CARD15/NOD2 in a Tunisian Population with Crohn’s Disease

Crohns disease (CD) is a heterogeneous disorder. A genetic linkage to chromosome 16 (IBD1) has been previously observed and replicated in unrelated populations. Recently, in this region, NOD2/CARD15 has been identified as a susceptibility gene. The aim of this report is to determine whether this gene is implicated in CD in a Tunisian population. One hundred thirty patients with CD and 90 healthy individuals were genotyped for the three common NOD2 variants (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11). Furthermore, the 11 exons of the NOD2 gene were sequenced in 20 patients with CD. Results showed that the frequency of the CARD15 variants in the Tunisian population is significantly lower than that observed in the European and American population. Direct sequencing of CARD15 did not permit us to identify a characteristic mutation in our population. No association was confirmed between CD and the NOD2 gene in our Tunisian population. Furthermore, the NOD2/CARD15 gene has a variable association with CD in different populations. These results indicate the genetic variation of CD in different ethnic groups.     

Association between NOD2/CARD15 gene polymorphisms and Crohn’s disease in Chinese Zhuang patients

AIM:To assess the relationship between the P268S,JW1 and N852S polymorphisms and Crohn’s disease(CD)susceptibility in Zhuang patients in Guangxi,China.METHODS:Intestinal tissues from 102 Zhuang[48CD and 54 ulcerative colitis(UC)]and 100 Han(50 CD and 50 UC)unrelated patients with inflammatory bowel disease and 72 Zhuang and 78 Han unrelated healthy individuals were collected in the Guangxi Zhuang Autonomous Region from January 2009 to March 2013.Genomic DNA was extracted using the phenol chloroform method.The P268S,JW1 and N852S polymorphisms were amplified using polymerase chain reaction(PCR),detected by restriction fragment length polymorphism(RFLP),and verified by gene sequencing.RESULTS:Heterozygous mutation of P268S in the NOD2/CARD15 gene was detected in 10 CD cases(six Zhuang and four Han),two Han UC cases,and one Zhuang healthy control,and P268S was strongly associated with the Chinese Zhuang and Han CD populations(P=0.016 and 0.022,respectively).No homozygous mutant P268S was detected in any of the groups.No significant difference was found in P268S genotype and allele frequencies between UC and control groups(P>0.05).Patients with CD who carried P268S were likely to be≤40 years of age(P=0.040),but were not significantly different with regard to race,lesion site,complications,and other clinical features(P>0.05).Neither JW1 nor N852S polymorphisms of the NOD2/CARD15gene were found in any of the subjects(P>0.05).CONCLUSION:P268S polymorphism may be associated with CD susceptibility in the Zhuang population in the Guangxi Zhuang Autonomous Region,China.In contrast,JW1 and N852S polymorphisms may not be related to CD susceptibility in these patients.     

The Prevalence of Crohn’s Disease in Israel: A 20-Year Survey

Objectives This is the third survey that we have performed in the kibbutz population in Israel. The previous two surveys were 10 years apart, in 1987 and 1997, demonstrating an increase in Crohn’s disease prevalence. The aim of the present study was to confirm the trend for increasing Crohn’s disease prevalence in Israel. Methods There are 269 kibbutz settlements in Israel, with a total of 117,700 people, accounting for 2.4% of the Jewish Israeli population. The local physician for each kibbutz was contacted by mail, e-mail, telephone, and fax in order to obtain information on Crohn’s disease patients. Data was retrieved and updated to 31st December 2007, the point prevalence date. Details of gender, age, origin, clinical spectrum of the disease, therapy, and complications were recorded. Results There were 133 confirmed cases of Crohn’s disease. The prevalence rate rose from 25.53/100,000 in 1987 to 65.11/100,000 in 1997, and then to 112.99 in 2007 (P < 0.0001). The prevalence rate was higher in women than men, and Israeli- or European/American-born than Asian/African-born individuals. The rise in prevalence was steady from 1987 to 1997 and then to 2007 in all subgroups, except for Asian/African-born kibbutz members. In the last group, a decrease in prevalence was demonstrated between 1987 and 1997, and then a sharp increase between 1997 and 2007. Conclusions We conclude that the incidence and prevalence of Crohn’s disease increased in the three ethnic groups of Israeli Jews. Differences still exist but become smaller, maybe due to the strong environmental influence that overcame genetic preponderance. The authors declare that there is no conflict of interest.     

Distribution of Common CARD15 Variants in Patients with Sporadic Crohn’s Disease: Cases from Turkey

Three common genetic variations, namely, R702W, G908R, and 1007fs, on CARD15 have been shown to increase the risk for Crohn’s disease (CD) in Caucasian populations. In this study the frequencies of these CARD15 variants were determined by genotyping in 56 patients with CD and 100 healthy ethnically matched controls from Turkey. Overall frequency of all three variants was 10.7% in CD patients, compared with 1.5% in controls (odds ratio [OR]: 7.9). Among them, the frequency of the G908R variant allele was 8% in CD cases, compared with 0% in controls (OR: 36.8). The allele frequencies of three CD-related CARD15 variants were considerably lower in the control group compared to the reported Caucasian populations. Among the described CARD15 variants, G908R confers an increased susceptibility to CD, whereas the more frequently reported associations in Europeans with R702W and 1007fs are not confirmed in this Turkish population.     

Prediction of Crohn’s disease aggression through NOD2/CARD15 gene sequencing in an Australian cohort

AIM:To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15(NOD2/CARD15)and the natural history of Crohn’s disease(CD)to identify patients who would benefit from early aggressive medical intervention.METHODS:We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000;Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not.Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3,5,7,10 and 12 and direct sequencing for exons 2,4,6,8,9 and 11 was conducted.CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.RESULTS:About 13.3%of the cohort(four patients)carried at least one mutant allele of 3020ins C of the NOD2/CARD15 gene.There were 20 males and 10females with a mean age of 43.3 years(range 25-69years).The mean follow up was 199.6 mo and a median of 189.5 mo.Sixteen sequence variations within the NOD2/CARD15 gene were identified,with 9 of them occurring with an allele frequency of greater than 10%.In this study,there was a trend to suggest that patients with the 3020ins C mutation have a higher frequency of operations compared to those without the mutation.Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery.This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.CONCLUSION:These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.     

NOD2/CARD15 , ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn’s disease

AIM: To assess whether the polymorphisms of NOD2/ CARD15 , autophagy-related 16-like 1 (ATG16L1 ), and interleukin-23 receptor (IL23R ) genes play a more critical role in the susceptibility of childhood-onset than in adult-onset Crohn’s disease (CD). METHODS: Polymorphisms R702W, G908R, and 3020insC of NOD2/CARD15 ; rs2241880 A/G of ATG16L1 , and rs11209026 (R381Q) of IL23R gene were assessed in 110 childhood-onset CD, 364 adult-onset CD, and 539 healthy individuals. Analysis of polymorphisms R702W, G908R, ...     

Associations between NOD2/CARD15 genotype andphenotype in Crohn’s disease-Are we there yet?

INTRODUCTION Chronic idiopathic inflammatory bowel diseases (IBD), made up predominantly of Crohn’s disease (CD) and ulcerative colitis, remain fertile ground for both clinical and basic science research. These conditions have been held up as classic exa…     

Crohn’s disease incidence evolution in North-western Greece is not associated with alteration of NOD2/CARD15 variants

AIM To assess the trends in the incidence of inflammatory bowel disease (IBD) over 23 years in the same area and to identify genetic factors related to incidence evolution.METHODS Patients with IBD arising from Northwestern Greece were systematically recorded through the 1983-2005 period. Trends in disease incidence and genetic patterns related to CARD15 variants were documented and correlated.RESULTS A total of 447 patients with IBD were recorded (23.5% Crohn's disease, 72.7% Ulcerative colitis and 3.8% indeterminate colitis). Mean annual incidence rates of CD and UC were 0.9/100000 (95% CI 0.1-1.7) and 2.7/100000 (95% CI 1.7-4.1) inhabitants,respectively. There was a statistically significant increase of CD incidence (P ＜ 0.01) during the study period, in contrast to the UC incidence. There were no statistical differences in CARD15 variants over the study period.CONCLUSION The incidence of CD in North-western Greece has risen disproportionately to that of UC in the 21st century. This is not related to alterations of genetic background though.     

Associations between NOD2/CARD15 genotype and phenotype in Crohn＇s disease-Are we there yet？

There have been multiple NOD2/CARD15 genotype-phenotype analyses undertaken in patients with Crohn's disease since the gene's discovery in 2001. This review focuses on the major published series based upon their size and on the presence of specific clinical and genetic information provided in the published material from 2001 to 2005. Twelve studies provided raw data to carry out comparisons of disease location while ten studies included analysis of NOD2/CARD15 genotypes. NOD2/CARD15 variant frequency in ileal disease did not differ significantly among studies, whereas a comparison of disease location demonstrated highly significant differences among studies. Meta-analysis confirmed significant associations between NOD2/CARD15 variants and both ileal and ileocolonic disease locations, and with both stricturing and penetrating forms of disease behavior. This review underlines the significant phenotypic differences that exist among populations, including similar ethnic groups, and has demonstrated the need for further studies of patients with long-term "inflammatory" Crohn's disease.     

Crohn’s Disease: Presentation and Severity Compared Between Black Patients and White Patients

PURPOSE Common belief based on clinical experience suggests that Crohn’s disease is more severe among black patients, although little data exists on the effect of race on Crohn’s disease. We compared multiple variables among black patients with Crohn’s disease requiring surgery to those of white patients presenting to a university colorectal surgery unit during a five-year period.METHODS A total of 345 patients required surgery for Crohn’s disease between June 1998 and September 2003. The following data were abstracted from patient charts and a prospectively maintained database: age at diagnosis; age at first Crohn’s disease surgery; presenting symptoms; incidence, number and location of fistulas at presentation; number of Crohn’s disease operations; and family history of inflammatory bowel disease. Data regarding medical insurance coverage also were obtained. Complete data were evaluable on 178 patients. Patient variables were analyzed using the chi-squared, Fisher exact, and Student t-tests.RESULTS Mean age at diagnosis was 28 years for white males, 20 years for black males, 30 years for white females, and 28 years for black females (all p > 0.05). Thirty-seven percent of white females presented with obstructive symptoms vs. 12 percent of black females. (P = 0.011). Sixty-five percent of black females presented with inflammatory symptoms compared with 28 percent of white females (P = 0.001). Of females presenting with fistulas, 15 percent of black patients had a rectovaginal fistula compared with 5 percent of white patients. Seventeen percent of black males and 21 percent of white males had intra-abdominal fistulas. None of these differences were statistically significant. The incidence of fistulas at presentation, mean number of fistulas, total number of operations, and family history of inflammatory bowel disease did not differ.CONCLUSIONS Contrary to expectations, Crohn’s disease does not seem to be more severe among black patients, who had an earlier age of diagnosis, although this was not statistically significant. Overall, there was no difference in disease presentation. White females were more likely to present with obstructive symptoms compared with black females, who more often presented with inflammatory symptoms. Among patients with fistulas, the incidence of rectovaginal fistulas was higher in black females compared with white females, and white males were somewhat more likely to have intra-abdominal fistulas than black males. Although there was no demonstrated difference in incidence and mean number of fistulas at presentation, the number of operations for Crohn’s disease, or family history of inflammatory bowel disease among blacks and whites, there are differences in presenting symptoms among these populations.Presented at the meeting of The American Society of Colon and Rectal Surgeons, Dallas, Texas, May 8 to 13, 2004.Reprints are not available.     

Diagnosis and Differential Diagnosis of Crohn’s Disease of the Ileal Pouch

Approximately 20%-30% of patients with ulcerative colitis will eventually require colectomy despite recent advances in medical therapy. Ileal pouch-anal anastomosis has become the surgical treatment of choice. A subset of patients with ileal pouches can develop Crohn's disease or a Crohn's-disease-like condition of the ileal pouch after surgery. Diagnosis, differential diagnosis, and management of Crohn's disease of the ileal pouch have been challenging. A combined assessment of clinical history, endoscopy, histology, abdominal/pelvic imaging, and examination under anesthesia is often necessary for accurate diagnosis, disease classification, management, and prognosis. A multidisciplinary approach with gastroenterologists, colorectal surgeons, gastrointestinal pathologists, and radiologists is advocated.     

The Fate of the Ileal Pouch in Patients Developing Crohn’s Disease

PURPOSE Recent studies have suggested that a subset of patients with Crohns colitis may have a favorable outcome after ileal pouch-anal anastomosis and have advocated elective ileal pouch-anal anastomosis in selected patients with Crohns disease. We have not offered ileal pouch-anal anastomosis to patients with known Crohns disease, but because of the overlap in clinical presentation of ulcerative colitis and indeterminate colitis, some patients receiving an ileal pouch-anal anastomosis are subsequently found to have Crohns disease. We review our experience with these patients to identify potential preoperative predictors of ultimate pouch failure.METHODS Patients with a final diagnosis of Crohns disease were identified from an ileal pouch-anal anastomosis registry. These patients are followed prospectively. Preoperative and postoperative clinical and pathologic characteristics were evaluated as predictors of outcome. Median (range) values are listed.RESULTS Thirty-two (18 females) patients (4.1 percent) with a final diagnosis of Crohns disease were identified from a registry of 790 ileal pouch-anal anastomosis patients (1980–2002). Patients underwent ileal pouch-anal anastomosis in two stages (11 patients) or three stages (21 patients). The preoperative diagnosis was ulcerative colitis in 24 patients and indeterminate colitis in 8 patients. Median follow-up was 153 (range, 13–231) months. The median time from ileal pouch-anal anastomosis to diagnosis of Crohns disease was 19 (range, 0–188) months. Complications occurred in 93 percent, including perineal abscess/fistula (63 percent), pouchitis (50 percent), and anal stricture (38 percent). Pouch failure (excision or current diversion) occurred in nine patients (29 percent) at a median of 66 (range, 6–187) months. Two of these 9 patients had preoperative anal disease (not significant). Comparing patients with failed pouches (n = 9) to patients with functioning pouches (n = 23), post-ileal pouch-anal anastomosis perineal abscess (67 vs. 26 percent, P = 0.05) and pouch fistula (89 vs. 30 percent, P = 0.01) were more commonly associated with pouch failure. Preoperative clinical, endoscopic, and pathologic features were not predictive of pouch failure or patient outcome. For those with a functional pouch, 50 percent have been or are currently on medication to treat active Crohns disease. This group had six bowel movements in 24 (range, 3–10) hours, with leakage in 60 percent and pad usage in 45 percent.CONCLUSIONS Patients who undergo ileal pouch-anal anastomosis and are subsequently found to have Crohns disease experience significant morbidity. Preoperative characteristics, including the presence of anal disease, were not predictive of subsequent pouch failure. We choose not to recommend the routine application of ileal pouch-anal anastomosis in any subset of patients with known Crohns disease.Reprints are not available.     

<Emphasis Type="Italic">CARD15</Emphasis> Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic Response

Background  

CARD15 mutations alter bowel immunity and increase susceptibility to Crohn′s disease (CD). However, the relation between these mutations and Crohn′s perianal fistulas has not been fully clarified.     

The vesicle-associated function of NOD2 as a link between Crohn’s disease and mycobacterial infection

Although Crohn’s disease (CD) etiology remains unclear, a growing body of evidence suggests that CD may include an infectious component, with Mycobacterium avium subsp. paratuberculosis (MAP) being the most likely candidate for this role. However, the molecular mechanism of the MAP involvement in CD pathogenesis remains unclear. The polymorphism of the NOD2 gene, coding for an intracellular pattern recognition receptor, is a factor of predisposition to mycobacterial infections and CD. Recent findings on NOD2 interactions and functions provide the missing pieces in the puzzle of a NOD2-mediated mechanism common for mycobacterial infections and CD. Implications of these new findings for the development of a better understanding and treatments of CD and mycobacterial infections are discussed.     

Comparison Between 1.5 and 3.0 Tesla Magnetic Resonance Enterography for the Assessment of Disease Activity and Complications in Ileo-Colonic Crohn’s Disease

Background

Magnetic resonance imaging (MRI) can assess disease activity and severity in Crohn’s disease (CD). Three-Tesla magnetic resonance (3T) increases signal-to-noise ratio (SNR) and reduces time of image acquisition (IAT). Whether 3T increases the accuracy of MRI in CD compared to 1.5T is unknown.

Aim

We aimed to compare prospectively the accuracy of 3 and 1.5T in ileo-colonic CD patients.

Methods

Twenty-six patients with ileo-colonic CD underwent 1.5 and 3T MR enterography at the same time. Ileocolonoscopy was the reference standard for luminal disease. Sensitivity, specificity and accuracy of MRI in evaluating six signs of active and complicated disease (localization, thickening, enhancement, strictures, entero-enteric fistulas, and ulcers) were calculated for both techniques.

Results

Three-Tesla resulted as sensitive, specific, and accurate as 1.5T in detecting disease location (accuracy 0.93 vs. 0.86), bowel wall thickening and enhancement (accuracy 0.92 vs. 0.80 for both parameters), strictures (accuracy 0.90 vs. 0.80) and entero-enteric fistulas (accuracy 0.92 vs. 0.92). 3T was superior to 1.5T in detecting ulcers (0.76 vs. 0.42, P < 0.05). SNR resulted higher in 3T, and IAT resulted shorter than 1.5.

Conclusions

We found that 3T is equally accurate as 1.5T in evaluating ileo-colonic CD. Because of superiority in detecting mucosal ulcers, 3T should be preferred in patients with ileo-colonic CD.