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CARD15 GENE MUTATIONS AND RISK OF RE-OPERATION IN CROHN'S DISEASE PATIENTS
42 tion, time to onset of fistulising or stricturing behaviour, need for surgery and presence of extra-intestinal manifestations. Results: With a median follow-up (FU) of 15.6y (IQR 8.5-23.1), 48.7% and 56.0% of patients developed fistulae and strictures respectively and 60% needed resective surgery. Using Kaplan-Meier method, a significant difference in stricture and surgery free survival rate was seen, with a gene dosage effect for 0, 1 and 2 CARD15 variants respectively (figure, logrank p<0.0001). This effect was independent of disease location as it was observed for both ileal and colonic disease. Patients with younger age at diagnosis developed more fistulae during their disease course (58% <16y, 51.1% 17-40y, 33.3% >40y), independent of FU time (multivariate p=0.009 for age at diagnosis and p=0.0002 for FU time). Conclusion: CD patients carrying CARD15 variants have a shorter time to onset of stricturing disease and subsequent abdominal surgery. Genotyping for CARD15 at the time of diagnosis may therefore be useful to identify those patients who might benefit from early introduction of aggressive treatment.
P148 MULTIDRUG RESISTANCE 1 GENE POLYMORPHISM AND SUSCEPTIBILITY TO INFLAMMATORY BOWEL DISEASE S. Ardizzone 1 , G. Maconi 1 , A. Russo 2 , E. Colombo 1 , A. Cassinotti 1, C.M. Penati 1 , M.L. Tenchini 3, G. Bianchi Porro 1 . 1 L. Sacco University Hospital, Department of Clinical Science, Gastroenterology Unit, Milan, Italy; 2 Department of Epidemiology, Local Health Authority, Milan, Italy; 3 Department of Biology and Genetics for Medical Science, University of Milan, Milan, Italy Background: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, that encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behaviour in inflammatory bowel disease, but with conflicting results. Methods: A total of 211 patients with Crohn' s disease, 97 patients with ulcerative colitis, and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphims. Genotype frequencies of Crohn' s disease and ulcerative colitis patients were compared to those observed in a control population. Genotype-phenotype correlations with the major clinical features were also established and estimated risks (OR with 95%IC) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. Results: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphims on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with positive family history for IBD (OR = 0.44; 95% CI 0.20-0.95), and articular manifestations (OR = 0.29; 95% CI 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific sub-phenotypes was found, nor was there any association with sub-phenotypic categories of UC and both SNPs. Conclusions: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far, may be the indirect expression of the complex role played by the MDR1 gene and its product P-glycoprotein 170 in the regulation of host-bacteria interaction and in the pathogenesis of IBD.
P149 NOD2/CARD15 GENE MUTATIONS AND RISK OF RE-OPERATION IN CROHN' S DISEASE PATIENTS G. Maconi 1 , E. Colombo 1 , G.L. Sampietro 2 , F. Lamboglia 3 , M. Daperno 4 , S. Ardizzone 1 , R. D' Incà 3 , A. Cassinotti 1, G.C. Sturniolo 3 , G. Bianchi Porro 1 . 1 Department of Gastroenterology, L.Sacco University Hospital, Milan, Italy; 2 Department of Surgery, L.Sacco University Hospital, Milan, Italy; 3 Department of Gastroenterology, University of Padua, Italy; 4 Department of Gastroenterology, Ospedale Mauriziano, Turin, Italy Background and Aims: Several studies have investigated the risk factors for re-operation in Crohn' s disease (CD) with conflicting results. Nod2/CARD15 gene mutations have been identified as a major risk factor for CD patients and associated with ileal disease, stenosis and surgery. Although Nod2/CARD15 gene mutations were implicated in ileal strictures and need of surgery, the data regarding the need for re-operation are scanty and inconsistent. This study evaluated whether Nod2/CARD15 gene mutations conferred an increased risk of surgical recurrence in those CD patients who have undergone surgery.
Poster Presentations Methods: 165 CD patients who were operated for ileal and/or colonic stenosis were included in the study. Clinical characteristics of CD, time and main indication for surgery, type of surgery, postoperative therapy and time of surgical recurrences were recorded. Nod2/CARD15 gene mutations were determined by DNA sequencing analysis. Surgical recurrence was estimated by Kaplan-Maier curves. Results: 63 out of 165 patients (38.2%) showed at least one Nod2/CARD15 mutation. The median length of follow-up of CD patients with Nod2/CARD15 mutations did not differ from that of patients without Nod2/CARD15 mutation (108 vs 118 months). During the follow-up, 69 patients had at least 1 (up to 8) surgical recurrence (29 patients more than 1 recurrence). Five, 10- and 15-year surgical recurrence rates were 31%, 58% and 66% in patients with Nod2/CARD15 variants, and 20%, 38% and 62% in patients without Nod2/CARD15 mutations, respectively (p:ns). The median time interval between first and second surgery was not different in patients with or without Nod2/CARD15 variants (62 vs 69 months). The number of surgeries was not statistically different between patients with or without Nod2/CARD15 mutations. Conclusion: Nod2/CARD15 gene mutations are not associated with increased risk of re-operation, with an early need of second surgery and with a more aggressive course of disease in CD patients requiring surgery for stenosis.
P150 PREGNANCY OUTCOME AND FERTILITY IN INFLAMMATORY BOWEL DISEASE IS INFLUENCED BY DISEASE PHENOTYPE C.W. Lees 1 , R.E. Gailer 1 , N.C. Johnston 1 , P. Warner 2, H.O. Critchley 3, J. Satsangi 1. 1 Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh; 2 Public Health Sciences, University of Edinburgh; 3 Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK Introduction: The incidence of the chronic inflammatory bowel diseases, Crohn' s disease (CD) and ulcerative colitis (UC) peaks between the ages of 10 and 40 years. Subsequently many females have IBD during their reproductive years and have concerns surrounding fertility, pregnancy, and childbirth. CD patients have fewer babies than expected; the most important determinant of fecundity is disease activity at conception. In UC there is a three-fold increase in subfertility in women with previous ileal pouch anal anastamosis. Aims: We aimed to describe pregnancy outcome, subfertility rates, and menstrual health in a large population of accurately phenotyped Scottish women whose IBD was diagnosed whilst they were of child-bearing age. Furthermore, we aimed to explore women' s perception as to how their IBD has affected their decisions regarding their family planning. Methods: A detailed questionnaire was sent to 554 female IBD patients from a single tertiary referral centre in Lothian, Scotland. All women were less than 50 years old at diagnosis (median 26.4 years; IQR 21.3-33.2). Data from 272 fully completed responses were analysed, comprising 137 patients with UC and 135 with CD. The median age at enrolment was 40.5 years (IQR 33.0-49.8). Control data on over 95% of the childbirths in Scotland were available for comparison (http://www.isdscotland.org/isd/1022.html). These data are recorded back to 1976 and include over 8000 births in Lothian from 2005. Results: 58.8% of women reported attempting pregnancy, with 90.6% of these successful. 36/160 (22.5%) of women attempting to be pregnant were referred for fertility treatment. 172/272 (63.2%) of respondents had been pregnant, with data available on a total of 365 pregnancies. 27/172 (15.7%) patients had at least one unplanned pregnancy; 12.2% were taking the oral contraceptive pill at the time of conception. Whilst women with CD took longer to conceive for each pregnancy than those with UC (6.64months vs. 3.83months, p=0.03), they had equivalent numbers of pregnancies. The proportion of low birthweight infants was more than expected in the background population (11.2% vs. 7.2%, p=0.01). Women with IBD during their pregnancy years had shorter gestations than those diagnosed after all pregnancies (38.9 vs. 39.7 weeks, p=0.0023) and more preterm babies (16.2% vs. 6.8%, p=0.021). Detailed phenotyping demonstrated that patients with ulcerative proctitis (E1) had significantly heavier birthweights than those with left sided or extensive colitis (E2 & E3) (3.43kg vs. 3.20kg, p=0.03). Women reported that IBD made their periods heavier and more painful, especially during periods of disease activity. Conclusions: Women with IBD in Lothian have pregnancies of shorter duration and babies of lower birthweight than the background population. However, women with limited ulcerative proctitis appear to be protected from these problems.
P148 MULTIDRUG RESISTANCE 1 GENE POLYMORPHISM AND SUSCEPTIBILITY TO INFLAMMATORY BOWEL DISEASE S. Ardizzone 1 , G. Maconi 1 , A. Russo 2 , E. Colombo 1 , A. Cassinotti 1, C.M. Penati 1 , M.L. Tenchini 3, G. Bianchi Porro 1 . 1 L. Sacco University Hospital, Department of Clinical Science, Gastroenterology Unit, Milan, Italy; 2 Department of Epidemiology, Local Health Authority, Milan, Italy; 3 Department of Biology and Genetics for Medical Science, University of Milan, Milan, Italy Background: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, that encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behaviour in inflammatory bowel disease, but with conflicting results. Methods: A total of 211 patients with Crohn' s disease, 97 patients with ulcerative colitis, and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphims. Genotype frequencies of Crohn' s disease and ulcerative colitis patients were compared to those observed in a control population. Genotype-phenotype correlations with the major clinical features were also established and estimated risks (OR with 95%IC) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. Results: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphims on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI 1.34-8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with positive family history for IBD (OR = 0.44; 95% CI 0.20-0.95), and articular manifestations (OR = 0.29; 95% CI 0.13-0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific sub-phenotypes was found, nor was there any association with sub-phenotypic categories of UC and both SNPs. Conclusions: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far, may be the indirect expression of the complex role played by the MDR1 gene and its product P-glycoprotein 170 in the regulation of host-bacteria interaction and in the pathogenesis of IBD.
P149 NOD2/CARD15 GENE MUTATIONS AND RISK OF RE-OPERATION IN CROHN' S DISEASE PATIENTS G. Maconi 1 , E. Colombo 1 , G.L. Sampietro 2 , F. Lamboglia 3 , M. Daperno 4 , S. Ardizzone 1 , R. D' Incà 3 , A. Cassinotti 1, G.C. Sturniolo 3 , G. Bianchi Porro 1 . 1 Department of Gastroenterology, L.Sacco University Hospital, Milan, Italy; 2 Department of Surgery, L.Sacco University Hospital, Milan, Italy; 3 Department of Gastroenterology, University of Padua, Italy; 4 Department of Gastroenterology, Ospedale Mauriziano, Turin, Italy Background and Aims: Several studies have investigated the risk factors for re-operation in Crohn' s disease (CD) with conflicting results. Nod2/CARD15 gene mutations have been identified as a major risk factor for CD patients and associated with ileal disease, stenosis and surgery. Although Nod2/CARD15 gene mutations were implicated in ileal strictures and need of surgery, the data regarding the need for re-operation are scanty and inconsistent. This study evaluated whether Nod2/CARD15 gene mutations conferred an increased risk of surgical recurrence in those CD patients who have undergone surgery.
Poster Presentations Methods: 165 CD patients who were operated for ileal and/or colonic stenosis were included in the study. Clinical characteristics of CD, time and main indication for surgery, type of surgery, postoperative therapy and time of surgical recurrences were recorded. Nod2/CARD15 gene mutations were determined by DNA sequencing analysis. Surgical recurrence was estimated by Kaplan-Maier curves. Results: 63 out of 165 patients (38.2%) showed at least one Nod2/CARD15 mutation. The median length of follow-up of CD patients with Nod2/CARD15 mutations did not differ from that of patients without Nod2/CARD15 mutation (108 vs 118 months). During the follow-up, 69 patients had at least 1 (up to 8) surgical recurrence (29 patients more than 1 recurrence). Five, 10- and 15-year surgical recurrence rates were 31%, 58% and 66% in patients with Nod2/CARD15 variants, and 20%, 38% and 62% in patients without Nod2/CARD15 mutations, respectively (p:ns). The median time interval between first and second surgery was not different in patients with or without Nod2/CARD15 variants (62 vs 69 months). The number of surgeries was not statistically different between patients with or without Nod2/CARD15 mutations. Conclusion: Nod2/CARD15 gene mutations are not associated with increased risk of re-operation, with an early need of second surgery and with a more aggressive course of disease in CD patients requiring surgery for stenosis.
P150 PREGNANCY OUTCOME AND FERTILITY IN INFLAMMATORY BOWEL DISEASE IS INFLUENCED BY DISEASE PHENOTYPE C.W. Lees 1 , R.E. Gailer 1 , N.C. Johnston 1 , P. Warner 2, H.O. Critchley 3, J. Satsangi 1. 1 Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh; 2 Public Health Sciences, University of Edinburgh; 3 Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK Introduction: The incidence of the chronic inflammatory bowel diseases, Crohn' s disease (CD) and ulcerative colitis (UC) peaks between the ages of 10 and 40 years. Subsequently many females have IBD during their reproductive years and have concerns surrounding fertility, pregnancy, and childbirth. CD patients have fewer babies than expected; the most important determinant of fecundity is disease activity at conception. In UC there is a three-fold increase in subfertility in women with previous ileal pouch anal anastamosis. Aims: We aimed to describe pregnancy outcome, subfertility rates, and menstrual health in a large population of accurately phenotyped Scottish women whose IBD was diagnosed whilst they were of child-bearing age. Furthermore, we aimed to explore women' s perception as to how their IBD has affected their decisions regarding their family planning. Methods: A detailed questionnaire was sent to 554 female IBD patients from a single tertiary referral centre in Lothian, Scotland. All women were less than 50 years old at diagnosis (median 26.4 years; IQR 21.3-33.2). Data from 272 fully completed responses were analysed, comprising 137 patients with UC and 135 with CD. The median age at enrolment was 40.5 years (IQR 33.0-49.8). Control data on over 95% of the childbirths in Scotland were available for comparison (http://www.isdscotland.org/isd/1022.html). These data are recorded back to 1976 and include over 8000 births in Lothian from 2005. Results: 58.8% of women reported attempting pregnancy, with 90.6% of these successful. 36/160 (22.5%) of women attempting to be pregnant were referred for fertility treatment. 172/272 (63.2%) of respondents had been pregnant, with data available on a total of 365 pregnancies. 27/172 (15.7%) patients had at least one unplanned pregnancy; 12.2% were taking the oral contraceptive pill at the time of conception. Whilst women with CD took longer to conceive for each pregnancy than those with UC (6.64months vs. 3.83months, p=0.03), they had equivalent numbers of pregnancies. The proportion of low birthweight infants was more than expected in the background population (11.2% vs. 7.2%, p=0.01). Women with IBD during their pregnancy years had shorter gestations than those diagnosed after all pregnancies (38.9 vs. 39.7 weeks, p=0.0023) and more preterm babies (16.2% vs. 6.8%, p=0.021). Detailed phenotyping demonstrated that patients with ulcerative proctitis (E1) had significantly heavier birthweights than those with left sided or extensive colitis (E2 & E3) (3.43kg vs. 3.20kg, p=0.03). Women reported that IBD made their periods heavier and more painful, especially during periods of disease activity. Conclusions: Women with IBD in Lothian have pregnancies of shorter duration and babies of lower birthweight than the background population. However, women with limited ulcerative proctitis appear to be protected from these problems.