers of repeated units of each polymorphism were calculated from the length of the DNA fragments. Association studies between each of the polymorphism with ulcerative colitis were performed by chi-square test. P value less than 0.05 was considered to be significant. Results: Comparison of the whole allele distribution of the intron zero polymorphisms between control and UC patients demonstrated no significant difference. Since FOXP3 gene is located on Xchromosomes, the analysis of each allele frequency was done by dividing female and male groups. There were no difference in comparison between control and UC patients for the (GT)15 and (GT)16 allele in both gender. However, the frequency of the (GT)15 allele in male UC patients was higher than control. No significant difference was observed in comparison of genotype frequencies in intron 6 polymorphism. Conclusions: We did not find the association
M1181 Disparities Between Caucasians and African Americans in Crohn's Disease Xiaoyu Yang, Sveta Shah, Eva H. Alsheik, Asyia S. Ahmad, Radha Menon, Frank Pandolfe, David E. Stein The incidence of Crohn's Disease (CD) is 3.1 to 14.6 cases per 100,000 person-years. CD has a 30-fold higher incidence in Caucasians versus African Americans (AA). Over the past 30 years, incidence in AA has been increasing. Furthermore, several studies have noted differences in disease characteristics among the races, though findings are variable in nature and have not been consistently associated with socioeconomic factors. AIM: To determine
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respectively). The alterations of fetus and aminosalicilates, corticosteroids or no drugs administrated during pregnancy are shown in table 1. Conclusion: The administration of aminosalicilates or corticosteroids during pregnancy in patients with IBD did not worsen fetus outcome. Table 1. Fetus outcome and drug administration during pregnancy.
of microsatellite polymorphisms of FOXP3 gene with ulcerative colitis. The larger scale investigation of other polymorphisms of this gene will be needed to conclude susceptibility.
(Arg753Gln and Arg677Trp), TLR6 (Ser249Pro) genes and the -159C/T promoter polymorphism of CD14 gene in 99 patients with ulcerative colitis (UC), 45 patients with Crohn disease (CD) and 178 healthy controls. Results: No TLR polymorphism was detected in any patients or healthy controls in Korean population. T allele and TT genotype frequencies were significantly higher in IBD patients than in healthy controls (57% vs 37%, P<0.001; 33% vs 15%, P<0.005, respectively). In subgroup analysis, both CD and UC patients also had significantly higher T allele and TT genotype frequencies compared to health controls (P<0.05). There was no association between CD14 polymorphism and disease phenotype patient's age, disease location, activity, response to therapy and history of surgery. In patients with UC, however, T allele frequency was significantly higher in pancolitis groups compared to [proctitis + Lt. sided colitis] group (67% vs 51%, P=0.02). Conclusion: There is no TLR 1, 2, 4, 6 polymorphism in Korean population. The promoter polymorphism of the CD14 gene at -159C/T is positively associated with UC and CD. In UC, CD14 polymorphism has positive association with pancolitis. These findings support the role of an abnormal immune response in the pathogenesis of IBD.
AGA Abstracts
M1184 A Pilot Study for Genetic Mutations in African American Patients with Crohn's Disease Kristin Braun, Sidney Cohen, Anthony J. DiMarino, Paolo Fortina BACKGROUND: Crohn's disease(CD) is a chronic, idiopathic inflammatory disorder thought to be caused by an interplay of environmental and genetic factors. To date a number of candidate genes have been identified in Caucasians through genome wide association studies, the first and most widely studied is the CARD 15 gene in the IBD 1 locus. Single nucleotide polymorphisms (SNPs) have been identified in the coding regions of the IBD 1 loci and are considered to confer susceptibility to CD. Carriage of these polymorphisms has an OR of 2.20 up to 17.1 for carriage of more than one allele. Despite these recent genetic discoveries in Caucasians, little is known about the genetics of CD in the African American population. Several clinical studies have suggested that there are racial differences in CD family history, disease location, disease severity and extra-intestinal manifestations and recent pediatric data indicates that African Americans rarely have the same IBD 1 risk haplotypes as Caucasians. AIM: To identify genotypic differences in minorities compared to Caucasians with CD in our institution. METHODS: DNA was extracted from whole blood and 25ul PCR reactions were performed using primers for detecting SNPs R702W, G908R, L1007fsinsC. PCR reactions were set up on a ABI 9700 thermo cycler with subsequent sequencing and analysis of the PCR products. Patient clinical information was obtained through a computer database search. RESULTS: The DNA of 18 African American patients with crohn's disease was sequenced. Sixty-six percent of the patients were female, 55% had perianal disease evidenced by fistulas, 33% had stricturing disease, 50% had at least one prior surgery and 33% of the patients had at least one prior small bowel obstruction. DNA sequencing revealed that only 1/18 patients had an insertion at the L1007fsinsC loci, the remainder were all deletions. 1/ 18 patients was a heterozygote at the R702W loci, the remainder were all homozygotes. There were no polymorphisms detected in G908R loci, all of the patients were homozygotes. CONCLUSION: DNA sequencing data indicates that carriage of IBD1 risk associated polymorphisms is rare in African American patients with CD, despite these patients having complicated disease with intestinal strictures and fistulas.
M1187 The Endoscopic Spectrum of Segmental Colitis Associated with Diverticulosis Antonio Tursi, Giovanni Brandimarte, Walter Elisei, GianMarco Giorgetti, Alfredo Papa Introduction: Although recognition of “segmental colitis associated with diverticulosis” (SCAD) is increasing in clinical practice, the information about endoscopic appearance of this disease are lacking. Aims & Methods: To assess the endoscopic spectrum of SCAD, comparing them with the histological findings and with clinical features of the disease. A prospective study from January 2004 to October 2007 was performed after agreement between endoscopists participating at this study on the endoscopic classification. Diagnosis of SCAD was performed by specific endoscopic and histological patterns. Results: 6230 consecutive colonoscopies were performed in these Units. SCAD was diagnosed in 92 patients (14.76%, 42 Males and 50 Females, mean age 62.3 years, range 52-73 years). We recognized four endoscopic patterns: pattern A, a typical SCAD pattern as “crescentic fold disease” (48 patients, 52.20%); pattern B, a “Mild-to moderate ulcerative colitis-like” pattern (28 patients, 30.40%); pattern C, a “Crohn's disease colitis-like” pattern (10 patients, 10.90%); pattern D, a “Severe ulcerative colitis-like” pattern (6 patients, 6.50%). Most of patients showing pattern A (28 patients, 58.33%, p<0.018) and pattern B (25 patients, 89.29%, p<0.00001) showed histological alteration resembling moderate ulcerative colitis (UC); patients showing pattern C showed larger variability of histological damage (p<0.01); all patients showing pattern D showed the typical histological alteration similar of severe UC (p<0.0001). Patients showing pattern A (29 patients, 60.42%, p=n.s.) and pattern B (13 patients, 46.43%, p= n.s.), experienced more frequently diarrhea; whilst abdominal pain was the most experienced symptom in pattern C (50%, p=n.s.) and pattern D (83.33%, p=n.s.) patients. Conclusions: Endoscopic pattern of SCAD may range from milder to severe damage. The histopathological findings but not clinical features showed a statistically significant association with the degree of endoscopic damage.
M1185 Gender-Specificity and Genotypic Interaction of Common Genetic Variants in the p53/MDM2-Network in Crohn Disease Vincent Zimmer, Gunter Assmann, Thomas Widmann, Monika B. Mueller, Mei Fang Ong, Klaus Römer, Frank Lammert Background & Aim: Defective p53-mediated apoptosis and cell cycle control has been implicated in the immunopathogenesis of Crohn disease (CD), promoting intestinal inflammation by activation and expansion of mucosal T cells (1+2). Common functional sequence variants of p53 (SNP72 G/C) and its key negative regulator mdm2 (SNP309 T/G) are considered to modulate cellular apoptotic capacity and cell cycling by a low apoptotic potential of the SNP72 C variant and enhanced mdm2 transcription of the SNP309 G allele (3+4). From this perspective, we aimed to elucidate the effects of these polymorphic variants on CD susceptibility. Methods: The variants p53/SNP72 G/C (rs1042522) and mdm2/ SNP309 T/G (rs2279744) were genotyped in 149 European CD patients and 478 healthy controls. Subgroup analysis was performed in relation to NOD2/CARD15 status, designated as, at least, heterozygosity in either CD-associated SNP (Arg702Trp, Gyl908Arg, Leu1007finsC), and to demographic/clinical characteristics. Results: The SNP72 CC genotype tended to be less frequent in CD, which reached significance in males (0 vs. 7.3%; p=0.037). By contrast, SNP309 genotypes and allele frequencies of both SNPs demonstrated no significant difference. Of note in SNP309 TT carriers, genotype SNP72 CC was significantly less frequent (0 vs. 9.7%; p=0.034). No association was observed between NOD2/CARD15 and the respective SNPs. Conclusions: In this association study, we report on a gender-specific protective effect of the low-apoptotic SNP72 CC genotype, and a genotypic interaction between SNP309 TT and SNP72 CC, which links common genetic variation of the p53/ mdm2 network to CD independent of NOD2/CARD15. Since the G allele of SNP309 increases cellular mdm2 availability, it might abrogate the attenuation of p53-mediated apoptosis conferred by the SNP72 CC genotype. Our findings do not support a primary genetic T cell apoptosis defect at the level of p53. However, with increased epithelial cell death impacting on mucosal barrier integrity (5), apoptosis seems to have a dual role in CD, and, if replicated in larger cohorts, it remains to be determined how SNP72 CC might affect distinct pathogenetic steps. References: 1. Sturm A, JCI, 2002 2. Sturm A, Gut, 2004 3. Dumont P, Nat Genet, 2003 4. Bond GL, Cell, 2004 5. Zeissig S, Gut, 2004
M1188 Overall and Cause-Specific Mortality in Crohn's Disease: A Meta-Analysis of Population-Based Studies Dana Duricova, Natalia Pedersen, Margarita Elkjaer, Pia S. Munkholm, Tine Jess Background and Aim: An overview of mortality risk in Crohn's disease (CD) in unselected population is lacking. We therefore performed a meta-analysis of population-based studies on overall and cause specific mortality in CD. Methods: MEDLINE (January 1965-February 2008) abstracts from international conferences (DDW, UEGW, 2004-2007) and reference lists of selected articles were searched systematically. All papers fulfilling the predefined inclusion criteria were scrutinized for data on population size, time of follow-up, gender, age and observed to expected deaths. STATA meta-analysis software was used to calculate overall and cause specific pooled risk estimates (SMR, observed/expected). Results: Nine studies were included with overall SMRs ranging from 0.72 to 3.2 resulting in a significantly increased pooled SMR of 1.39 (95%CI: 1.30-1.50). Regarding cause-specific mortality, a significantly increased risk of death from cancer (in particular of the digestive system and lung), chronic obstructive pulmonary disease (COPD), gastrointestinal diseases and genitourinary diseases was observed (Table 1). Conclusion: Among unselected patients with CD, the overall mortality is slightly but significantly higher compared to the general population and primarily explained by death from gastrointestinal, respiratory and genitourinary diseases. It is notable that death from colorectal cancer is not increased. Table 1. Cause -Specific Mortality in Patients with Crohn's Disease
M1186 A Polymorphism of CD14 Is Associated with Inflammatory Bowel Disease in Korean Population Kang-Moon Lee, Woo Chul Chung, Chang Nyol Paik, Bo-In Lee, Jeong Rok Lee, Sung Hoon Jung, Min Kyoung Lee, Kyu Yong Choi Background: Inappropriate and exaggerated immune response to luminal bacteria is implicated in the pathogenesis of inflammatory bowel disease (IBD). Evidence is accumulating that mutations in the genes for pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NODs, are associated with IBD in Western populations. However, lack of NOD2 or TLR4 genetic polymorphisms in Japanese and Chinese population suggests the difference in genetic background between Asian and Western population. We analyzed the frequencies of TLR1, 2, 4, 6 and CD14 mutations in Korean patients to investigate the association between those polymorphisms and the susceptibility to IBD in Korean population. Methods: Using a polymerase chain reaction based restriction fragment length polymorphism, we evaluated mutations of TLR4 (Asp299Gly and Thr399Ile), TLR1 (Arg80Thr), TLR2
AGA Abstracts
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