80 results on '"Aumais G."'
Search Results
2. Patterns and predictors of long-term retention of inflammatory bowel or rheumatoid disease patients on innovator infliximab: an analysis of a Canadian prescriptions claims database
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Baer PA, Aumais G, Ewara EM, Khraishi M, Marrache AM, Panaccione R, Wade JP, and Marshall JK
- Subjects
Inflammatory bowel disease ,rheumatologic diseases ,anti-TNF drugs ,biologicals ,retention ,Medicine (General) ,R5-920 - Abstract
Philip A Baer,1 Guy Aumais,2 Emmanuel M Ewara,3 Majed Khraishi,4 A Marilise Marrache,5 Remo Panaccione,6 John P Wade,7 John K Marshall8 1Baer Weinberg MPC, Scarborough, ON, 2Department of Medicine, Université de Montréal, Gastro-enterology Unit, Hôpital Maisonneuve-Rosemont, Montréal, QC, 3Government Affairs and Market Access, Janssen Inc., Toronto, ON, 4Medical Affairs, Janssen Inc., Toronto, ON, 5Faculty of Medicine, Division of Rheumatology, Memorial University of Newfoundland and Nexus Clinical Research, St John’s, NL, 6Inflammatory Bowel Disease Unit, Department of Medicine, University of Calgary, Calgary, AB, 7Department of Medicine, Division of Rheumatology, University of British Columbia, Vancouver, BC, 8Department of Medicine, Division of Gastroenterology, McMaster University and Farncombe Family Digestive Health Research Institute, Hamilton, ON, Canada Background: Long-term effectiveness is an important factor when considering treatment decisions. Objective: To determine the long-term retention patterns of Canadian inflammatory bowel disease (IBD) and rheumatologic disease (RD) patients, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with innovator infliximab (IFX) and to assess the impact of year-over-year cumulative IFX exposure on retention in both patient populations. Patients and methods: This analysis used a Canadian longitudinal prescription claims database to measure retention on IFX over a period of 5 years. Twelve-month unadjusted odds ratios of retention by time on IFX were calculated for the overall cohort, and within-group comparisons evaluated differences according to age, sex, region, insurance coverage, use of concomitant immunosuppressant therapy, indication (RD cohort only), and previous biologic experience. Between-group analyses compared unadjusted 5-year retention among the same variables. Variables that were independently associated with longer retention on IFX were identified using multivariable regression. Results: Seven thousand eight hundred and six IBD patients and 2,935 RD patients on stable treatment with IFX were included in the analysis. Sixty-nine percent of IBD patients and 66% of RD patients were retained on IFX after 1 year and 33% and 29%, respectively, were retained after 5 years. Moreover, the probability of being retained on IFX significantly increased with cumulative time on IFX. Independent predictors of 5-year retention included sex, region, and type of insurance coverage among IBD patients and region, type of insurance, prior biologic therapy, and specific indication among RD patients. Patients with IBD were 17% more likely to be retained on IFX over 5 years compared to patients with RD. Conclusion: Real-world Canadian IBD and RD patients on IFX have good overall long-term treatment retention. Previous duration of IFX treatment predicts better future retention, and this knowledge could help inform treatment decisions when patients have been stable on IFX treatment for varying periods of time. Keywords: administrative database, inflammation, anti-TNF drugs, biologicals, retention
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- 2018
3. A198 THE LONG-TERM IMPACT OF ENVIRONMENTAL EXPOSURES ON HOST HEALTH AND THE RISK FACTORS OF CROHN'S DISEASE
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Xue, M, primary, Turpin, W, additional, Haim, L, additional, Lee, S -H, additional, Neustaeter, A, additional, Mei, D, additional, Xu, W, additional, Espin-Garcia, O, additional, Madsen, K L, additional, Guttman, D S, additional, Griffiths, A M, additional, Huynh, H, additional, Turner, D, additional, Panancionne, R, additional, Steinhart, H, additional, Aumais, G, additional, Bitton, A, additional, Jacobson, K, additional, Mack, D, additional, and Croitoru, K, additional
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- 2023
- Full Text
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4. A238 BILE ACID COMPOSITION AND DIETARY FAT: IMPLICATIONS FOR CROHN’S DISEASE IN A COHORT OF HEALTHY FIRST-DEGREE RELATIVES
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Neustaeter, A, primary, Shao, J, additional, Xue, M, additional, Antonio Hernández Rocha, C, additional, Lee, S -H, additional, Leibovitzh, H, additional, Madsen, K, additional, Meddings, J B, additional, Espin-Garcia, O, additional, Griffiths, A M, additional, Moayyedi, P, additional, Steinhart, A H, additional, Panancionne, R, additional, Huynh, H, additional, Jacobson, K, additional, Aumais, G, additional, Mack, D, additional, Bernstein, C, additional, Marshall, J K, additional, Xu, W, additional, Turpin, W, additional, and Croitoru, K, additional
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- 2023
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5. A39 HEALTHY FIRST-DEGREE RELATIVES FROM MULTIPLEX FAMILIES VERSUS SIMPLEX HARBOR A HIGHER RISK OF DEVELOPING CROHN'S DISEASE AND ARE ASSOCIATED WITH SUBCLINICAL INFLAMMATION AND ALTERED MICROBIOME COMPOSITION
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Olivera, P, primary, Martinez-Lozano, H, additional, Leibovitzh, H, additional, Xue, M, additional, Xu, W, additional, Espin-Garcia, O, additional, Madsen, K, additional, Meddings, J, additional, Guttman, D, additional, Griffiths, A, additional, Huynh, H, additional, Turner, D, additional, Panancionne, R, additional, Steinhart, H, additional, Aumais, G, additional, Jacobson, K, additional, Mack, D, additional, Marshall, J, additional, Moayyedi, P, additional, Lee, S -H, additional, Turpin, W, additional, and Croitoru, K, additional
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- 2023
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6. A218 ASSOCIATIONS BETWEEN ADHERENCE TO LITERATURE-DERIVED DIETARY INDICES AND PRE-DISEASE BIOMARKERS: IMPLICATIONS FOR CROHN’S DISEASE PREVENTION
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Neustaeter, A, primary, Lee, S -H, additional, Xue, M, additional, Leibovitzh, H, additional, Madsen, K, additional, Meddings, J B, additional, Espin-Garcia, O, additional, Griffiths, A M, additional, Moayyedi, P, additional, Steinhart, A H, additional, Panancionne, R, additional, Huynh, H, additional, Jacobson, K, additional, Aumais, G, additional, Mack, D, additional, Bernstein, C, additional, Marshall, J K, additional, Xu, W, additional, Turpin, W, additional, and Croitoru, K, additional
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- 2023
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7. A236 ASSOCIATION OF STOOL METABOLOMIC PROFILE AND MICROBIOME COMPOSITION RISK SCORE WITH FUTURE ONSET OF CROHN’S DISEASE
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Lee, S, primary, Raygoza Garay, J, additional, Turpin, W, additional, Smith, M I, additional, Goethel, A, additional, Griffiths, A, additional, Moayyedi, P, additional, Espin-Garcia, O, additional, Aumais, G, additional, Bernstein, C N, additional, Avni-Biron, I, additional, Cino, M, additional, Deslandres, C, additional, Dotan, I, additional, El-Matary, W, additional, Feagan, B G, additional, Guttmen, D S, additional, Huynh, H Q, additional, Hyams, J, additional, Jacobson, K, additional, Mack, D R, additional, Marshall, J, additional, Otley, A, additional, Panaccione, R, additional, Silverberg, M S, additional, Steinhart, H, additional, Turner, D, additional, Xu, W, additional, and Croitoru, K, additional
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- 2022
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8. A157 DEFINITIONS OF MEDITERRANEAN DIET INCONSISTENTLY ASSOCIATE WITH MARKERS OF GUT BARRIER FUNCTION OR SUBCLINICAL INFLAMMATION IN A POPULATION-BASED COHORT
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Neustaeter, A, primary, Timpano, J, additional, Lee, S, additional, Xue, M, additional, Leibovitzh, H, additional, Madsen, K, additional, Meddings, J, additional, Espin-Garcia, O, additional, Goethel, A, additional, Griffiths, A, additional, Moayyedi, P, additional, Steinhart, H, additional, Panaccione, R, additional, Huynh, H Q, additional, Jacobson, K, additional, Aumais, G, additional, Mack, D R, additional, Bernstein, C N, additional, Marshall, J, additional, Xu, W, additional, Turpin, W, additional, and Croitoru, K, additional
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- 2022
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9. P701 Compositional and functional alterations of the gut microbiome are associated with impaired intestinal permeability in healthy relatives of patients with Crohn’s disease
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Leibovitzh, H, primary, Lee, S H, additional, Xue, M, additional, Raygoza Garay, J A, additional, Hernandez-Rocha, C, additional, Madsen, K L, additional, Meddings, J B, additional, Guttman, D S, additional, Espin-Garcia, O, additional, Smith, M I, additional, Goethel, A, additional, Moayyedi, P, additional, Steinhart, A H, additional, Panancionne, R, additional, Huynh, H, additional, Jacobson, K, additional, Aumais, G, additional, Mack, D R, additional, Abreu, M, additional, Bernstein, C N, additional, Marshall, J K, additional, Turner, D, additional, Xu, W, additional, Turpin, W, additional, and Croitoru, K, additional
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- 2022
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10. P700 The GEM Project: Stool metabolomic profile is associated with microbiome risk score and with future onset of Crohn’s disease in healthy first-degree relatives
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Lee, S H, primary, Raygoza Garay, J A, additional, Turpin, W, additional, Smith, M I, additional, Goethel, A, additional, Griffiths, A, additional, Moayyedi, P, additional, Espin-Garcia, O, additional, Abreu, M, additional, Aumais, G, additional, Bernstein, C N, additional, Biron, I, additional, Cino, M, additional, Deslandres, C, additional, Dotan, I, additional, El-Matary, W, additional, Feagan, B, additional, Guttman, D, additional, Huynh, H, additional, Hyams, J, additional, Jacobson, K, additional, Mack, D, additional, Marshall, J, additional, Otley, A, additional, Panaccione, R, additional, Ropeleski, M, additional, Silverberg, M S, additional, Steinhart, A H, additional, Turner, D, additional, Yerushalmi, B, additional, Xu, W, additional, and Croitoru, K, additional
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- 2022
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11. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
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Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Daly, Mark J. [0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, Beck, K, Bernard, EJ, Binion, DG, Bitton, A, Brant, SR, Cho, JH, Cohen, A, Croitoru, K, Daly, MJ, Datta, LW, Deslandres, C, Duerr, RH, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, GR, Haritunians, T, Jobin, G, Katz, S, Lahaie, RG, McGovern, DP, Nelson, L, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barnes, C, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, CM, Coffey, AJ, Mc Connell, J, Conrad, DF, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Frayling, TM, Freathy, RM, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Marchini, JL, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, McVean, G, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Munroe, PB, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Ovington, NR, Owen, MJ, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, JRB, Phillips, A, Plagnol, V, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Sawcer, SJ, Schuilenburg, H, Scott, CE, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stirrups, K, Stone, MA, Strachan, DP, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Tobin, MD, Travers, ME, Turnbull, C, Vukcevic, D, Wain, LV, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Yau, C, Young, AH, Zeggini, E, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Hurles, ME, Duncanson, A, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Kwiatkowski, DP, McCarthy, MI, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Jankowski, J, Markus, HS, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, and Kwiatkowski, D
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Male ,692/4020/1503/257/1402 ,Genotype ,Genotyping Techniques ,LOCI ,45/43 ,lcsh:Medicine ,Polymorphism, Single Nucleotide ,Crohn's disease, genetics, genome wide association ,Article ,Deep Learning ,Crohn Disease ,INDEL Mutation ,Genetics research ,Humans ,genetics ,Genetic Predisposition to Disease ,129 ,lcsh:Science ,Alleles ,Science & Technology ,genome wide association ,RISK PREDICTION ,45 ,Models, Genetic ,lcsh:R ,Decision Trees ,692/308/2056 ,ASSOCIATION ,Multidisciplinary Sciences ,Crohn's disease ,Logistic Models ,Nonlinear Dynamics ,ROC Curve ,Area Under Curve ,Science & Technology - Other Topics ,lcsh:Q ,Female ,Neural Networks, Computer ,INFLAMMATORY-BOWEL-DISEASE ,Genome-Wide Association Study - Abstract
Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.
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- 2019
12. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
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Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Annese, V, Aumais, G, Baidoo, L, Baldassano, RN, Bampton, PA, Barclay, M, Barrett, JC, Bayless, TM, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, Hui, KY, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, TH, Kennedy, NA, Khan, MA, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, IC, Lee, JC, Lees, CW, Leja, M, van Limbergen, J, Lionetti, P, Liu, JZ, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Radford-Smith, G, Rahier, JF, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, JD, Ripke, S, Roberts, R, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schadt, EE, Schreiber, S, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, Zhao, ZZ, Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, A, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, Mj, vander Meulen-de Jong, Ae, van der Woude, Cj, Visschedijk, Mc, Lathrop, M, Hugot, Jp, Weersma, Rk, De Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, Jp, Ahmad, T, Ananthakrishnan, An, Andersen, V, Anderson, Ca, Andrews, Jm, Annese, V, Aumais, G, Baidoo, L, Baldassano, Rn, Bampton, Pa, Barclay, M, Barrett, Jc, Bayless, Tm, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Buning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, Denapiene, G, Denson, La, Devaney, Kl, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, Am, Guthery, Sl, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, Hart, A, Hawkey, C, Hayward, Nk, Hedl, M, Henderson, P, Hu, Xh, Huang, Hl, Hui, Ky, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, Th, Kennedy, Na, Khan, Ma, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, Ic, Lee, Jc, Lees, Cw, Leja, M, Van Limbergen, J, Lionetti, P, Liu, Jz, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dpb, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sme, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, Cy, Potocnik, U, Prescott, Nj, Proctor, Dd, Radford-Smith, G, Rahier, Jf, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, Jd, Ripke, S, Roberts, R, Russell, Rk, Sanderson, Jd, Sans, M, Satsangi, J, Schadt, Ee, Schreiber, S, Schulte, D, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, M, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, Ah, Stempak, Jm, Stronati, L, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, Hy, Zhao, Zz, Gastroenterology & Hepatology, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, and UCL - (MGD) Service de gastro-entérologie
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Adult ,Male ,Multifactorial Inheritance ,QUANTITATIVE TRAIT LOCUS ,Genotype ,SEQUENCING DATA ,Quantitative Trait Loci ,SUSCEPTIBILITY ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,CODING VARIANTS ,Crohn Disease ,80 and over ,Journal Article ,Medicine and Health Sciences ,LOCUS ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,GENOME-WIDE ASSOCIATION ,Genetic Association Studies ,Aged ,Aged, 80 and over ,Science & Technology ,Female ,Gene Expression Profiling ,Inflammatory Bowel Diseases ,Middle Aged ,Sequence Analysis, DNA ,COMPLEX TRAITS ,Biology and Life Sciences ,Single Nucleotide ,DNA ,CROHNS-DISEASE ,Multidisciplinary Sciences ,QUANTITATIVE TRAIT ,RARE VARIANTS ,Science & Technology - Other Topics ,LOW-FREQUENCY ,Sequence Analysis ,INFLAMMATORY-BOWEL-DISEASE - Abstract
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach., Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.
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- 2018
13. Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients
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AUMAIS, G., LEFEBVRE, M., TREMBLAY, C., BITTON, A., MARTIN, F., GIARD, A., MADI, M., and SPÉNARD, J.
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- 2003
14. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
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Momozawa, Y., Dmitrieva, J., Theatre, E., Deffontaine, V., Rahmouni, S., Charloteaux, B., Crins, F., Docampo, E., Elansary, M., Gori, A.S., Lecut, C., Mariman, R., Mni, M., Oury, C., Altukhov, I., Alexeev, D., Aulchenko, Y., Amininejad, L., Bouma, G., Hoentjen, F., Lowenberg, M., Oldenburg, B., Pierik, M.J., vander Meulen-de Jong, A.E., Woude, C.J. van der, Visschedijk, M.C., Lathrop, M., Hugot, J.P., Weersma, R.K., Vos, M. de, Franchimont, D., Vermeire, S., Kubo, M., Louis, E., Georges, M., Abraham, C., Achkar, J.P., Ahmad, T., Ananthakrishnan, A.N., Andersen, V., Anderson, C.A., Andrews, J.M., Annese, V., Aumais, G., Baidoo, L., Baldassano, R.N., Bampton, P.A., Barclay, M., Barrett, J.C., Bayless, T.M., Bethge, J., Bitton, A., Boucher, G., Brand, S., Brandt, B., Brant, S.R., Buning, C., Chew, A., Cho, J.H., Cleynen, I., Cohain, A., Croft, A., Daly, M.J., D'Amato, M., Danese, S., Jong, D. de, Denapiene, G., Denson, L.A., Devaney, K.L., Dewit, O., D'Inca, R., Dubinsky, M., Duerr, R.H., Edwards, C., Ellinghaus, D., Essers, J., Ferguson, L.R., Festen, E.A., Fleshner, P., Florin, T., Franke, A., Fransen, K., Gearry, R., Gieger, C., Glas, J., Goyette, P., Green, T., Griffiths, A.M., Guthery, S.L., Hakonarson, H., Halfvarson, J., Hanigan, K., Haritunians, T., Hart, A., Hawkey, C., Hayward, N.K., Hedl, M., Henderson, P., Hu, X.H., Huang, H.L., Hui, K.Y., Imielinski, M., Ippoliti, A., Jonaitis, L., Jostins, L., Karlsen, T.H., Kennedy, N.A., Khan, M.A., Kiudelis, G., Krishnaprasad, K., Kugathasan, S., Kupcinskas, L., Latiano, A., Laukens, D., Lawrance, I.C., Lee, J.C., Lees, C.W., Leja, M., Limbergen, J. van, Lionetti, P., Liu, J.Z., Mahy, G., Mansfield, J., Massey, D., Mathew, C.G., McGovern, D.P.B., Milgrom, R., Mitrovic, M., Montgomery, G.W., Mowat, C., Newman, W., Ng, A., Ng, S.C., Ng, S.M.E., Nikolaus, S., Ning, K., Nothen, M., Oikonomou, I., Palmieri, O., Parkes, M., Phillips, A., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Proctor, D.D., Radford-Smith, G., Rahier, J.F., Raychaudhuri, S., Regueiro, M., Rieder, F., Rioux, J.D., Ripke, S., Roberts, R., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schadt, E.E., Schreiber, S., Schulte, D., Schumm, L.P., Scott, R., Seielstad, M., Sharma, Y., Silverberg, M.S., Simms, L.A., Skieceviciene, J., Spain, S.L., Steinhart, A.H., Stempak, J.M., Stronati, L., Sventoraityte, J., Targan, S.R., Taylor, K.M., Velde, A. ter, Torkvist, L., Tremelling, M., Sommeren, S. van, Vasiliauskas, E., Verspaget, H.W., Walters, T., Wang, K., Wang, M.H., Wei, Z., Whiteman, D., Wijmenga, C., Wilson, D.C., Winkelmann, J., Xavier, R.J., Zhang, B., Zhang, C.K., Zhang, H., Zhang, W., Zhao, H.Y., Zhao, Z.Z., and Int IBD Genetics Consortium
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- 2018
15. A91 UNMET NEEDS OF INFLAMMATORY BOWEL DISEASE PATIENTS IN CANADA: RESULTS OF A WEB SURVEY
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Gray, J R, primary, Attara, G, additional, Aumais, G, additional, Panaccione, R, additional, and Marshall, J, additional
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- 2019
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16. Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease
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Sandborn, Wj, Feagan, Bg, Rutgeerts, P, Hanauer, S, Colombel, Jf, Sands, Be, Lukas, M, Fedorak, Rn, Lee, S, Bressler, B, Fox, I, Rosario, M, Sankoh, S, Xu, J, Stephens, K, Milch, C, Parikh, A, Bampton P, GEMINI 2 Study G. r. o. u. p., Borody, T, Chung, A, Debinski, H, Florin, T, Hetzel, D, Jakobovits, S, Lawrance, I, Leong, R, Macrae, F, Mitchell, B, Moore, G, Pavli, P, Samuel, D, Weltman, M, Haas, T, Reinisch, W, Vogel, W, Baert, F, De Maeyer, M, De Vos, M, Dewit, O, D'Haens, G, Louis, E, Muls, V, Van Assche, G, Krastev, Z, Nikolovska, D, Petrov, P, Petrov, A, Stoinov, S, Tchernev, K, Vasileva, G, Aumais, G, Axler, J, Bailey, R, Bernstein, C, Bitton, A, Bourdages, R, Cohen, A, Devroede, G, Dhalla, S, Feagan, B, Fedorak, R, Green, D, Greenberg, G, Jones, J, Larkai, E, Macintosh, D, Panaccione, R, Ponich, T, Singh, R, Sy, R, Wiesinger, H, Albin, A, Douda, L, Horny, I, Stehlik, J, Stuksa, J, Volfova, M, Vyhnalek, P, Zadorova, Z, Andersen, V, Bendtsen, F, Fallingborg, J, Rannem, T, Maelt, A, Margus, B, Salupere, R, Allez, M, Des Varennes SB, Desreumaux, P, Dupas, Jl, Grimaud, Jc, Hebuterne, X, Lerebours, E, Picon, L, Zerbib, F, Aldinger, V, Baumgart, D, Buening, C, Dollinger, M, Hoffmann, P, Howaldt, S, Klaus, J, Konturek, Jw, Krummenerl, T, Malfertheiner, P, Schmidt, W, Schreiber, S, Seidler, U, Stallmach, A, Stremmel, W, Zeitz, M, Mantzaris, G, Triantafyllou, K, Ng, C, Bene, L, Fazekas, I, Fejes, R, Gall, J, Horvat, G, Hunyady, B, Salamon, A, Toth, T, Tulassay, Z, Varga, E, Varga, M, Varga Szabo, L, Vincze, A, Oddsson, E, Örvar, K, Ahuja, V, Amarapurkar, D, Chandra, A, Koshy, A, Krishna, P, Ramakrishna, K, Reddy, N, Thorat, V, Patchett, S, Ryan, B, Ben Horin, S, Fishman, S, Lavy, A, Rachmilewitz, D, Ardizzone, S, Corazziari, E, Danese, S, Fries, Walter, Gasbarrini, A, Kohn, A, Sturniolo, Gc, Danilans, A, George, Am, Hilmi, In, Engels, Lg, Ponsioen, Cy, van der Woude CJ, Gearry, R, Haines, M, Schultz, M, Wallace, I, Wyeth, J, Florholmen, J, Jahnsen, J, Lygren, I, Röseth, A, Ciecko Michalska, I, Gonciarz, M, Horynski, M, Huk, J, Jamrozik Kruk, Z, Janke, A, Klupinska, G, Marecik, J, Paradowski, L, Rudzinski, J, Rydzewska, G, Han, Ds, Hong, Sp, Kim, Hj, Kim, Js, Kim, Ko, Kim, Yh, Yang, Sk, Gheorghe, Ls, Voiosu, Rm, Alexeeva, O, Baranovsky, A, Bunkova, E, Burnevich, E, Dolgikh, O, Grinevich, V, Lakhin, A, Tarabar, D, Ling, Kl, Bunganic, I, Cernok, S, Gregus, M, Coetzer, T, Grundling, H, Moola, Sa, Wright, Jp, Ziady, C, Bermejo, F, Calvet, X, Herrerias, Jm, Perez Calle JL, Perez Gisbert, J, Hertervig, E, Karlen, P, Michetti, P, Rogler, G, Seibold, F, Wu, Dc, Atug, O, Kurdas, Oo, Datsenko, O, Dorofyeyev, A, Dudar, L, Golovchenko, O, Klyarits'Ka, I, Skrypnyk, I, Hawthorne, Ab, Middleton, S, Abreu, M, Bala, N, Becker, S, Behm, B, Braun, R, Bukhari, M, Chen, S, Coates, A, Dar, S, Dassopoulos, T, De Villiers, W, Desautels, S, Desta, T, Dimitroff, J, Dryden, G, Duvall, A, Farraye, F, Fein, S, Liu, Bf, Gatof, D, Geenen, D, Ginsburg, P, Glombicki, A, Glover, S, Gordon, G, Grisolano, S, Hanson, J, Hardi, R, Hoffman, B, Isaacs, K, Kim, C, Koval, G, Lashner, B, Lawitz, E, Leman, B, Levine, J, Loftus, E, Mahadevan, U, Mannon, P, Marcet, J, Matsuyama, R, Matusow, G, Mccabe, R, Mirkin, K, Murphy, M, Mushahwar, A, Mutlu, E, Nagrani, M, Nguyen, D, Nichols, M, Nieves Ramirez, A, Oubre, B, Pace, S, Pandak, W, Perera, L, Quadri, A, Quallich, L, Rajapakse, R, Randall, C, Regueiro, M, Safdi, A, Sandborn, W, Sands, B, Saubermann, L, Scherl, E, Schwartz, D, Sedghi, S, Shafran, I, Shepard, R, Siegel, C, Stein, L, Tatum, H, Triebling, A, Vasudeva, R, Winston, B, Wolf, D, Younes, Z, Jewell, D, Mahon, J, Rothstein, R, Snydman, D, Massaro, J, Clifford, D, Berger, J, Major, E, Provenzale, J, Lev, M., GEMINI 2 Study Group, Bampton, P., Borody, T., Chung, A., Debinski, H., Florin, T., Hetzel, D., Jakobovits, S., Lawrance, I., Leong, R., Macrae, F., Mitchell, B., Moore, G., Pavli, P., Samuel, D., Weltman, M., Haas, T., Reinisch, W., Vogel, W., Baert, F., De Maeyer, M., De Vos, M., Dewit, O., D'Haens, G., Louis, E., Muls, V., Van Assche, G., Krastev, Z., Nikolovska, D., Petrov, P., Petrov, A., Stoinov, S., Tchernev, K., Vasileva, G., Aumais, G., Axler, J., Bailey, R., Bernstein, C., Bitton, A., Bourdages, R., Bressler, B., Cohen, A., Devroede, G., Dhalla, S., Feagan, B., Fedorak, R., Green, D., Greenberg, G., Jones, J., Larkai, E., MacIntosh, D., Panaccione, R., Ponich, T., Singh, R., Sy, R., Wiesinger, H., Albin, A., Douda, L., Horny, I., Lukas, M., Stehlik, J., Stuksa, J., Volfova, M., Vyhnalek, P., Zadorova, Z., Andersen, V., Bendtsen, F., Fallingborg, J., Rannem, T., Maelt, A., Margus, B., Salupere, R., Allez, M., Des Varennes SB., Desreumaux, P., Dupas, JL., Grimaud, JC., Hebuterne, X., Lerebours, E., Picon, L., Zerbib, F., Aldinger, V., Baumgart, D., Buening, C., Dollinger, M., Hoffmann, P., Howaldt, S., Klaus, J., Konturek, JW., Krummenerl, T., Malfertheiner, P., Schmidt, W., Schreiber, S., Seidler, U., Stallmach, A., Stremmel, W., Zeitz, M., Mantzaris, G., Triantafyllou, K., Ng, C., Bene, L., Fazekas, I., Fejes, R., Gall, J., Horvat, G., Hunyady, B., Salamon, A., Toth, T., Tulassay, Z., Varga, E., Varga, M., Varga-Szabo, L., Vincze, A., Oddsson, E., Örvar, K., Ahuja, V., Amarapurkar, D., Chandra, A., Koshy, A., Krishna, P., Ramakrishna, K., Reddy, N., Thorat, V., Patchett, S., Ryan, B., Ben Horin, S., Fishman, S., Lavy, A., Rachmilewitz, D., Ardizzone, S., Corazziari, E., Danese, S., Fries, W., Gasbarrini, A., Kohn, A., Sturniolo, GC., Danilans, A., George, AM., Hilmi, IN., Engels, LG., Ponsioen, CY., van der Woude CJ., Gearry, R., Haines, M., Schultz, M., Wallace, I., Wyeth, J., Florholmen, J., Jahnsen, J., Lygren, I., Röseth, A., Ciecko-Michalska, I., Gonciarz, M., Horynski, M., Huk, J., Jamrozik-Kruk, Z., Janke, A., Klupinska, G., Marecik, J., Paradowski, L., Rudzinski, J., Rydzewska, G., Han, DS., Hong, SP., Kim, HJ., Kim, JS., Kim, KO., Kim, YH., Yang, SK., Gheorghe, LS., Voiosu, RM., Alexeeva, O., Baranovsky, A., Bunkova, E., Burnevich, E., Dolgikh, O., Grinevich, V., Lakhin, A., Tarabar, D., Ling, KL., Bunganic, I., Cernok, S., Gregus, M., Coetzer, T., Grundling, H., Moola, SA., Wright, JP., Ziady, C., Bermejo, F., Calvet, X., Herrerias, JM., Perez Calle JL., Perez Gisbert, J., Hertervig, E., Karlen, P., Michetti, P., Rogler, G., Seibold, F., Wu, DC., Atug, O., Kurdas, OO., Datsenko, O., Dorofyeyev, A., Dudar, L., Golovchenko, O., Klyarits'ka, I., Skrypnyk, I., Hawthorne, AB., Middleton, S., Abreu, M., Bala, N., Becker, S., Behm, B., Braun, R., Bukhari, M., Chen, S., Coates, A., Dar, S., Dassopoulos, T., De Villiers, W., Desautels, S., Desta, T., Dimitroff, J., Dryden, G., Duvall, A., Farraye, F., Fein, S., Liu, BF., Gatof, D., Geenen, D., Ginsburg, P., Glombicki, A., Glover, S., Gordon, G., Grisolano, S., Hanauer, S., Hanson, J., Hardi, R., Hoffman, B., Isaacs, K., Kim, C., Koval, G., Lashner, B., Lawitz, E., Lee, S., Leman, B., Levine, J., Loftus, E., Mahadevan, U., Mannon, P., Marcet, J., Matsuyama, R., Matusow, G., McCabe, R., Mirkin, K., Murphy, M., Mushahwar, A., Mutlu, E., Nagrani, M., Nguyen, D., Nichols, M., Nieves Ramirez, A., Oubre, B., Pace, S., Pandak, W., Perera, L., Quadri, A., Quallich, L., Rajapakse, R., Randall, C., Regueiro, M., Safdi, A., Sandborn, W., Sands, B., Saubermann, L., Scherl, E., Schwartz, D., Sedghi, S., Shafran, I., Shepard, R., Siegel, C., Stein, L., Tatum, H., Triebling, A., Vasudeva, R., Winston, B., Wolf, D., Younes, Z., Feagan, BG., Colombel, JF., Rutgeerts, P., Sandborn, WJ., Sands, BE., Jewell, D., Mahon, J., Rothstein, R., Snydman, D., Massaro, J., Clifford, D., Berger, J., Major, E., Provenzale, J., Lev, M., and Medical Microbiology & Infectious Diseases
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Adult ,Male ,Integrins ,medicine.medical_specialty ,HUMAN POLYOMAVIRUSES ,JC ,Antibodies/blood ,Antibodies, Monoclonal, Humanized/adverse effects ,Antibodies, Monoclonal, Humanized/immunology ,Crohn Disease/drug therapy ,Double-Blind Method ,Drug Administration Schedule ,Drug Therapy, Combination ,Female ,Glucocorticoids/therapeutic use ,Humans ,Immunosuppressive Agents/therapeutic use ,Induction Chemotherapy ,Infusions, Intravenous/adverse effects ,Integrins/antagonists & inhibitors ,Integrins/immunology ,Maintenance Chemotherapy ,Middle Aged ,PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ,Antibodies, Monoclonal, Humanized ,Placebo ,Gastroenterology ,Inflammatory bowel disease ,Antibodies ,Vedolizumab ,CERTOLIZUMAB PEGOL ,Natalizumab ,Crohn Disease ,Maintenance therapy ,HUMANIZED ANTIBODY ,Internal medicine ,Ustekinumab ,medicine ,Certolizumab pegol ,Infusions, Intravenous ,Glucocorticoids ,NATALIZUMAB ,business.industry ,Induction chemotherapy ,General Medicine ,medicine.disease ,PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY, RELAPSING MULTIPLE-SCLEROSIS, INFLAMMATORY-BOWEL-DISEASE, HUMAN POLYOMAVIRUSES, HUMANIZED ANTIBODY, CERTOLIZUMAB PEGOL, ULCERATIVE-COLITIS, RANDOMIZED-TRIAL, NATALIZUMAB, JC ,RANDOMIZED-TRIAL ,digestive system diseases ,Surgery ,ULCERATIVE-COLITIS ,RELAPSING MULTIPLE-SCLEROSIS ,business ,Immunosuppressive Agents ,INFLAMMATORY-BOWEL-DISEASE ,medicine.drug - Abstract
BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P
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- 2013
17. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
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Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), Zhao, Z.Z. (Zhen Z.), Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), and Zhao, Z.Z. (Zhen Z.)
- Abstract
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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- 2018
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18. A269 IRRITABLE BOWEL SYNDROME PATIENT EXPERIENCE IN CANADA
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Attara, G P, Gray, J, and Aumais, G
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Poster Presentations - Abstract
BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, often debilitating, functional gastrointestinal disorder with symptoms that include abdominal pain and altered bowel behaviours of constipation and/or diarrhea, affecting approximately 13–20% of Canadians. The real world experience of patients is still poorly understood. AIMS: To learn the how the symptoms of irritable bowel syndrome affect these patients in Canada. METHODS: The Gastrointestinal Society hosted a survey on its English (www.badgut.org) and French (www.mauxdeventre.org) websites during spring 2016. Links to this survey were posted on social media and via invitation using a market research company. To qualify, survey participants had to be living in Canada and have IBS or be the parent/guardian of a child with IBS. Questions were on a broad range of topics, including symptom severity, medication use, diet, experience with the health care system, comorbidities, and quality of life. RESULTS: Respondents from every province and territory totalled 2,961. 90% were between 30–69 years of age, 86% female, 97% were adults with IBS. 53% had IBS for more than 10 years. 35% had IBS-D, 18% IBS-C, 41% IBS-M, and 6% unsure. In IBS-C patients, abdominal pain was identified as a distinct predominant symptom. Those with IBS-D experienced many symptoms, with abdominal pain, bloating, urgency, and diarrhea identified as highly concerning. 24% experienced severe abdominal pain in the last 3 months, with severe pain being constant in a high proportion. 62% of patients indicated they experienced pain continuing after bowel movement. The top factors driving patients to see their physician were pain/discomfort and impact of IBS on their personal/professional/daily life. Approximately 93% and 49% of patients consulted with a family doctor and gastroenterologist, respectively, for their IBS. 60% had a colonoscopy. 12% have been hospitalized for IBS. 76% indicated that their symptoms interfere with everyday life and 46% missed work or school due to IBS. Most IBS patients use ≥2 medications on a regular basis to control their symptoms yet only 21% are confident their symptoms are under control. Compounding the issue, 16% are unable to afford any of their prescribed medications, and 26% can only afford some of them. CONCLUSIONS: Canadian IBS patients suffer from multiple symptoms, with the pain experienced by patients being the prime motivating factor to seek care. 79% have symptoms not under control. The conventional standard of care for IBS requires many different treatments to manage the multiple symptoms, with the majority of IBS patients requiring 2 or more treatments on a regular basis. IBS patients experience a wide range of symptoms and comorbidities. It can be a struggle for them to find treatments that are effective and affordable. FUNDING AGENCIES: The Gastrointestinal Society received funding from Actavis Specialty Pharmaceuticals Co., an affiliate of Allergan PLC to conduct this independent survey (Gail Attara is an employee); the physicians were not paid.
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- 2018
19. A35 GENOME WIDE ASSOCIATION STUDY OF ABNORMAL INTESTINAL PERMEABILITY IN HEALTHY FIRST DEGREE RELATIVES OF CROHN’S PATIENTS
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Turpin, W, primary, Bedrani, L, additional, Espin-Garcia, O, additional, Smith, M, additional, Guttman, D, additional, Madsen, K, additional, Griffiths, A, additional, Moayyedi, P, additional, Panaccione, R, additional, Huynh, H Q, additional, Dieleman, L A, additional, Steinhart, A, additional, Aumais, G, additional, Silverberg, M S, additional, Wei, X, additional, Paterson, A, additional, and Croitoru, K, additional
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- 2018
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20. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes:a genetic association study
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Cleynen, Isabelle, Boucher, Gabrielle, Jostins, Luke, Schumm, L. Philip, Zeissig, Sebastian, Ahmad, Tariq, Andersen, Vibeke, Andrews, Jane M., Annese, Vito, Brand, Stephan, Brant, Steven R., Cho, Judy H., Daly, Mark J., Dubinsky, Marla, Duerr, Richard H., Ferguson, Lynnette R., Franke, Andre, Gearry, Richard B., Goyette, Philippe, Hakonarson, Hakon, Halfvarson, Jonas, Hov, Johannes R., Huang, Hailang, Kennedy, Nicholas A., Kupcinskas, Limas, Lawrance, Ian C., Lee, James C., Satsangi, Jack, Schreiber, Stephan, Théâtre, Emilie, Van Der Meulen De Jong, Andrea E, Weersma, Rinse K., Wilson, David C., Parkes, Miles, Vermeire, Severine, Rioux, John D., Mansfield, John, Silverberg, Mark S., Radford Smith, Graham, Mcgovern, Dermot P. B., Barrett, Jeffrey C., Lees, Charlie W, Abraham, C, Achkar, Jp, Ahmad, T, Amininejad, L, Ananthakrishnan, An, Andersen, V, Anderson, Ca, Andrews, Jm, Annese, V, Aumais, G, Baidoo, L, Baldassano, Rn, Bampton, Pa, Barclay, M, Barrett, Jc, Bayless, Tm, Bethge, J, Bis, Jc, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Büning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, De Vos, M, Denapiene, G, Denson, La, Devaney, K, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franchimont, D, Franke, A, Fransen, K, Gearry, R, Georges, M, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, Am, Guthery, Sl, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, Hart, A, Hawkey, C, Hayward, Nk, Hedl, M, Henderson, P, Hu, X, Huang, H, Hui, Ky, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, Th, Kennedy, Na, Khan, Ma, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, Ic, Lee, Jc, Lees, Cw, Leja, M, Van Limbergen, J, Lionetti, P, Liu, Jz, Louis, E, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dp, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sm, Nikolaus, S, Ning, K, Nöthen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, Cy, Potocnik, U, Prescott, Nj, Proctor, Dd, Radford Smith, G, Rahier, Jf, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, Jd, Ripke, S, Roberts, R, Russell, Rk, Sanderson, Jd, Sans, M, Satsangi, J, Schadt, Ee, Schreiber, S, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, Ms, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, A, Stempak, Jm, Stronati, Laura, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Theatre, E, Torkvist, L, Tremelling, M, van der Meulen, A, van Sommeren, S, Vasiliauskas, E, Vermeire, S, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Weersma, Rk, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zeissig, S, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, H, Zhao, Zz, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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Male ,0301 basic medicine ,CLINICAL-COURSE ,Nod2 Signaling Adaptor Protein ,Disease ,SUSCEPTIBILITY ,Inflammatory bowel disease ,Major Histocompatibility Complex ,0302 clinical medicine ,Crohn Disease ,Maintenance therapy ,NOD2 ,Medicine and Health Sciences ,POPULATION ,Immunoassay ,RISK ,Medicine(all) ,education.field_of_study ,Crohn's disease ,Hepatocyte Growth Factor ,Medicine (all) ,INDUCTION ,Articles ,General Medicine ,PRIMARY SCLEROSING CHOLANGITIS ,Ulcerative colitis ,3. Good health ,Phenotype ,Female ,030211 gastroenterology & hepatology ,Adult ,medicine.medical_specialty ,MAINTENANCE THERAPY ,Genotype ,Population ,Polymorphism, Single Nucleotide ,Risk Assessment ,CLASSIFICATION ,Primary sclerosing cholangitis ,Young Adult ,03 medical and health sciences ,inflammatory bowel disease ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Alleles ,Genetic Association Studies ,business.industry ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Immunology ,Colitis, Ulcerative ,business ,FOLLOW-UP ,HLA-DRB1 Chains ,INFLAMMATORY-BOWEL-DISEASE - Abstract
Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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- 2016
21. Ustekinumab as induction and maintenance therapy for Crohn's disease
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Feagan, Bg, Sandborn, Wj, Gasink, C, Jacobstein, D, Lang, Y, Friedman, Jr, Blank, Ma, Johanns, J, Gao, Ll, Miao, Y, Adedokun, Oj, Sands, Be, Hanauer, Sb, Vermeire, S, Targan, S, Ghosh, S, de Villiers WJ, Colombel, Jf, Tulassay, Z, Seidler, U, Salzberg, Ba, Desreumaux, P, Lee, Sd, Loftus EV Jr, Dieleman, La, Katz, S, Rutgeerts, P, Bampton, P, Chung, A, Connor, S, Debinski, H, Leong, R, Macrae, F, Pavli, P, Sorrentino, D, van den Bogaerde, J, Vogel, W, Vogelsang, H, Louis, E, Mana, F, Zaltman, C, Aumais, G, Bernstein, C, Bressler, B, Dhalla, S, Dieleman, L, Feagan, B, Marshall, J, Panaccione, R, Ropeleski, M, Stehlik, J, Volfova, M, Brynskov, J, Glerup, H, Abitbol-Selinger, V, Allez, M, Beaugerie, L, Bourreille, A, Cadiot, G, Dupas, J, Grimaud, J, Laharie, D, Lerebours, E, Moreau, J, Baumgart, D, Brand, S, Ebert, M, Ehehalt, R, Hasselblatt, P, Howaldt, S, Klaus, J, Krummenerl, P, Kucharzik, T, Lügering, A, Mudter, J, Preiss, J, Schreiber, S, Stallmach, A, Stein, J, Strauch, U, Salamon, A, Patchett, S, Lahat-Zok, A, Rachmilewitz, D, Annese, V, Bossa, F, Guidi, L, Kohn, A, Rocca, R, Ando, A, Ashida, T, Hanai, H, Ishida, T, Ito, H, Matsumoto, T, Motoya, S, Nakamura, S, Sameshima, Y, Suzuki, Y, Watanabe, K, Yamagami, H, Yamamoto, T, Yao, K, Kim, H, Kim, Y, D'Haens, G, Pierik, M, van Bodegraven, A, van der Woude CJ, Gearry, R, Ciecko-Michalska, I, Malecka-Panas, E, Jojic, N, Aboo, N, Wright, J, Arranz, M, Viso, L, Ahmad, T, Bloom, S, Campbell, S, Creed, T, Cummings, F, Hawthorne, B, Iqbal, T, Ireland, A, Parkes, M, Pollok, R, Shaw, I, Shonde, A, Smith, M, Steel, A, Subramanian, S, Travis, S, Tremelling, M, Aberra, F, Abraham, B, Barish, C, Behm, B, Birbara, C, Bochner, R, Bologna, S, Brant, S, Charles, R, Cohen, N, de Villers, W, Dryden, G, Duvall, A, Flasar, M, Fleisher, M, Florez, D, Fogel, R, Gagneja, H, Gross, C, Hamilton, J, Hanauer, S, Hanson, J, Hardi, R, Higgins, P, Isaacs, K, Katz, J, Kaur, N, Khan, N, Lee, S, Leman, B, Levenson, S, Lichtiger, S, Loftus, E, Malik, P, Mcnair, A, Melmed, G, Miner, P, Nichols, M, Noar, M, Oikonomou, I, Oubre, B, Peterson, K, Pruitt, R, Quirk, D, Safdi, A, Safdi, M, Salzberg, B, Sandborn, W, Saubermann, L, Scherl, E, Schwartz, D, Schwarz, R, Sedghi, S, Selby, L, Shafran, I, Siegel, C, Sninsky, C, Stern, M, Stockwell, D, Stone, C, Swaminath, A, Swoger, J, Taormina, M, Williams, E, Winstead, N, Wolf, D, Wolosin, J, Yacyshyn, B, Yajnik, V, Yen, E, Hetzel, D, Muls, V, Bafutto, M, Francesconi, C, Sipahi, A, Steinwurz, F, Churchev, J, Kotzev, I, Marinova, I, Penchev, P, Spassova, Z, Stoinov, S, Takov, D, Vassileva, G, Fowler, S, Greenberg, G, Jones, J, Saibil, F, Salh, B, Banić, M, Duvnjak, M, Stimac, D, Goujon, G, Pelletier, A, Peyrin-Biroulet, L, Aldinger, V, Bokemeyer, B, Büning, C, Konturek, J, Krummenerl, T, Ochsenkuehn, T, Altorjay, I, Kis, J, Pecsi, G, Székely, A, Varga, M, Vincze, A, Wacha, J, Oddsson, E, Orvar, K, Avni-Biron, I, Fishman, S, Fraser, G, Konikoff, F, Melzer, E, Oren, R, Shirin, H, Danese, S, Marino, M, Sturniolo, Gc, Horiki, N, Iijima, H, Iwabuchi, M, Kanai, T, Kunisaki, R, Maemoto, A, Matsuoka, K, Osada, T, Sugimoto, K, Tanaka, S, Cheon, Jh, Han, Ds, Jang, Bi, Kim, Hj, Kim, Js, Kim, Yh, Park, Sj, Yang, Sk, Arnold, M, Claydon, A, Haines, M, Hill, J, Rowbotham, D, Schultz, M, Wallace, I, Bochenek, A, Niezgoda, K, Szura, M, Arutyunov, G, Baranovsky, A, Khalif, I, Osipenko, M, Milinic, N, Bloch, H, Kruger, Fc, Prins, M, Watermeyer, G, Ziady, C, Calvo, Xc, Domínguez-Muñoz, Je, Gisbert, Jp, Arsenescu, R, Beaulieu, D, Bedford, R, Behrend, C, Cleavinger, P, Cohen, J, Ertan, A, Freilich, B, Friedenberg, K, Glover, S, Gordon, G, Gunaratnam, N, Gupta, N, Holbrook, R, Jones, M, Kaufman, B, Khan, Nh, Khurana, S, Legnani, P, Mutlu, E, Phillips, R, Rai, R, Reichelderfer, M, Ritter, T, Safdi, Ma, Sands, B, Schulman, M, Smith, J, Suiter, D, Taylor, D, Vasudeva, R, Winstead, T, Zwick, A, Savoye, G, Atreya, R, Ochsenkuhn, T, Ott, C, Goldin, E, Motohiro, E, Takanori, K, Park, S, James, B, Cummings, J, Tariq, A, Willert, R, Allan, M, Bulat, R, Devilliers, W, Eaker, E, Hou, J, Mendu, S, Nicols, M, Proctor, D, Thosani, N, Zhang, C, and UNITI-IM-UNITI Study Group
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030203 arthritis & rheumatology ,Adult ,Male ,Infusions ,Medicine (all) ,Remission Induction ,Crohn Disease ,Female ,Humans ,Induction Chemotherapy ,Infusions, Intravenous ,Maintenance Chemotherapy ,Middle Aged ,Ustekinumab ,General Medicine ,Orvostudományok ,Klinikai orvostudományok ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Intravenous - Abstract
Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score150). The primary end point for the maintenance trial was remission at week 44 (CDAI score150).The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).
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- 2016
22. High-density mapping of the MHC identifies a shared role for HLA-DRB1∗01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis
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Goyette, P, Boucher, G, Mallon, D, Ellinghaus, E, Jostins, L, Huang, H, Ripke, S, Gusareva, ES, Annese, V, Hauser, SL, Oksenberg, JR, Thomsen, I, Leslie, S, Daly, MJ, Van Steen, K, Duerr, RH, Barrett, JC, McGovern, DPB, Schumm, LP, Traherne, JA, Carrington, MN, Kosmoliaptsis, V, Karlsen, TH, Franke, A, Rioux, JD, Abraham, C, Achkar, JP, Ahmad, T, Amininejad, L, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Aumais, G, Baidoo, L, Baldassano, RN, Balschun, T, Bampton, PA, Barclay, M, Bayless, TM, Bethge, J, Bis, JC, Bitton, A, Brand, S, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, D'Amato, M, Danese, S, De Jong, D, De Vos, M, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franchimont, D, Fransen, K, Gearry, R, Georges, M, Gieger, C, and Glas, J
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digestive system diseases - Abstract
© 2015 Nature America, Inc. All rights reserved. Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1∗01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
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- 2015
23. Vedolizumab as induction and maintenance therapy for ulcerative colitis
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Feagan, Bg, Rutgeerts, P, Sands, Be, Hanauer, S, Colombel, Jf, Sandborn, Wj, Van Assche, G, Axler, J, Kim, Hj, Danese, S, Fox, I, Milch, C, Sankoh, S, Wyant, T, Xu, J, Parikh, A, Bampton P, GEMINI 1 Study G. r. o. u. p., Chung, A, Debinski, H, Florin, T, Hetzel, D, Kronborg, I, Lawrance, I, Leong, R, Macrae, F, Moore, G, Pavli, P, Radford Smith, G, Weltman, M, Haas, T, Reinisch, W, Stockenhuber, F, Vogel, W, De Maeyer, M, De Vos, M, D'Haens, G, Louis, E, Muls, V, Petrov, P, Aumais, G, Bitton, A, Bourdages, R, Bressler, B, Cohen, A, Fedorak, R, Greenberg, G, Jones, J, Kutcher, W, Macintosh, D, Ponich, T, Singh, R, Steinhart, H, Sy, R, Douda, L, Lukas, M, Samek, M, Vyhnalek, P, Woznica, V, Zadorova, Z, Andersen, V, Rannem, T, Staun, M, Maelt, A, Margus, B, Bonaz, B, Coffin, B, Desreumaux, P, Laharie, D, Reimund, Jm, Karaus, M, Pace, A, Ross, M, Schmidt, W, Witthoeft, T, Zeitz, M, Karamanolis, D, Mantzaris, G, Maris, T, Ng, C, Gall, J, Hunyady, B, Szepes, A, Toth, T, Vincze, A, Oddsson, E, Jósefsspktali, Kö, Ahuja, V, Amarapurkar, D, Goenka, M, Habeeb, Ma, Jalihal, U, Kalambe, B, Koshy, A, Kumar, R, Prasad, V, Reddy, N, Sekar, T, Shankar, R, Tantry, V, Ryan, B, Avni, Y, Ben Horin, S, Ardizzone, S, Armuzzi, A, Corazziari, E, Fries, Walter, Kohn, A, Lisova, D, George, Am, Hilmi, In, Bhaskaran, Sk, Soon, Sy, Engels, L, Ponsioen, C, Wallace, I, Wyeth, J, Florholmen, J, Jahnsen, J, Lygren, I, Röseth, A, Ciecko Michalska, I, Gonciarz, M, Huk, J, Jamrozik Kruk, Z, Kondusz Szklarz, M, Paradowski, L, Wiechowska Kozlowska, A, Han, Ds, Hong, Sp, Kim, Js, Kim, Ko, Kim, Yh, Yang, Sk, Alexeeva, O, Bunkova, E, Burnevich, E, Dolgikh, O, Kasherininova, I, Khovaeva, Y, Lakhin, A, Ling, Kl, Bester, F, Coetzer, T, Grundling Hde, K, Jackson, Ld, Spies, P, Wright, Jp, Ziady, C, Garcia Planella, E, Perez Gisbert, J, Rogler, G, Seibold, F, Kao, Aw, Wu, Dc, Atug, O, Kurdas, Oo, Hawthorne, Ab, Lindsay, J, Abreu, M, Aggarwal, A, Bala, N, Becker, S, Behm, B, Braun, R, Cohn, W, Cross, R, Dar, S, Dassopoulos, T, De Villiers, W, Desta, T, Dryden, G, Duvall, A, Farraye, F, Fein, S, Liu, Bf, Gatof, D, Geenen, D, Ginsburg, P, Glover, S, Gopal, V, Hanson, J, Hardi, R, Isaacs, K, Jain, R, Karyotakis, N, Korzenik, J, Koshy, G, Koval, G, Lawitz, E, Lee, S, Loftus, E, Luther, R, Mahadevan, U, Mannon, P, Matsuyama, R, Mcintosh, A, Melmed, G, Mirkin, K, Nichols, M, Oubre, B, Pandak, W, Quadri, A, Quallich, L, Randall, C, Rausher, D, Regueiro, M, Safdi, A, Sands, B, Scherl, E, Schneier, J, Schwartz, D, Sedghi, S, Shafran, I, Siegel, C, Stein, L, Tatum, H, Weinberg, D, Winston, B, Wolf, D, Younes, Z, Jewell, D, Mahon, J, Rothstein, R, Snydman, D, Massaro, J, Clifford, D, Berger, J, Major, E, Provenzale, J, Abstract, Lev M., Feagan, Bg, Rutgeerts, P, Sands, Be, Hanauer, S, Colombel, Jf, Sandborn, Wj, Van Assche, G, Axler, J, Kim, Hj, Danese, S, Fox, I, Milch, C, Sankoh, S, Wyant, T, Xu, J, and Parikh, A
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Adult ,Male ,medicine.medical_specialty ,Integrins ,Placebo ,Antibodies, Monoclonal, Humanized ,Drug Administration Schedule ,law.invention ,Vedolizumab ,Maintenance Chemotherapy ,Maintenance therapy ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,medicine ,Humans ,Glucocorticoids ,Aged ,business.industry ,General Medicine ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Ulcerative colitis ,Infliximab ,Surgery ,Clinical trial ,Cohort ,Colitis, Ulcerative ,Drug Therapy, Combination ,Female ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).
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- 2013
24. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis
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Beaudoin, Melissa, Goyette, Philippe, Goel, Gautam, Louis, E., Mansfield, J. C., Mathew, C. G., McGovern, D. P., Mitrovic, M., Montgomery, G. W., Mowat, C., Newman, W., Palmieri, O., Panés, J., Lagace, Caroline, Parkes, M., Phillips, A., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Proctor, D. D., Radford-Smith, G. L., Regueiro, M., Rioux, J. D., Roberts, R., Annese, Vito, Rotter, J. I., Rutgeerts, P., Sanderson, J., Sans, M., Satsangi, J., Schreiber, S., Schumm, P., Seibold, F., Sharma, Y., Silverberg, M. S., Bitton, Alain, Simms, L. A., Steinhart, A., Targan, S. R., Taylor, K. D., Torkvist, L., Vermeire, S., Halfvarson, J., Verspaget, H. W., De Vos, M., Walters, T., Begun, Jakob, Wang, K., Weersma, R. K., Whiteman, D., Wijmenga, C., Brant, Steven R., Bresso, Francesca, Cho, Judy H., Duerr, Richard H., Halfvarson, Jonas, Boucher, Gabrielle, McGovern, Dermot P. B., Radford-Smith, Graham, Schreiber, Stefan, Schumm, Philip L., Sharma, Yashoda, Silverberg, Mark S., Weersma, Rinse K., Quebec IBD Genetics Consortium, NIDDK IBD Genetics Consortium, International IBD Genetics Consortium (IIBDGC), Lo, Ken Sin, D'Amato, Mauro, Vermeire, Severine, Franke, Andre, Lettre, Guillaume, Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Aumais, G., Bernard, E. J., Bitton, A., Rivas, Manuel A., Cohen, A., Deslandres, C., Lahaie, R., Paré, P., Brant, S. R., Cho, J. H., Duerr, R. H., Stevens, Christine, Ahmad, T., Anderson, C. A., Annese, V., Baldassano, R. N., Balschun, T., Barclay, M., Barrett, J. C., Bayless, T. M., Bis, J. C., Alikashani, Azadeh, Brand, S., Bumpstead, S., Buning, C., Colombel, J. F., Cottone, M., D'Amato, M., D'Inca, R., Ladouceur, Martin, Daly, M. J., Denson, T., Dubinsky, M., Edwards, C., Ellinghaus, D., Florin, T., Franchimont, D., Franke, A., Gearry, R., Ellinghaus, David, Georges, M., Glas, J., Van Gossum, A., Griffiths, A. M., Guthery, S. L., Hakonarson, H., Haritunians, T., Hugot, J. P., de Jong, D. J., Jostins, L., Torkvist, Leif, Kugathasan, S., Kullak-Ublick, G., Latiano, A., Laukens, D., Lawrance, I., Lee, J., Lees, C. W., Lemann, M., Levine, A., Libioulle, C., and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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Cancer Research ,Génétique clinique ,LIVER ,Genome-wide association study ,Inflammatory bowel disease ,0302 clinical medicine ,Crohn Disease ,GENETIC-VARIANTS ,Medicine and Health Sciences ,Ethnicity ,UBIQUITIN LIGASES ,Genetics(clinical) ,Genetics (clinical) ,Genetics ,0303 health sciences ,Ecology ,High-Throughput Nucleotide Sequencing ,CROHN-DISEASE ,CROHNS-DISEASE ,3. Good health ,030220 oncology & carcinogenesis ,Medical genetics ,Biologie ,Research Article ,EXPRESSION ,medicine.medical_specialty ,Canada ,lcsh:QH426-470 ,SUSCEPTIBILITY LOCI ,Evolution ,Ubiquitin-Protein Ligases ,Ethnic Groups ,Evolution des espèces ,Biology ,Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2] ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Behavior and Systematics ,medicine ,Humans ,Genetic Predisposition to Disease ,Ligase activity ,MODULATION ,Allele ,GENOME-WIDE ASSOCIATION ,Molecular Biology ,Genotyping ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Genetic association ,Ecologie ,Biologie moléculaire ,Receptors, Interleukin ,medicine.disease ,NUCLEAR FACTOR 4-ALPHA ,Genetic architecture ,Cancérologie ,CARD Signaling Adaptor Proteins ,lcsh:Genetics ,CELLS ,Colitis, Ulcerative ,INTESTINAL EPITHELIAL-CELLS ,Genome-Wide Association Study ,INFLAMMATORY-BOWEL-DISEASE - Abstract
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2013
25. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
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Jostins, Luke, Ripke, Stephan, Weersma, Rinse K., Duerr, Richard H., Mcgovern, Dermot P., Hui, Ken Y., Lee, James C., Philip Schumm, L., Sharma, Yashoda, Anderson, Carl A., Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L., Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Andrews, Jane M., Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A., Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D'Amato, Mauro, De Jong, Dirk, Devaney, Kathy L., Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R., Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Xinli, Hu, Karlsen, Tom H., Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R., Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Regueiro, Miguel, Rotter, Jerome I., Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A., Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kent D., Tremelling, Mark, Verspaget, Hein W., De Vos, Martine, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhao, Hongyu, Silverberg, Mark S., Annese, Vito, Hakonarson, Hakon, Brant, Steven R., Radford Smith, Graham, Mathew, Christopher G., Rioux, John D., Schadt, Eric E., Daly, Mark J., Franke, Andre, Parkes, Miles, Vermeire, Severine, Barrett, Jeffrey C., Cho, Judy H., Barclay, M, Peyrin Biroulet, L, Chamaillard, M, Colombel, Jf, Cottone, M, Croft, A, D'Incà, R, Halfvarson J, Hanigan K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lémann, M, Levine, A, Massey, D, Milla, M, Montgomery, Gw, Ng, Sm, Oikonomou, I, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, Laura, Taylor, Km, Törkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Andrews, Jm, Bampton, Pa, Florin, Th, Gearry, R, Krishnaprasad, K, Lawrance, Ic, Mahy, G, Radford Smith, G, Roberts, Rl, Simms, La, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie AM 3rd, Beck, K, Bernard, Ej, Binion, Dg, Bitton, A, Brant, Sr, Cho, Jh, Cohen, A, Croitoru, K, Daly, Mj, Datta, Lw, Deslandres, C, Duerr, Rh, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, Gr, Haritunians, T, Jobin, G, Katz, S, Lahaie, Rg, Mcgovern, Dp, Nelson, L, Ning, K, Paré, P, Regueiro, Md, Rioux, Jd, Ruggiero, E, Schumm, L, Schwartz, M, Scott, R, Sharma, Y, Silverberg, Ms, Spears, D, Steinhart, A, Stempak, Jm, Swoger, Jm, Tsagarelis, C, Zhang, C, Zhao, H, Aerts, J, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, Sg, Balmforth, Aj, Barnes, C, Barrett, Jc, Barroso, I, Barton, A, Bennett, Aj, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, Oj, Braund, Ps, Bredin, F, Breen, G, Brown, Mj, Bruce, In, Bull, J, Burren, Os, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, Cm, Coffey, Aj, Connell, Jm, Conrad, Df, Cooper, Jd, Dominiczak, Af, Downes, K, Drummond, He, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, Dm, Evans, G, Eyre, S, Farmer, A, Ferrier, In, Flynn, E, Forbes, A, Forty, L, Franklyn, Ja, Frayling, Tm, Freathy, Rm, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon Smith, K, Gray, E, Green, E, Groves, Cj, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, Ga, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, Jm, Hughes, D, Hunt, S, Isaacs, Jd, Jain, M, Jewell, Dp, Johnson, T, Jolley, Jd, Jones, Ir, Jones, La, Kirov, G, Langford, Cf, Lango Allen, H, Lathrop, Gm, Lee, J, Lee, Kl, Lees, C, Lewis, K, Lindgren, Cm, Maisuria Armer, M, Maller, J, Mansfield, J, Marchini, Jl, Martin, P, Massey, Dc, Mcardle, Wl, Mcguffin, P, Mclay, Ke, Mcvean, G, Mentzer, A, Mimmack, Ml, Morgan, Ae, Morris, Ap, Mowat, C, Munroe, Pb, Myers, S, Newman, W, Nimmo, Er, O'Donovan, Mc, Onipinla, A, Ovington, Nr, Owen, Mj, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, Jr, Phillips, A, Plagnol, V, Prescott, Nj, Prokopenko, I, Quail, Ma, Rafelt, S, Rayner, Nw, Reid, Dm, Renwick, A, Ring, Sm, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, Jg, Sanderson, Jd, Sawcer, Sj, Schuilenburg, H, Scott, Ce, Seal, S, Shaw Hawkins, S, Shields, Bm, Simmonds, Mj, Smyth, Dj, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, He, Stirrups, K, Stone, Ma, Strachan, Dp, Su, Z, Symmons, Dp, Thompson, Jr, Thomson, W, Tobin, Md, Travers, Me, Turnbull, C, Vukcevic, D, Wain, Lv, Walker, M, Walker, Nm, Wallace, C, Warren Perry, M, Watkins, Na, Webster, J, Weedon, Mn, Wilson, Ag, Woodburn, M, Wordsworth, Bp, Yau, C, Young, Ah, Zeggini, E, Brown, Ma, Burton, Pr, Caulfield, Mj, Compston, A, Farrall, M, Gough, Sc, Hall, As, Hattersley, At, Hill, Av, Mathew, Cg, Pembrey, M, Satsangi, J, Stratton, Mr, Worthington, J, Hurles, Me, Duncanson, A, Ouwehand, Wh, Parkes, M, Rahman, N, Todd, Ja, Samani, Nj, Kwiatkowski, Dp, Mccarthy, Mi, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, Jm, Bramon, E, Casas, Jp, Corvin, A, Jankowski, J, Markus, Hs, Palmer, Cn, Plomin, R, Rautanen, A, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
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Genome-wide association study ,Disease ,SUSCEPTIBILITY ,Inflammatory bowel disease ,NUMBER ,0302 clinical medicine ,Crohn Disease ,NETWORK ,Genetics ,0303 health sciences ,Multidisciplinary ,Genomics ,Ulcerative colitis ,3. Good health ,Colitis, Ulcerative ,Genetic Predisposition to Disease ,Genome, Human ,Haplotypes ,Humans ,Inflammatory Bowel Diseases ,Mycobacterium ,Mycobacterium Infections ,Mycobacterium tuberculosis ,Phenotype ,Polymorphism, Single Nucleotide ,Reproducibility of Results ,Genome-Wide Association Study ,Host-Pathogen Interactions ,IRGM ,Medical genetics ,030211 gastroenterology & hepatology ,EXPRESSION ,medicine.medical_specialty ,Immunology ,Biology ,Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2] ,TUBERCULOSIS ,03 medical and health sciences ,Medical research ,medicine ,Allele ,METAANALYSIS ,030304 developmental biology ,HYPER-IGE SYNDROME ,MUTATIONS ,medicine.disease ,RISK LOCI ,Genetic architecture ,digestive system diseases - Abstract
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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- 2012
26. Vedolizumab as induction and maintenance therapy for Crohn's disease.
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GEMINI 2 Study Group, Bampton, P., Borody, T., Chung, A., Debinski, H., Florin, T., Hetzel, D., Jakobovits, S., Lawrance, I., Leong, R., Macrae, F., Mitchell, B., Moore, G., Pavli, P., Samuel, D., Weltman, M., Haas, T., Reinisch, W., Vogel, W., Baert, F., De Maeyer, M., De Vos, M., Dewit, O., D'Haens, G., Louis, E., Muls, V., Van Assche, G., Krastev, Z., Nikolovska, D., Petrov, P., Petrov, A., Stoinov, S., Tchernev, K., Vasileva, G., Aumais, G., Axler, J., Bailey, R., Bernstein, C., Bitton, A., Bourdages, R., Bressler, B., Cohen, A., Devroede, G., Dhalla, S., Feagan, B., Fedorak, R., Green, D., Greenberg, G., Jones, J., Larkai, E., MacIntosh, D., Panaccione, R., Ponich, T., Singh, R., Sy, R., Wiesinger, H., Albin, A., Douda, L., Horny, I., Lukas, M., Stehlik, J., Stuksa, J., Volfova, M., Vyhnalek, P., Zadorova, Z., Andersen, V., Bendtsen, F., Fallingborg, J., Rannem, T., Maelt, A., Margus, B., Salupere, R., Allez, M., Des Varennes SB., Desreumaux, P., Dupas, JL., Grimaud, JC., Hebuterne, X., Lerebours, E., Picon, L., Zerbib, F., Aldinger, V., Baumgart, D., Buening, C., Dollinger, M., Hoffmann, P., Howaldt, S., Klaus, J., Konturek, JW., Krummenerl, T., Malfertheiner, P., Schmidt, W., Schreiber, S., Seidler, U., Stallmach, A., Stremmel, W., Zeitz, M., Mantzaris, G., Triantafyllou, K., Ng, C., Bene, L., Fazekas, I., Fejes, R., Gall, J., Horvat, G., Hunyady, B., Salamon, A., Toth, T., Tulassay, Z., Varga, E., Varga, M., Varga-Szabo, L., Vincze, A., Oddsson, E., Örvar, K., Ahuja, V., Amarapurkar, D., Chandra, A., Koshy, A., Krishna, P., Ramakrishna, K., Reddy, N., Thorat, V., Patchett, S., Ryan, B., Ben Horin, S., Fishman, S., Lavy, A., Rachmilewitz, D., Ardizzone, S., Corazziari, E., Danese, S., Fries, W., Gasbarrini, A., Kohn, A., Sturniolo, GC., Danilans, A., George, AM., Hilmi, IN., Engels, LG., Ponsioen, CY., van der Woude CJ., Gearry, R., Haines, M., Schultz, M., Wallace, I., Wyeth, J., Florholmen, J., Jahnsen, J., Lygren, I., Röseth, A., Ciecko-Michalska, I., Gonciarz, M., Horynski, M., Huk, J., Jamrozik-Kruk, Z., Janke, A., Klupinska, G., Marecik, J., Paradowski, L., Rudzinski, J., Rydzewska, G., Han, DS., Hong, SP., Kim, HJ., Kim, JS., Kim, KO., Kim, YH., Yang, SK., Gheorghe, LS., Voiosu, RM., Alexeeva, O., Baranovsky, A., Bunkova, E., Burnevich, E., Dolgikh, O., Grinevich, V., Lakhin, A., Tarabar, D., Ling, KL., Bunganic, I., Cernok, S., Gregus, M., Coetzer, T., Grundling, H., Moola, SA., Wright, JP., Ziady, C., Bermejo, F., Calvet, X., Herrerias, JM., Perez Calle JL., Perez Gisbert, J., Hertervig, E., Karlen, P., Michetti, P., Rogler, G., Seibold, F., Wu, DC., Atug, O., Kurdas, OO., Datsenko, O., Dorofyeyev, A., Dudar, L., Golovchenko, O., Klyarits'ka, I., Skrypnyk, I., Hawthorne, AB., Middleton, S., Abreu, M., Bala, N., Becker, S., Behm, B., Braun, R., Bukhari, M., Chen, S., Coates, A., Dar, S., Dassopoulos, T., De Villiers, W., Desautels, S., Desta, T., Dimitroff, J., Dryden, G., Duvall, A., Farraye, F., Fein, S., Liu, BF., Gatof, D., Geenen, D., Ginsburg, P., Glombicki, A., Glover, S., Gordon, G., Grisolano, S., Hanauer, S., Hanson, J., Hardi, R., Hoffman, B., Isaacs, K., Kim, C., Koval, G., Lashner, B., Lawitz, E., Lee, S., Leman, B., Levine, J., Loftus, E., Mahadevan, U., Mannon, P., Marcet, J., Matsuyama, R., Matusow, G., McCabe, R., Mirkin, K., Murphy, M., Mushahwar, A., Mutlu, E., Nagrani, M., Nguyen, D., Nichols, M., Nieves Ramirez, A., Oubre, B., Pace, S., Pandak, W., Perera, L., Quadri, A., Quallich, L., Rajapakse, R., Randall, C., Regueiro, M., Safdi, A., Sandborn, W., Sands, B., Saubermann, L., Scherl, E., Schwartz, D., Sedghi, S., Shafran, I., Shepard, R., Siegel, C., Stein, L., Tatum, H., Triebling, A., Vasudeva, R., Winston, B., Wolf, D., Younes, Z., Feagan, BG., Colombel, JF., Rutgeerts, P., Sandborn, WJ., Sands, BE., Jewell, D., Mahon, J., Rothstein, R., Snydman, D., Massaro, J., Clifford, D., Berger, J., Major, E., Provenzale, J., Lev, M., Sandborn, W.J., Feagan, B.G., Colombel, J.F., Sands, B.E., Fedorak, R.N., Fox, I., Rosario, M., Sankoh, S., Xu, J., Stephens, K., Milch, C., Parikh, A., GEMINI 2 Study Group, Bampton, P., Borody, T., Chung, A., Debinski, H., Florin, T., Hetzel, D., Jakobovits, S., Lawrance, I., Leong, R., Macrae, F., Mitchell, B., Moore, G., Pavli, P., Samuel, D., Weltman, M., Haas, T., Reinisch, W., Vogel, W., Baert, F., De Maeyer, M., De Vos, M., Dewit, O., D'Haens, G., Louis, E., Muls, V., Van Assche, G., Krastev, Z., Nikolovska, D., Petrov, P., Petrov, A., Stoinov, S., Tchernev, K., Vasileva, G., Aumais, G., Axler, J., Bailey, R., Bernstein, C., Bitton, A., Bourdages, R., Bressler, B., Cohen, A., Devroede, G., Dhalla, S., Feagan, B., Fedorak, R., Green, D., Greenberg, G., Jones, J., Larkai, E., MacIntosh, D., Panaccione, R., Ponich, T., Singh, R., Sy, R., Wiesinger, H., Albin, A., Douda, L., Horny, I., Lukas, M., Stehlik, J., Stuksa, J., Volfova, M., Vyhnalek, P., Zadorova, Z., Andersen, V., Bendtsen, F., Fallingborg, J., Rannem, T., Maelt, A., Margus, B., Salupere, R., Allez, M., Des Varennes SB., Desreumaux, P., Dupas, JL., Grimaud, JC., Hebuterne, X., Lerebours, E., Picon, L., Zerbib, F., Aldinger, V., Baumgart, D., Buening, C., Dollinger, M., Hoffmann, P., Howaldt, S., Klaus, J., Konturek, JW., Krummenerl, T., Malfertheiner, P., Schmidt, W., Schreiber, S., Seidler, U., Stallmach, A., Stremmel, W., Zeitz, M., Mantzaris, G., Triantafyllou, K., Ng, C., Bene, L., Fazekas, I., Fejes, R., Gall, J., Horvat, G., Hunyady, B., Salamon, A., Toth, T., Tulassay, Z., Varga, E., Varga, M., Varga-Szabo, L., Vincze, A., Oddsson, E., Örvar, K., Ahuja, V., Amarapurkar, D., Chandra, A., Koshy, A., Krishna, P., Ramakrishna, K., Reddy, N., Thorat, V., Patchett, S., Ryan, B., Ben Horin, S., Fishman, S., Lavy, A., Rachmilewitz, D., Ardizzone, S., Corazziari, E., Danese, S., Fries, W., Gasbarrini, A., Kohn, A., Sturniolo, GC., Danilans, A., George, AM., Hilmi, IN., Engels, LG., Ponsioen, CY., van der Woude CJ., Gearry, R., Haines, M., Schultz, M., Wallace, I., Wyeth, J., Florholmen, J., Jahnsen, J., Lygren, I., Röseth, A., Ciecko-Michalska, I., Gonciarz, M., Horynski, M., Huk, J., Jamrozik-Kruk, Z., Janke, A., Klupinska, G., Marecik, J., Paradowski, L., Rudzinski, J., Rydzewska, G., Han, DS., Hong, SP., Kim, HJ., Kim, JS., Kim, KO., Kim, YH., Yang, SK., Gheorghe, LS., Voiosu, RM., Alexeeva, O., Baranovsky, A., Bunkova, E., Burnevich, E., Dolgikh, O., Grinevich, V., Lakhin, A., Tarabar, D., Ling, KL., Bunganic, I., Cernok, S., Gregus, M., Coetzer, T., Grundling, H., Moola, SA., Wright, JP., Ziady, C., Bermejo, F., Calvet, X., Herrerias, JM., Perez Calle JL., Perez Gisbert, J., Hertervig, E., Karlen, P., Michetti, P., Rogler, G., Seibold, F., Wu, DC., Atug, O., Kurdas, OO., Datsenko, O., Dorofyeyev, A., Dudar, L., Golovchenko, O., Klyarits'ka, I., Skrypnyk, I., Hawthorne, AB., Middleton, S., Abreu, M., Bala, N., Becker, S., Behm, B., Braun, R., Bukhari, M., Chen, S., Coates, A., Dar, S., Dassopoulos, T., De Villiers, W., Desautels, S., Desta, T., Dimitroff, J., Dryden, G., Duvall, A., Farraye, F., Fein, S., Liu, BF., Gatof, D., Geenen, D., Ginsburg, P., Glombicki, A., Glover, S., Gordon, G., Grisolano, S., Hanauer, S., Hanson, J., Hardi, R., Hoffman, B., Isaacs, K., Kim, C., Koval, G., Lashner, B., Lawitz, E., Lee, S., Leman, B., Levine, J., Loftus, E., Mahadevan, U., Mannon, P., Marcet, J., Matsuyama, R., Matusow, G., McCabe, R., Mirkin, K., Murphy, M., Mushahwar, A., Mutlu, E., Nagrani, M., Nguyen, D., Nichols, M., Nieves Ramirez, A., Oubre, B., Pace, S., Pandak, W., Perera, L., Quadri, A., Quallich, L., Rajapakse, R., Randall, C., Regueiro, M., Safdi, A., Sandborn, W., Sands, B., Saubermann, L., Scherl, E., Schwartz, D., Sedghi, S., Shafran, I., Shepard, R., Siegel, C., Stein, L., Tatum, H., Triebling, A., Vasudeva, R., Winston, B., Wolf, D., Younes, Z., Feagan, BG., Colombel, JF., Rutgeerts, P., Sandborn, WJ., Sands, BE., Jewell, D., Mahon, J., Rothstein, R., Snydman, D., Massaro, J., Clifford, D., Berger, J., Major, E., Provenzale, J., Lev, M., Sandborn, W.J., Feagan, B.G., Colombel, J.F., Sands, B.E., Fedorak, R.N., Fox, I., Rosario, M., Sankoh, S., Xu, J., Stephens, K., Milch, C., and Parikh, A.
- Abstract
BACKGROUND: The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown. METHODS: In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. RESULTS: At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%). CONCLUSIONS: Vedolizumab-treated patients with active Crohn's disease were more likely than patients rec
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- 2013
27. Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
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Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Regueiro, M, Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, and Regueiro, M
- Abstract
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al.
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- 2013
28. Review and clinical perspectives for the use of infliximab in ulcerative colitis.
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Panaccione, R, Fedorak, R, Aumais, G, Bernard, Edmond-Jean, Bernstein, C N, Bitton, A, Croitoru, K, Dieleman, L A, Enns, Richard H., Feagan, B G, Franchimont, Denis, Greenberg, G R, Griffiths, Anne-Marie, Marshall, John K, Pare, P, Patel, S, Penner, R, Render, C, Seidman, E, Steinhart, A H, Panaccione, R, Fedorak, R, Aumais, G, Bernard, Edmond-Jean, Bernstein, C N, Bitton, A, Croitoru, K, Dieleman, L A, Enns, Richard H., Feagan, B G, Franchimont, Denis, Greenberg, G R, Griffiths, Anne-Marie, Marshall, John K, Pare, P, Patel, S, Penner, R, Render, C, Seidman, E, and Steinhart, A H
- Abstract
Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published
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- 2008
29. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis
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Goyette, P, primary, Lefebvre, C, additional, Ng, A, additional, Brant, S R, additional, Cho, J H, additional, Duerr, R H, additional, Silverberg, M S, additional, Taylor, K D, additional, Latiano, A, additional, Aumais, G, additional, Deslandres, C, additional, Jobin, G, additional, Annese, V, additional, Daly, M J, additional, Xavier, R J, additional, and Rioux, J D, additional
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- 2008
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30. Pharmacokinetics and tissue distribution of a new mesalamine rectal gel in ulcerative colitis patients
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Aumais, G, primary
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- 2004
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31. Rectal tissue, plasma and urine concentrations of mesalazine after single and multiple administrations of 500 mg suppositories to healthy volunteers and ulcerative proctitis patients
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Aumais, G., primary, Lefebvre, M., additional, Tremblay, C., additional, Bitton, A., additional, Martin, F., additional, Giard, A., additional, Madi, M., additional, and Spénard, J., additional
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- 2002
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32. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis
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Beaudoin, Melissa, Goyette, Philippe, Boucher, Gabrielle, Lo, Ken Sin, Rivas, Manuel A., Stevens, Christine, Alikashani, Azadeh, Ladouceur, Martin, Ellinghaus, David, Torkvist, Leif, Goel, Gautam, Lagace, Caroline, Annese, Vito, Bitton, Alain, Begun, Jakob, Brant, Steven R., Bresso, Francesca, Cho, Judy H., Duerr, Richard H., Halfvarson, Jonas, McGovern, Dermot P. B., Radford-Smith, Graham, Schreiber, Stefan, Schumm, Philip L., Sharma, Yashoda, Silverberg, Mark S., Weersma, Rinse K., Quebec IBD Genetics Consortium, NIDDK IBD Genetics Consortium, International IBD Genetics Consortium (IIBDGC), D'Amato, Mauro, Vermeire, Severine, Franke, Andre, Lettre, Guillaume, Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Aumais, G., Bernard, E. J., Bitton, A., Cohen, A., Deslandres, C., Lahaie, R., Paré, P., Rioux, J. D., Brant, S. R., Cho, J. H., Duerr, R. H., McGovern, D. P., Silverberg, M. S., Ahmad, T., Anderson, C. A., Annese, V., Baldassano, R. N., Balschun, T., Barclay, M., Barrett, J. C., Bayless, T. M., Bis, J. C., Brand, S., Bumpstead, S., Buning, C., Colombel, J. F., Cottone, M., D'Amato, M., D'Inca, R., Daly, M. J., Denson, T., Dubinsky, M., Edwards, C., Ellinghaus, D., Florin, T., Franchimont, D., Franke, A., Gearry, R., Georges, M., Glas, J., Van Gossum, A., Griffiths, A. M., Guthery, S. L., Hakonarson, H., Haritunians, T., Hugot, J. P., De Jong, D. J., Jostins, L., Kugathasan, S., Kullak-Ublick, G., Latiano, A., Laukens, D., Lawrance, I., Lee, J., Lees, C. W., Lemann, M., Levine, A., Libioulle, C., Louis, E., Mansfield, J. C., Mathew, C. G., Mitrovic, M., Montgomery, G. W., Mowat, C., Newman, W., Palmieri, O., Panés, J., Parkes, M., Phillips, A., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Proctor, D. D., Radford-Smith, G. L., Regueiro, M., Roberts, R., Rotter, J. I., Rutgeerts, P., Sanderson, J., Sans, M., Satsangi, J., Schreiber, S., Schumm, P., Seibold, F., Sharma, Y., Simms, L. A., Steinhart, A., Targan, S. R., Taylor, K. D., Torkvist, L., Vermeire, S., Halfvarson, J., Verspaget, H. W., De Vos, M., Walters, T., Wang, K., Weersma, R. K., Whiteman, D., and Wijmenga, C.
- Subjects
3. Good health - Abstract
PLoS genetics 9(9), e1003723 (2013). doi:10.1371/journal.pgen.1003723, Published by Public Library of Science, San Francisco, Calif.
33. Rectal tissue, plasma, and urine concentrations of mesalamine (5-ASA) after single and multiple administrations of suppositories to ulcerative proctitis (UP) patients
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Aumais, G., Bitton, A., Martin, F., Giard, A., Marc, L., Tremblay, C., and Spenard, J.
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- 2001
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34. Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study
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Silvio Danese, Jean-Frederic Colombel, Milan Lukas, Javier P Gisbert, Geert D'Haens, Bu'hussain Hayee, Remo Panaccione, Hyun-Soo Kim, Walter Reinisch, Helen Tyrrell, Young S Oh, Swati Tole, Akiko Chai, Kirsten Chamberlain-James, Meina Tao Tang, Stefan Schreiber, Nazimuddin Aboo, Tariq Ahmad, Xavier Aldeguer Mante, Matthieu Allez, Sven Almer, Romain Altwegg, Montserrat Andreu Garcia, Ramesh Arasaradnam, Sandro Ardizzone, Alessandro Armuzzi, Ian Arnott, Guy Aumais, Irit Avni-Biron, Peter Barrow, Ian Beales, Fernando Bermejo San Jose, Abraham Bezuidenhout, Livia Biancone, Michael Blaeker, Stuart Bloom, Bernd Bokemeyer, Fabrizio Bossa, Peter Bossuyt, Guillaume Bouguen, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Arnaud Bourreille, Christian Boustiere, Tomas Brabec, Stephan Brand, Carsten Buening, Anthony Buisson, Guillaume Cadiot, Xavier Calvet Calvo, Franck Carbonnel, Daniel Carpio, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Nicoleta-Claudia Cimpoeru, Martin Clodi, Gino Roberto Corazza, Rocco Cosintino, Jose Cotter, Thomas Creed, Fraser Cummings, Gian Luigi de' Angelis, Marc De Maeyer, Milind Desai, Etienne Desilets, Pierre Desreumaux, Olivier Dewit, Johanna Dinter, Ecaterina Daniela Dobru, Tomas Douda, Dan Lucian Dumitrascu, Matthias Ebert, Ana Echarri Piudo, Magdy Elkhashab, Chang Soo Eun, Brian Feagan, Roland Fejes, Catarina Fidalgo, Sigal Fishman, Bernard Flourié, Sharyle Fowler, Walter Fries, Csaba Fulop, Mathurin Fumery, Gyula G Kiss, Sonja Gassner, Daniel Gaya, Bastianello Germanà, Liliana Simona Gheorghe, Cyrielle Gilletta de Saint Joseph, Paolo Gionchetti, Adrian-Eugen Goldis, Raquel Gonçalves, Jean-Charles Grimaud, Tibor Gyökeres, Herve Hagege, Andrei Haidar, Heinz Hartmann, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Per Hellström, Pieter Hindryckx, Helena Hlavova, Frank Hoentjen, Stefanie Howaldt, Ludek Hrdlicka, Kyu Chan Huh, Maria Isabel Iborra Colomino, Florentina Ionita-Radu, Peter Irving, Jørgen Jahnsen, ByungIk Jang, Jeroen Jansen, Seong Woo Jeon, Rodrigo Jover Martinez, Pascal Juillerat, Per Karlén, Arthur Kaser, Radan Keil, Deepak Kejariwal, Dan Keret, Reena Khanna, Dongwoo Kim, Duk Hwan Kim, Hyo-Jong Kim, Joo Sung Kim, Kueongok Kim, Kyung-Jo Kim, Sung Kook Kim, Young-Ho Kim, Jochen Klaus, Anna Kohn, Vladimir Kojecky, Ja Seol Koo, Robert Kozak, Milan Kremer, Tunde Kristof, Frederik Kruger, David Laharie, Adi Lahat-zok, Evgeny Landa, Jonghun Lee, Kang-Moon Lee, Kook Lae Lee, YooJin Lee, Frank Lenze, Wee Chian Lim, Jimmy Limdi, James Lindsay, Pilar Lopez Serrano, Edouard Louis, Stefan Lueth, Giovanni Maconi, Fazia Mana, Steven Mann, John Mansfield, Santino Marchi, Marco Marino, John Marshall, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, John McLaughlin, Simon McLaughlin, Ehud Melzer, Jessica Mertens, Paul Mitrut, Tamas Molnar, Vinciane Muls, Pushpakaran Munuswamy, Charles Murray, Timna Naftali, Visvakuren Naidoo, Yusuf Nanabhay, Lucian Negreanu, Augustin Nguyen, Thomas Ochsenkuehn, Ambrogio Orlando, Julian Panes Diaz, Maya Paritsky, Dong Il Park, Jihye Park, Luca Pastorelli, Markus Peck-Radosavljevic, Farhad Peerani, Javier Perez Gisbert, Laurent Peyrin-Biroulet, Laurence Picon, Marieke Pierik, Terry Ponich, Francisco Portela, Maartens Jeroen Prins, Istvan Racz, Khan Fareed Rahman, Jean-Marie Reimund, Max Reinshagen, Xavier Roblin, Rodolfo Rocca, Francesca Rogai, Gerhard Rogler, Agnes Salamon, Ennaliza Salazar, Zoltan Sallo, Sunil Samuel, Miquel de los Santos Sans Cuffi, Edoardo Vincenzo Savarino, Vincenzo Savarino, Guillaume Savoye, Andrada Seicean, Christian Selinger, David Martins Serra, Hang Hock Shim, SungJae Shin, Britta Siegmund, Jesse Siffledeen, Wayne Simmonds, Jan Smid, Jose Sollano, Geun Am Song, Alexander Speight, Ioan Sporea, Dirk Staessen, George Stancu, Alan Steel, David Stepek, Victor Stoica, Andreas Sturm, Gyorgy Szekely, Teck Kiang Tan, Carlos Taxonera Samso, John Thomson, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Marcello Vangeli, Marta Varga, Ana Vieira, Stephanie Viennot, Erica Villa, Petr Vitek, Harald Vogelsang, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Byong Duk Ye, Christopher Ziady, Danese S., Colombel J.-F., Lukas M., Gisbert J.P., D'Haens G., Hayee B., Panaccione R., Kim H.-S., Reinisch W., Tyrrell H., Oh Y.S., Tole S., Chai A., Chamberlain-James K., Tang M.T., Schreiber S., Aboo N., Ahmad T., Aldeguer Mante X., Allez M., Almer S., Altwegg R., Andreu Garcia M., Arasaradnam R., Ardizzone S., Armuzzi A., Arnott I., Aumais G., Avni-Biron I., Barrow P., Beales I., Bermejo San Jose F., Bezuidenhout A., Biancone L., Blaeker M., Bloom S., Bokemeyer B., Bossa F., Bossuyt P., Bouguen G., Bouhnik Y., Bouma G., Bourdages R., Bourreille A., Boustiere C., Brabec T., Brand S., Buening C., Buisson A., Cadiot G., Calvet Calvo X., Carbonnel F., Carpio D., Cheon J.H., Chiba N., Chioncel C., Cimpoeru N.-C., Clodi M., Corazza G.R., Cosintino R., Cotter J., Creed T., Cummings F., de' Angelis G.L., De Maeyer M., Desai M., Desilets E., Desreumaux P., Dewit O., Dinter J., Dobru E.D., Douda T., Dumitrascu D.L., Ebert M., Echarri Piudo A., Elkhashab M., Eun C.S., Feagan B., Fejes R., Fidalgo C., Fishman S., Flourie B., Fowler S., Fries W., Fulop C., Fumery M., G Kiss G., Gassner S., Gaya D., Germana B., Gheorghe L.S., Gilletta de Saint Joseph C., Gionchetti P., Goldis A.-E., Goncalves R., Grimaud J.-C., Gyokeres T., Hagege H., Haidar A., Hartmann H., Hasselblatt P., Hebuterne X., Hellstrom P., Hindryckx P., Hlavova H., Hoentjen F., Howaldt S., Hrdlicka L., Huh K.C., Iborra Colomino M.I., Ionita-Radu F., Irving P., Jahnsen J., Jang B., Jansen J., Jeon S.W., Jover Martinez R., Juillerat P., Karlen P., Kaser A., Keil R., Kejariwal D., Keret D., Khanna R., Kim D., Kim D.H., Kim H.-J., Kim J.S., Kim K., Kim K.-J., Kim S.K., Kim Y.-H., Klaus J., Kohn A., Kojecky V., Koo J.S., Kozak R., Kremer M., Kristof T., Kruger F., Laharie D., Lahat-zok A., Landa E., Lee J., Lee K.-M., Lee K.L., Lee Y., Lenze F., Lim W.C., Limdi J., Lindsay J., Lopez Serrano P., Louis E., Lueth S., Maconi G., Mana F., Mann S., Mansfield J., Marchi S., Marino M., Marshall J., Martin Arranz M.D., Mateescu R.-B., McLaughlin J., McLaughlin S., Melzer E., Mertens J., Mitrut P., Molnar T., Muls V., Munuswamy P., Murray C., Naftali T., Naidoo V., Nanabhay Y., Negreanu L., Nguyen A., Ochsenkuehn T., Orlando A., Panes Diaz J., Paritsky M., Park D.I., Park J., Pastorelli L., Peck-Radosavljevic M., Peerani F., Perez Gisbert J., Peyrin-Biroulet L., Picon L., Pierik M., Ponich T., Portela F., Prins M.J., Racz I., Rahman K.F., Reimund J.-M., Reinshagen M., Roblin X., Rocca R., Rogai F., Rogler G., Salamon A., Salazar E., Sallo Z., Samuel S., Sans Cuffi M.D.L.S., Savarino E.V., Savarino V., Savoye G., Seicean A., Selinger C., Serra D.M., Shim H.H., Shin S., Siegmund B., Siffledeen J., Simmonds W., Smid J., Sollano J., Song G.A., Speight A., Sporea I., Staessen D., Stancu G., Steel A., Stepek D., Stoica V., Sturm A., Szekely G., Tan T.K., Taxonera Samso C., Thomson J., Tichy M., Toth G.T., Tulassay Z., Vangeli M., Varga M., Vieira A., Viennot S., Villa E., Vitek P., Vogelsang H., Vyhnalek P., Wahab P., Walldorf J., Ye B.D., and Ziady C.
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Population ,Antibodies, Monoclonal, Humanized ,Injections, Subcutaneou ,Placebo ,Severity of Illness Index ,Gastroenterology ,Young Adult ,Double-Blind Method ,Internal medicine ,Gastrointestinal Agent ,Clinical endpoint ,medicine ,education ,Adverse effect ,Aged ,Aged, 80 and over ,education.field_of_study ,Hepatology ,business.industry ,Middle Aged ,medicine.disease ,Ulcerative colitis ,Infliximab ,Treatment Outcome ,Etrolizumab ,Concomitant ,Colitis, Ulcerative ,Female ,business ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Human ,medicine.drug - Abstract
Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.
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- 2022
35. Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial
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Laurent Peyrin-Biroulet, Ailsa Hart, Peter Bossuyt, Millie Long, Matthieu Allez, Pascal Juillerat, Alessandro Armuzzi, Edward V Loftus, Elham Ostad-Saffari, Astrid Scalori, Young S Oh, Swati Tole, Akiko Chai, Jennifer Pulley, Stuart Lacey, William J Sandborn, Humberto Aguilar, Tariq Ahmad, Evangelos Akriviadis, Xavier Aldeguer Mante, Istvan Altorjay, Ashwin Ananthakrishnan, Vibeke Andersen, Montserrat Andreu Garcia, Guy Aumais, Irit Avni-Biron, Jeffrey Axler, Kamran Ayub, Filip Baert, Mauro Bafutto, George Bamias, Isaac Bassan, Curtis Baum, Laurent Beaugerie, Brian Behm, Pradeep Bekal, Michael Bennett, Fernando Bermejo San Jose, Charles Bernstein, Dominik Bettenworth, Sudhir Bhaskar, Livia Biancone, Bahri Bilir, Michael Blaeker, Stuart Bloom, Verle Bohman, Francisco Javier Bosques Padilla, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Stephan Brand, Brian Bressler, Markus Brückner, Carsten Buening, Franck Carbonnel, Thomas Caves, Jonathon Chapman, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Dimitrios Christodoulou, Martin Clodi, Albert Cohen, Gino Roberto Corazza, Richard Corlin, Rocco Cosintino, Fraser Cummings, Robin Dalal, Silvio Danese, Marc De Maeyer, Carlos Fernando De Magalhães Francesconi, Aminda De Silva, Henry Debinski, Pierre Desreumaux, Olivier Dewit, Geert D'Haens, Sandra Di Felice Boratto, John Nik Ding, Tyler Dixon, Gerald Dryden, George Aaron Du Vall, Matthias Ebert, Ana Echarri Piudo, Robert Ehehalt, Magdy Elkhashab, Craig Ennis, Jason Etzel, Jan Fallingborg, Brian Feagan, Roland Fejes, Daniel Ferraz de Campos Mazo, Valéria Ferreira de Almeida Borges, Andreas Fischer, Alan Fixelle, Mark Fleisher, Sharyle Fowler, Bradley Freilich, Keith Friedenberg, Walter Fries, Csaba Fulop, Mathurin Fumery, Sergio Fuster, Gyula G Kiss, Santiago Garcia Lopez, Sonja Gassner, Kanwar Gill, Cyrielle Gilletta de Saint Joseph, Philip Ginsburg, Paolo Gionchetti, Eran Goldin, Adrian-Eugen Goldis, Hector Alejandro Gomez Jaramillo, Maciej Gonciarz, Glenn Gordon, Daniel Green, Jean-Charles Grimaud, Rogelio Guajardo Rodriguez, Zoltan Gurzo, Alexandra Gutierrez, Tibor Gyökeres, Ki Baik Hahm, Stephen Hanauer, John Hanson, William Harlan III, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Peter Hendy, Melvin Heyman, Peter Higgins, Raouf Hilal, Pieter Hindryckx, Frank Hoentjen, Peter Hoffmann, Frank Holtkamp-Endemann, Gerald Holtmann, Gyula Horvat, Stefanie Howaldt, Samuel Huber, Ikechukwu Ibegbu, Maria Isabel Iborra Colomino, Peter Irving, Kim Isaacs, Kiran Jagarlamudi, Rajesh Jain, Sender Jankiel Miszputen, Jeroen Jansen, Jennifer Jones, John Karagiannis, Nicholas Karyotakis, Arthur Kaser, Lior Katz, Seymour Katz, Leo Katz, Nirmal Kaur, Edita Kazenaite, Reena Khanna, Sunil Khurana, Joo Sung Kim, Young-Ho Kim, Sung Kook Kim, Dongwoo Kim, Jochen Klaus, Dariusz Kleczkowski, Pavel Kohout, Bartosz Korczowski, Georgios Kouklakis, Ioannis Koutroubakis, Richard Krause, Tunde Kristof, Ian Kronborg, Annette Krummenerl, Limas Kupcinskas, Jorge Laborda Molteni, David Laharie, Adi Lahat-zok, Jonghun Lee, Kang-Moon Lee, Rupert Leong, Henry Levine, Jimmy Limdi, James Lindsay, Nilesh Lodhia, Edward Loftus, Randy Longman, Pilar Lopez Serrano, Edouard Louis, Maria Helena Louzada Pereira, John Lowe, Stefan Lueth, Milan Lukas, Giovanni Maconi, Finlay Macrae, Laszlo Madi-Szabo, Uma Mahadevan-Velayos, Everson Fernando Malluta, Fazia Mana, Peter Mannon, Gerasimos Mantzaris, Ignacio Marin Jimenez, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, Felipe Mazzoleni, Agnieszka Meder, Ehud Melzer, Jessica Mertens, Konstantinos Mimidis, Brent Mitchell, Tamas Molnar, Gregory Moore, Luis Alonso Morales Garza, Reme Mountifield, Vinciane Muls, Charles Murray, Bela Nagy, Markus Neurath, Augustin Nguyen, Remo Panaccione, William Pandak, Julian Panes Diaz, Jihye Park, Luca Pastorelli, Bhaktasharan Patel, Markus Peck-Radosavljevic, Gyula Pecsi, Farhad Peerani, Javier Perez Gisbert, Martin Pesta, Robert Petryka, Raymond Phillips, Marieke Pierik, Vijayalakshmi Pratha, Vlastimil Prochazka, Istvan Racz, Graham Radford-Smith, Daniel Ramos Castañeda, Odery Ramos Júnior, Jaroslaw Regula, Jean-Marie Reimund, Bryan Robbins, Xavier Roblin, Francesca Rogai, Gerhard Rogler, Jerzy Rozciecha, David Rubin, Azalia Yuriria Ruiz Flores, Maciej Rupinski, Grazyna Rydzewska, Sumona Saha, Simone Saibeni, Agnes Salamon, Zoltan Sallo, Bruce Salzberg, Douglas Samuel, Sunil Samuel, William Sandborn, Edoardo Vincenzo Savarino, Anja Schirbel, Robert Schnabel, Stefan Schreiber, John Scott, Shahriar Sedghi, Frank Seibold, Jakob Seidelin, Ursula Seidler, Ahmad Shaban, Ira Shafran, Aasim Sheikh, Alex Sherman, Haim Shirin, Patryk Smolinski, Geun Am Song, Konstantinos Soufleris, Alexander Speight, Dirk Staessen, Andreas Stallmach, Michael Staun, Daniel Stein, Hillary Steinhart, Jonathas Stifft, David Stokesberry, Andreas Sturm, Keith Sultan, Gyorgy Szekely, Kuldeep Tagore, Hugo Tanno, Lena Thin, Syed Thiwan, Carlton Thomas, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Jan Ulbrych, John Valentine, Marta Varga, Eduardo Vasconcellos, Byron Vaughn, Brenda Velasco, Francisco Velazquez, Severine Vermeire, Erica Villa, Aron Vincze, Harald Vogelsang, Miroslava Volfova, Lucine Vuitton, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Mattitiahu Waterman, John Weber, L. Michael Weiss, Anna Wiechowska-Kozlowska, Elise Wiesner, Thomas Witthoeft, Robert Wohlman, Barbara Wozniak-Stolarska, Bruce Yacyshyn, Byong-Duk Ye, Ziad Younes, Lígia Yukie Sassaki, Cyrla Zaltman, Stefan Zeuzem, Neurosurgery, ANS - Neurovascular Disorders, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Peyrin-Biroulet L., Hart A., Bossuyt P., Long M., Allez M., Juillerat P., Armuzzi A., Loftus E.V., Ostad-Saffari E., Scalori A., Oh Y.S., Tole S., Chai A., Pulley J., Lacey S., Sandborn W.J., Aguilar H., Ahmad T., Akriviadis E., Aldeguer Mante X., Altorjay I., Ananthakrishnan A., Andersen V., Andreu Garcia M., Aumais G., Avni-Biron I., Axler J., Ayub K., Baert F., Bafutto M., Bamias G., Bassan I., Baum C., Beaugerie L., Behm B., Bekal P., Bennett M., Bermejo San Jose F., Bernstein C., Bettenworth D., Bhaskar S., Biancone L., Bilir B., Blaeker M., Bloom S., Bohman V., Bosques Padilla F.J., Bouhnik Y., Bouma G., Bourdages R., Brand S., Bressler B., Bruckner M., Buening C., Carbonnel F., Caves T., Chapman J., Cheon J.H., Chiba N., Chioncel C., Christodoulou D., Clodi M., Cohen A., Corazza G.R., Corlin R., Cosintino R., Cummings F., Dalal R., Danese S., De Maeyer M., De Magalhaes Francesconi C.F., De Silva A., Debinski H., Desreumaux P., Dewit O., D'Haens G., Di Felice Boratto S., Ding J.N., Dixon T., Dryden G., Du Vall G.A., Ebert M., Echarri Piudo A., Ehehalt R., Elkhashab M., Ennis C., Etzel J., Fallingborg J., Feagan B., Fejes R., Ferraz de Campos Mazo D., Ferreira de Almeida Borges V., Fischer A., Fixelle A., Fleisher M., Fowler S., Freilich B., Friedenberg K., Fries W., Fulop C., Fumery M., Fuster S., G Kiss G., Garcia Lopez S., Gassner S., Gill K., Gilletta de Saint Joseph C., Ginsburg P., Gionchetti P., Goldin E., Goldis A.-E., Gomez Jaramillo H.A., Gonciarz M., Gordon G., Green D., Grimaud J.-C., Guajardo Rodriguez R., Gurzo Z., Gutierrez A., Gyokeres T., Hahm K.B., Hanauer S., Hanson J., Harlan III W., Hasselblatt P., Hayee B., Hebuterne X., Hendy P., Heyman M., Higgins P., Hilal R., Hindryckx P., Hoentjen F., Hoffmann P., Holtkamp-Endemann F., Holtmann G., Horvat G., Howaldt S., Huber S., Ibegbu I., Iborra Colomino M.I., Irving P., Isaacs K., Jagarlamudi K., Jain R., Jankiel Miszputen S., Jansen J., Jones J., Karagiannis J., Karyotakis N., Kaser A., Katz L., Katz S., Kaur N., Kazenaite E., Khanna R., Khurana S., Kim J.S., Kim Y.-H., Kim S.K., Kim D., Klaus J., Kleczkowski D., Kohout P., Korczowski B., Kouklakis G., Koutroubakis I., Krause R., Kristof T., Kronborg I., Krummenerl A., Kupcinskas L., Laborda Molteni J., Laharie D., Lahat-zok A., Lee J., Lee K.-M., Leong R., Levine H., Limdi J., Lindsay J., Lodhia N., Loftus E., Longman R., Lopez Serrano P., Louis E., Louzada Pereira M.H., Lowe J., Lueth S., Lukas M., Maconi G., Macrae F., Madi-Szabo L., Mahadevan-Velayos U., Malluta E.F., Mana F., Mannon P., Mantzaris G., Marin Jimenez I., Martin Arranz M.D., Mateescu R.-B., Mazzoleni F., Meder A., Melzer E., Mertens J., Mimidis K., Mitchell B., Molnar T., Moore G., Morales Garza L.A., Mountifield R., Muls V., Murray C., Nagy B., Neurath M., Nguyen A., Panaccione R., Pandak W., Panes Diaz J., Park J., Pastorelli L., Patel B., Peck-Radosavljevic M., Pecsi G., Peerani F., Perez Gisbert J., Pesta M., Petryka R., Phillips R., Pierik M., Pratha V., Prochazka V., Racz I., Radford-Smith G., Ramos Castaneda D., Ramos Junior O., Regula J., Reimund J.-M., Robbins B., Roblin X., Rogai F., Rogler G., Rozciecha J., Rubin D., Ruiz Flores A.Y., Rupinski M., Rydzewska G., Saha S., Saibeni S., Salamon A., Sallo Z., Salzberg B., Samuel D., Samuel S., Sandborn W., Savarino E.V., Schirbel A., Schnabel R., Schreiber S., Scott J., Sedghi S., Seibold F., Seidelin J., Seidler U., Shaban A., Shafran I., Sheikh A., Sherman A., Shirin H., Smolinski P., Song G.A., Soufleris K., Speight A., Staessen D., Stallmach A., Staun M., Stein D., Steinhart H., Stifft J., Stokesberry D., Sturm A., Sultan K., Szekely G., Tagore K., Tanno H., Thin L., Thiwan S., Thomas C., Tichy M., Toth G.T., Tulassay Z., Ulbrych J., Valentine J., Varga M., Vasconcellos E., Vaughn B., Velasco B., Velazquez F., Vermeire S., Villa E., Vincze A., Vogelsang H., Volfova M., Vuitton L., Vyhnalek P., Wahab P., Walldorf J., Waterman M., Weber J., Weiss L.M., Wiechowska-Kozlowska A., Wiesner E., Witthoeft T., Wohlman R., Wozniak-Stolarska B., Yacyshyn B., Ye B.-D., Younes Z., Yukie Sassaki L., Zaltman C., and Zeuzem S.
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Adult ,Male ,Ulcerative Colitis Flare ,medicine.medical_specialty ,Asia ,Adolescent ,Oceania ,Population ,Antibodies, Monoclonal, Humanized ,Injections, Subcutaneou ,Placebo ,Severity of Illness Index ,law.invention ,Middle East ,Young Adult ,Maintenance therapy ,Randomized controlled trial ,law ,Internal medicine ,Gastrointestinal Agent ,medicine ,Adverse effect ,education ,Aged ,Aged, 80 and over ,Tumor Necrosis Factor Inhibitor ,education.field_of_study ,Hepatology ,business.industry ,Remission Induction ,Gastroenterology ,Middle Aged ,South America ,medicine.disease ,Ulcerative colitis ,Europe ,Treatment Outcome ,Etrolizumab ,North America ,Colitis, Ulcerative ,Female ,business ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Human - Abstract
Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.
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- 2022
36. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease
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Naomi Hotte, Guy Aumais, Richard N. Fedorak, John Marshall, Robert J Bailey, Pierre Paré, Robert Enns, Remo Panaccione, Charles N. Bernstein, Cindy J. Wong, Karen Madsen, Alan Cockeram, A. Hillary Steinhart, Naoki Chiba, Alaa Rostom, Levinus A. Dieleman, Des Leddin, Alain Bitton, Denis Petrunia, Paolo Gionchetti, William T. Depew, Brian G. Feagan, Fedorak, Rn, Feagan, Bg, Hotte, N, Leddin, D, Dieleman, La, Petrunia, Dm, Enns, R, Bitton, A, Chiba, N, Parè, P, Rostom, A, Marshall, J, Depew, W, Bernestein, Cn, Panaccione, R, Aumais, G, Steinhart, Ah, Cockeram, A, Bailey, Rj, Gionchetti, P, Wong, C, and Madsen, K
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Adult ,Male ,medicine.medical_specialty ,Immunoglobulin Light Chains, Surrogate ,Biopsy ,Anti-Inflammatory Agents ,Colonoscopy ,Ileum ,medicine.disease_cause ,Placebo ,Gastroenterology ,Inflammatory bowel disease ,law.invention ,Placebos ,Probiotic ,Crohn Disease ,Double-Blind Method ,Bifidobacteria ,Recurrence ,law ,Internal medicine ,medicine ,Humans ,IBDQ ,Crohn's disease ,Hepatology ,medicine.diagnostic_test ,Streptococcus ,business.industry ,Probiotics ,Microbiota ,Inflammatory Bowel Disease ,Middle Aged ,medicine.disease ,Crohn's Disease Activity Index ,Surgery ,Treatment ,Treatment Outcome ,medicine.anatomical_structure ,Cytokines ,Female ,business ,Streptococcu - Abstract
BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence
- Published
- 2015
37. Early Life Exposure to Parental Crohn's Disease Is Associated With Offspring's Gut Microbiome, Gut Permeability, and Increased Risk of Future Crohn's Disease.
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Lee SH, Bushra M, Qiu L, Griffiths AM, Turpin W, Croitoru K, Abreu M, Beck P, Bernstein C, Croitoru K, Dieleman L, Feagan B, Griffiths A, Guttman D, Jacobson K, Kaplan G, Krause DO, Madsen K, Marshall J, Moayyedi P, Ropeleski M, Seidman E, Silverberg M, Snapper S, Stadnyk A, Steinhart AH, Surette M, Turner D, Walters T, Vallance B, Aumais G, Bitton A, Cino M, Critch J, Denson L, Deslandres C, El-Matary W, Herfarth H, Higgins P, Huynh HQ, Hyams J, Mack D, McGrath J, Otley A, Panancionne R, Abreu M, Aumais G, Baldassano R, Bernstein C, Cino M, Denson L, Deslandres C, El-Matary W, Griffiths AM, Hedin C, Herfarth H, Higgins P, Hussey S, Huynh HQ, Jacobson K, Keljo D, Kevans D, Lees C, Mack D, Marshall J, McGrath J, Murthy S, Otley A, Panaccione R, Parekh N, Plamondon S, Radford-Smith G, Ropeleski M, Rosh J, Rubin D, Schultz M, Seidman E, Siegel C, Snapper S, Steinhart AH, and Turner D
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- 2024
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38. Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have a Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn's Disease.
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Olivera PA, Martinez-Lozano H, Leibovitzh H, Xue M, Neustaeter A, Espin-Garcia O, Xu W, Madsen KL, Guttman DS, Bernstein CN, Yerushalmi B, Hyams JS, Abreu MT, Marshall JK, Wrobel I, Mack DR, Jacobson K, Bitton A, Aumais G, Panacionne R, Dieleman LA, Silverberg MS, Steinhart AH, Moayyedi P, Turner D, Griffiths AM, Turpin W, Lee SH, and Croitoru K
- Abstract
Background & Aims: Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders., Methods: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores, urinary fractional excretion of lactulose-to-mannitol ratio, fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset., Results: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (P = .026) but not with baseline CD-polygenic risk scores or the lactulose-to-mannitol ratio. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio, 3.65; 95% confidence interval, 2.18-6.11, P < .001)., Conclusion: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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39. Environmental Factors Associated With Risk of Crohn's Disease Development in the Crohn's and Colitis Canada - Genetic, Environmental, Microbial Project.
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Xue M, Leibovitzh H, Jingcheng S, Neustaeter A, Dong M, Xu W, Espin-Garcia O, Griffiths AM, Steinhart AH, Turner D, Huynh HQ, Dieleman LA, Panaccione R, Aumais G, Bressler B, Bitton A, Murthy S, Marshall JK, Hyams JS, Otley A, Bernstein CN, Moayyedi P, El-Matary W, Fich A, Denson LA, Ropeleski MJ, Abreu MT, Deslandres C, Cino M, Avni-Biron I, Lee SH, Turpin W, and Croitoru K
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- Humans, Female, Male, Adult, Canada epidemiology, Young Adult, Adolescent, Child, Animals, Middle Aged, Gastrointestinal Microbiome, Child, Preschool, RNA, Ribosomal, 16S genetics, Mannitol urine, Risk Assessment, Lactulose urine, Crohn Disease microbiology, Environmental Exposure adverse effects, Feces microbiology, Feces chemistry
- Abstract
Background & Aims: To date, it is unclear how environmental factors influence Crohn's disease (CD) risk and how they interact with biological processes. This study investigates the association between environmental exposures and CD risk and evaluates their association with pre-disease biomarkers., Methods: We studied 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn's and Colitis Canada - Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing., Results: Over a 5.62-year median follow-up, 86 FDRs developed CD. Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40-0.96; P = .034), and living with a large family size in the first year of life (HR, 0.43; 95% CI, 0.21-0.85; P = .016) were associated with decreased CD risk, whereas having a bird at the time of recruitment (HR, 2.78; 95% CI, 1.36-5.68; P = .005) was associated with an increased CD risk. Furthermore, living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity, whereas bird owners had higher FCP levels. Large family during participants' first year of life was associated with altered microbiota composition without affecting FCP or LMR., Conclusion: This study identifies environmental variables associated with CD risk. These variables were also associated with altered barrier function, subclinical inflammation, and gut microbiome composition shifts, suggesting potential roles in CD pathogenesis., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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- 2024
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40. Irritable Bowel Syndrome Patient Experience: A Survey of Patient-Reported Symptoms by Irritable Bowel Syndrome Subtype and Impact on Quality of Life.
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Bhinder G, Meza-Cardona JM, Low A, Aumais G, Attara GP, and Gray JR
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Objectives: Irritable bowel syndrome (IBS) is a chronic, debilitating, functional gastrointestinal disorder with symptoms of abdominal pain, bloating, and altered bowel behaviours of constipation (IBS-C), diarrhea (IBS-D), or a mixture of both (IBS-M). There is limited information published on the impact of symptoms on everyday life in the Canadian population., Methods: An online survey was conducted with individuals diagnosed with IBS to capture the severity and frequency of patient-reported symptoms, including impact on productivity, quality of life, healthcare utilization, treatment access, and corresponding symptom relief. Responses from the three subtypes of IBS were categorized to illustrate differences among these., Results: There were 2,470 qualified respondents (filtered from 2,981, which included nonspecific IBS). IBS-M was the most common subtype, at 44 percent. Most individuals from all three IBS subtypes reported experiencing moderate to severe abdominal pain (63-70 percent) and bloating (59-75 percent) over the previous 3 months. Persons living with IBS-C reported severe bloating (32 percent), straining (72 percent), and tenesmus (78 percent) whereas those with IBS-D experienced severe urgency (63 percent) and incontinence (29 percent). Symptoms interfered in daily life, sometimes in 46 percent and often in 23 percent of respondents. Patients reported mood and anxiety disorders as common comorbidities with IBS (mood disorders: 30-34 percent; anxiety disorders: 25-30 percent)., Conclusions: This study focuses on the differences among the IBS subtypes. IBS impacts productivity and healthcare utilization, which requires further investigation on approaches to improve treatment. The frequency and severity of symptoms in IBS are high and only a few respondents reported that their symptoms are under control., Competing Interests: There are no conflicts to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)
- Published
- 2023
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41. Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis.
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Leibovitzh H, Lee SH, Raygoza Garay JA, Espin-Garcia O, Xue M, Neustaeter A, Goethel A, Huynh HQ, Griffiths AM, Turner D, Madsen KL, Moayyedi P, Steinhart AH, Silverberg MS, Deslandres C, Bitton A, Mack DR, Jacobson K, Cino M, Aumais G, Bernstein CN, Panaccione R, Weiss B, Halfvarson J, Xu W, Turpin W, and Croitoru K
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- Humans, Case-Control Studies, Proteomics, Biomarkers, Immunity, Crohn Disease metabolism
- Abstract
Objective: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort., Design: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay., Results: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all)., Conclusion: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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42. Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease.
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Leibovitzh H, Lee SH, Xue M, Raygoza Garay JA, Hernandez-Rocha C, Madsen KL, Meddings JB, Guttman DS, Espin-Garcia O, Smith MI, Goethel A, Griffiths AM, Moayyedi P, Steinhart AH, Panaccione R, Huynh HQ, Jacobson K, Aumais G, Mack DR, Abreu MT, Bernstein CN, Marshall JK, Turner D, Xu W, Turpin W, and Croitoru K
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- Humans, RNA, Ribosomal, 16S genetics, Lactulose, Tryptophan, Mannitol, Threonine, Glutamates, Gastrointestinal Microbiome genetics, Crohn Disease microbiology
- Abstract
Background & Aims: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease., Methods: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function., Results: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R
2 = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6)., Conclusions: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier., (Copyright © 2022 AGA Institute. All rights reserved.)- Published
- 2022
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43. Mediterranean-Like Dietary Pattern Associations With Gut Microbiome Composition and Subclinical Gastrointestinal Inflammation.
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Turpin W, Dong M, Sasson G, Raygoza Garay JA, Espin-Garcia O, Lee SH, Neustaeter A, Smith MI, Leibovitzh H, Guttman DS, Goethel A, Griffiths AM, Huynh HQ, Dieleman LA, Panaccione R, Steinhart AH, Silverberg MS, Aumais G, Jacobson K, Mack D, Murthy SK, Marshall JK, Bernstein CN, Abreu MT, Moayyedi P, Paterson AD, Xu W, and Croitoru K
- Subjects
- Bacteria, Diet adverse effects, Feces microbiology, Humans, Inflammation, Leukocyte L1 Antigen Complex analysis, Crohn Disease diagnosis, Crohn Disease microbiology, Diet, Mediterranean, Gastrointestinal Microbiome genetics
- Abstract
Background & Aims: Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD., Methods: As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters., Results: DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota., Conclusions: Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases., (Copyright © 2022 AGA Institute. All rights reserved.)
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- 2022
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44. Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.
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Lee SH, Turpin W, Espin-Garcia O, Raygoza Garay JA, Smith MI, Leibovitzh H, Goethel A, Turner D, Mack D, Deslandres C, Cino M, Aumais G, Panaccione R, Jacobson K, Bitton A, Steinhart AH, Huynh HQ, Princen F, Moayyedi P, Griffiths AM, Silverberg MS, Paterson AD, Xu W, and Croitoru K
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- Adolescent, Adult, Asymptomatic Diseases, Biomarkers blood, Case-Control Studies, Child, Crohn Disease blood, Crohn Disease genetics, Crohn Disease microbiology, Female, Genetic Predisposition to Disease, Host-Pathogen Interactions, Humans, Inflammation Mediators blood, Israel, Male, Mediation Analysis, North America, Permeability, Prospective Studies, Risk Assessment, Risk Factors, Young Adult, Antibodies, Bacterial blood, Antigens, Bacterial immunology, C-Reactive Protein analysis, Crohn Disease immunology, Intestinal Mucosa metabolism
- Abstract
Background and Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development., Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis., Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation., Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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45. Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.
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Turpin W, Bedrani L, Espin-Garcia O, Xu W, Silverberg MS, Smith MI, Garay JAR, Lee SH, Guttman DS, Griffiths A, Moayyedi P, Panaccione R, Huynh H, Steinhart HA, Aumais G, Dieleman LA, Turner D, Paterson AD, and Croitoru K
- Subjects
- Adolescent, Adult, Alleles, Child, Cohort Studies, Crohn Disease diagnosis, Crohn Disease microbiology, Family, Female, Firmicutes classification, Firmicutes genetics, Gene Frequency, Genotype, Humans, Male, Microbiota genetics, Microbiota physiology, Young Adult, Crohn Disease genetics, Feces microbiology, Firmicutes physiology, Genetic Predisposition to Disease genetics, Nod2 Signaling Adaptor Protein genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset., Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals., Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae., Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
- Published
- 2020
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46. Jejunal Wall Thickening and Ulceration in a Patient With Amyloid Light-chain (AL) Amyloidosis.
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Drory SB, Boileau M, Urena Campos SR, Ferreira J, Rioux LC, Trépanier JS, and Aumais G
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- 2020
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47. FUT2 genotype and secretory status are not associated with fecal microbial composition and inferred function in healthy subjects.
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Turpin W, Bedrani L, Espin-Garcia O, Xu W, Silverberg MS, Smith MI, Guttman DS, Griffiths A, Moayyedi P, Panaccione R, Huynh H, Steinhart H, Aumais G, Shestopaloff K, Dieleman LA, Turner D, Paterson AD, and Croitoru K
- Subjects
- Adolescent, Adult, Bacteria classification, Bacteria genetics, Cohort Studies, Female, Fucosyltransferases metabolism, Genotype, Healthy Volunteers, Humans, Male, Phenotype, Polymorphism, Single Nucleotide, Young Adult, Galactoside 2-alpha-L-fucosyltransferase, Bacteria isolation & purification, Feces microbiology, Fucosyltransferases genetics, Gastrointestinal Microbiome
- Abstract
Heritability analysis of the microbiota has demonstrated the importance of host genotype in defining the human microbiota. The alpha (1,2)-fucosyltransferase 2 encoded by FUT2 is involved in the formation of the H antigen and the SNP, rs601338 is associated with ABO histo-blood group antigen secretion in the intestinal mucosa. Previous studies have provided non replicated results for the association of this polymorphism with the composition and inferred function of intestinal microbiota. We aimed to assess this relationship in a large cohort of 1,190 healthy individuals. Genotyping was performed using the HumanCoreEXOME chip, microbial composition was addressed by 16S rRNA gene sequencing. Firmicutes, Bacteroidetes, and Actinobacteria were the dominant phyla in this cohort. Although we have sufficient power to detect significant associations of FUT2 genotype/ inferred phenotype with the microbiota, our data demonstrate that FUT2 genotype and secretor status is not associated with microbial alpha diversity, microbial composition or inferred microbial function after correction for multiple testing. Thus, FUT2 genotype and inferred phenotype are not associated with human fecal microbial composition and imputed function.
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- 2018
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48. Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation.
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Stern S, Ward AJ, Saint-Laurent Thibault C, Camacho F, Rahme E, Naessens D, Aumais G, Bernard EJ, Bourdages R, Cohen A, Pare P, and Dyrda P
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- Antibodies, Monoclonal therapeutic use, Colitis, Ulcerative diagnosis, Colitis, Ulcerative economics, Female, Humans, Male, Markov Chains, Models, Economic, Quebec, Severity of Illness Index, Antibodies, Monoclonal economics, Colitis, Ulcerative drug therapy, Cost-Benefit Analysis, Health Care Costs
- Abstract
Objective: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada)., Methods: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs)., Results: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY., Limitations: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze., Conclusion: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000-$100,000 per QALY.
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- 2018
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49. A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.
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Li D, Achkar JP, Haritunians T, Jacobs JP, Hui KY, D'Amato M, Brand S, Radford-Smith G, Halfvarson J, Niess JH, Kugathasan S, Büning C, Schumm LP, Klei L, Ananthakrishnan A, Aumais G, Baidoo L, Dubinsky M, Fiocchi C, Glas J, Milgrom R, Proctor DD, Regueiro M, Simms LA, Stempak JM, Targan SR, Törkvist L, Sharma Y, Devlin B, Borneman J, Hakonarson H, Xavier RJ, Daly M, Brant SR, Rioux JD, Silverberg MS, Cho JH, Braun J, McGovern DP, and Duerr RH
- Subjects
- Alleles, Case-Control Studies, Colitis, Ulcerative microbiology, Crohn Disease microbiology, Female, Genetic Pleiotropy, Genotype, Humans, Male, Risk Factors, Cation Transport Proteins genetics, Colitis, Ulcerative genetics, Crohn Disease genetics, Gastrointestinal Microbiome genetics, Mutation, Missense
- Abstract
Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA)., Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing., Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16))., Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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50. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease.
- Author
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Fedorak RN, Feagan BG, Hotte N, Leddin D, Dieleman LA, Petrunia DM, Enns R, Bitton A, Chiba N, Paré P, Rostom A, Marshall J, Depew W, Bernstein CN, Panaccione R, Aumais G, Steinhart AH, Cockeram A, Bailey RJ, Gionchetti P, Wong C, and Madsen K
- Subjects
- Adult, Biopsy, Colonoscopy, Crohn Disease surgery, Cytokines analysis, Double-Blind Method, Female, Humans, Ileum pathology, Immunoglobulin Light Chains, Surrogate, Male, Middle Aged, Placebos administration & dosage, Recurrence, Treatment Outcome, Anti-Inflammatory Agents administration & dosage, Crohn Disease prevention & control, Probiotics administration & dosage
- Abstract
Background & Aims: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial., Methods: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90., Results: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups., Conclusions: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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