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2. Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment

Author

Abu-Shawareb, H, Acree, R, Adams, P, Adams, J, Addis, B, Aden, R, Adrian, P, Afeyan, BB, Aggleton, M, Aghaian, L, Aguirre, A, Aikens, D, Akre, J, Albert, F, Albrecht, M, Albright, BJ, Albritton, J, Alcala, J, Alday, C, Alessi, DA, Alexander, N, Alfonso, J, Alfonso, N, Alger, E, Ali, SJ, Ali, ZA, Alley, WE, Amala, P, Amendt, PA, Amick, P, Ammula, S, Amorin, C, Ampleford, DJ, Anderson, RW, Anklam, T, Antipa, N, Appelbe, B, Aracne-Ruddle, C, Araya, E, Arend, M, Arnold, P, Arnold, T, Asay, J, Atherton, LJ, Atkinson, D, Atkinson, R, Auerbach, JM, Austin, B, Auyang, L, Awwal, AS, Ayers, J, Ayers, S, Ayers, T, Azevedo, S, Bachmann, B, Back, CA, Bae, J, Bailey, DS, Bailey, J, Baisden, T, Baker, KL, Baldis, H, Barber, D, Barberis, M, Barker, D, Barnes, A, Barnes, CW, Barrios, MA, Barty, C, Bass, I, Batha, SH, Baxamusa, SH, Bazan, G, Beagle, JK, Beale, R, Beck, BR, Beck, JB, Bedzyk, M, Beeler, RG, Behrendt, W, Belk, L, Bell, P, Belyaev, M, Benage, JF, Bennett, G, Benedetti, LR, Benedict, LX, Berger, R, Bernat, T, Bernstein, LA, Berry, B, Bertolini, L, Besenbruch, G, Betcher, J, Bettenhausen, R, Betti, R, Bezzerides, B, Bhandarkar, SD, Bickel, R, Biener, J, Biesiada, T, Bigelow, K, Bigelow-Granillo, J, Bigman, V, Bionta, RM, Birge, NW, Bitter, M, Black, AC, Bleile, R, Bleuel, DL, Bliss, E, Blue, B, Boehly, T, Boehm, K, Boley, CD, Bonanno, R, Bond, EJ, Bond, T, Bonino, MJ, Borden, M, Bourgade, J-L, Bousquet, J, Bowers, J, Bowers, M, Boyd, R, Bozek, A, Bradley, DK, Bradley, KS, Bradley, PA, Bradley, L, Brannon, L, Brantley, PS, Braun, D, Braun, T, Brienza-Larsen, K, Briggs, TM, Britten, J, Brooks, ED, Browning, D, Bruhn, MW, Brunner, TA, Bruns, H, Brunton, G, Bryant, B, Buczek, T, Bude, J, Buitano, L, Burkhart, S, Burmark, J, Burnham, A, Burr, R, Busby, LE, Butlin, B, Cabeltis, R, Cable, M, Cabot, WH, Cagadas, B, Caggiano, J, Cahayag, R, Caldwell, SE, Calkins, S, Callahan, DA, Calleja-Aguirre, J, Camara, L, Camp, D, Campbell, EM, Campbell, JH, Carey, B, Carey, R, Carlisle, K, Carlson, L, Carman, L, Carmichael, J, Carpenter, A, Carr, C, Carrera, JA, Casavant, D, Casey, A, Casey, DT, Castillo, A, Castillo, E, Castor, JI, Castro, C, Caughey, W, Cavitt, R, Celeste, J, Celliers, PM, Cerjan, C, Chandler, G, Chang, B, Chang, C, Chang, J, Chang, L, Chapman, R, Chapman, T, Chase, L, Chen, H, Chen, K, Chen, L-Y, Cheng, B, Chittenden, J, Choate, C, Chou, J, Chrien, RE, Chrisp, M, Christensen, K, Christensen, M, Christopherson, AR, Chung, M, Church, JA, Clark, A, Clark, DS, Clark, K, Clark, R, Claus, L, Cline, B, Cline, JA, Cobble, JA, Cochrane, K, Cohen, B, Cohen, S, Collette, MR, Collins, G, Collins, LA, Collins, TJB, Conder, A, Conrad, B, Conyers, M, Cook, AW, Cook, D, Cook, R, Cooley, JC, Cooper, G, Cope, T, Copeland, SR, Coppari, F, Cortez, J, Cox, J, Crandall, DH, Crane, J, Craxton, RS, Cray, M, Crilly, A, Crippen, JW, Cross, D, Cuneo, M, Cuotts, G, Czajka, CE, Czechowicz, D, Daly, T, Danforth, P, Darbee, R, Darlington, B, Datte, P, Dauffy, L, Davalos, G, Davidovits, S, Davis, P, Davis, J, Dawson, S, Day, RD, Day, TH, Dayton, M, Deck, C, Decker, C, Deeney, C, DeFriend, KA, Deis, G, Delamater, ND, Delettrez, JA, Demaret, R, Demos, S, Dempsey, SM, Desjardin, R, Desjardins, T, Desjarlais, MP, Dewald, EL, DeYoreo, J, Diaz, S, Dimonte, G, Dittrich, TR, Divol, L, Dixit, SN, Dixon, J, Dodd, ES, Dolan, D, Donovan, A, Donovan, M, Döppner, T, Dorrer, C, Dorsano, N, Douglas, MR, Dow, D, Downie, J, Downing, E, Dozieres, M, Draggoo, V, Drake, D, Drake, RP, Drake, T, Dreifuerst, G, DuBois, DF, DuBois, PF, Dunham, G, Dylla-Spears, R, Dymoke-Bradshaw, AKL, Dzenitis, B, Ebbers, C, Eckart, M, Eddinger, S, Eder, D, Edgell, D, Edwards, MJ, Efthimion, P, Eggert, JH, Ehrlich, B, Ehrmann, P, Elhadj, S, Ellerbee, C, Elliott, NS, Ellison, CL, Elsner, F, Emerich, M, Engelhorn, K, England, T, English, E, Epperson, P, Epstein, R, Erbert, G, Erickson, MA, Erskine, DJ, Erlandson, A, Espinosa, RJ, Estes, C, Estabrook, KG, Evans, S, Fabyan, A, Fair, J, Fallejo, R, Farmer, N, Farmer, WA, Farrell, M, Fatherley, VE, Fedorov, M, Feigenbaum, E, Feit, M, Ferguson, W, Fernandez, JC, Fernandez-Panella, A, Fess, S, Field, JE, Filip, CV, Fincke, JR, Finn, T, Finnegan, SM, Finucane, RG, Fischer, M, Fisher, A, Fisher, J, Fishler, B, Fittinghoff, D, Fitzsimmons, P, Flegel, M, Flippo, KA, Florio, J, Folta, J, Folta, P, Foreman, LR, Forrest, C, Forsman, A, Fooks, J, Foord, M, Fortner, R, Fournier, K, Fratanduono, DE, Frazier, N, Frazier, T, Frederick, C, Freeman, MS, Frenje, J, Frey, D, Frieders, G, Friedrich, S, Froula, DH, Fry, J, Fuller, T, Gaffney, J, Gales, S, Le Galloudec, B, Le Galloudec, KK, Gambhir, A, Gao, L, Garbett, WJ, Garcia, A, Gates, C, Gaut, E, Gauthier, P, Gavin, Z, Gaylord, J, Geissel, M, Génin, F, Georgeson, J, Geppert-Kleinrath, H, Geppert-Kleinrath, V, Gharibyan, N, Gibson, J, Gibson, C, Giraldez, E, Glebov, V, Glendinning, SG, Glenn, S, Glenzer, SH, Goade, S, Gobby, PL, Goldman, SR, Golick, B, Gomez, M, Goncharov, V, Goodin, D, Grabowski, P, Grafil, E, Graham, P, Grandy, J, Grasz, E, Graziani, F, Greenman, G, Greenough, JA, Greenwood, A, Gregori, G, Green, T, Griego, JR, Grim, GP, Grondalski, J, Gross, S, Guckian, J, Guler, N, Gunney, B, Guss, G, Haan, S, Hackbarth, J, Hackel, L, Hackel, R, Haefner, C, Hagmann, C, Hahn, KD, Hahn, S, Haid, BJ, Haines, BM, Hall, BM, Hall, C, Hall, GN, Hamamoto, M, Hamel, S, Hamilton, CE, Hammel, BA, Hammer, JH, Hampton, G, Hamza, A, Handler, A, Hansen, S, Hanson, D, Haque, R, Harding, D, Harding, E, Hares, JD, Harris, DB, Harte, JA, Hartouni, EP, Hatarik, R, Hatchett, S, Hauer, AA, Havre, M, Hawley, R, Hayes, J, Hayes, S, Hayes-Sterbenz, A, Haynam, CA, Haynes, DA, Headley, D, Heal, A, Heebner, JE, Heerey, S, Heestand, GM, Heeter, R, Hein, N, Heinbockel, C, Hendricks, C, Henesian, M, Heninger, J, Henrikson, J, Henry, EA, Herbold, EB, Hermann, MR, Hermes, G, Hernandez, JE, Hernandez, VJ, Herrmann, MC, Herrmann, HW, Herrera, OD, Hewett, D, Hibbard, R, Hicks, DG, Hill, D, Hill, K, Hilsabeck, T, Hinkel, DE, Ho, DD, Ho, VK, Hoffer, JK, Hoffman, NM, Hohenberger, M, Hohensee, M, Hoke, W, Holdener, D, Holdener, F, Holder, JP, Holko, B, Holunga, D, Holzrichter, JF, Honig, J, Hoover, D, Hopkins, D, Berzak Hopkins, L, Hoppe, M, Hoppe, ML, Horner, J, Hornung, R, Horsfield, CJ, Horvath, J, Hotaling, D, House, R, Howell, L, Hsing, WW, Hu, SX, Huang, H, Huckins, J, Hui, H, Humbird, KD, Hund, J, Hunt, J, Hurricane, OA, Hutton, M, Huynh, KH-K, Inandan, L, Iglesias, C, Igumenshchev, IV, Izumi, N, Jackson, M, Jackson, J, Jacobs, SD, James, G, Jancaitis, K, Jarboe, J, Jarrott, LC, Jasion, D, Jaquez, J, Jeet, J, Jenei, AE, Jensen, J, Jimenez, J, Jimenez, R, Jobe, D, Johal, Z, Johns, HM, Johnson, D, Johnson, MA, Gatu Johnson, M, Johnson, RJ, Johnson, S, Johnson, SA, Johnson, T, Jones, K, Jones, O, Jones, M, Jorge, R, Jorgenson, HJ, Julian, M, Jun, BI, Jungquist, R, Kaae, J, Kabadi, N, Kaczala, D, Kalantar, D, Kangas, K, Karasiev, VV, Karasik, M, Karpenko, V, Kasarky, A, Kasper, K, Kauffman, R, Kaufman, MI, Keane, C, Keaty, L, Kegelmeyer, L, Keiter, PA, Kellett, PA, Kellogg, J, Kelly, JH, Kemic, S, Kemp, AJ, Kemp, GE, Kerbel, GD, Kershaw, D, Kerr, SM, Kessler, TJ, Key, MH, Khan, SF, Khater, H, Kiikka, C, Kilkenny, J, Kim, Y, Kim, Y-J, Kimko, J, Kimmel, M, Kindel, JM, King, J, Kirkwood, RK, Klaus, L, Klem, D, Kline, JL, Klingmann, J, Kluth, G, Knapp, P, Knauer, J, Knipping, J, Knudson, M, Kobs, D, Koch, J, Kohut, T, Kong, C, Koning, JM, Koning, P, Konior, S, Kornblum, H, Kot, LB, Kozioziemski, B, Kozlowski, M, Kozlowski, PM, Krammen, J, Krasheninnikova, NS, Kraus, B, Krauser, W, Kress, JD, Kritcher, AL, Krieger, E, Kroll, JJ, Kruer, WL, Kruse, MKG, Kucheyev, S, Kumbera, M, Kumpan, S, Kunimune, J, Kustowski, B, Kwan, TJT, Kyrala, GA, Laffite, S, Lafon, M, LaFortune, K, Lahmann, B, Lairson, B, Landen, OL, Langenbrunner, J, Lagin, L, Land, T, Lane, M, Laney, D, Langdon, AB, Langer, SH, Langro, A, Lanier, NE, Lanier, TE, Larson, D, Lasinski, BF, Lassle, D, LaTray, D, Lau, G, Lau, N, Laumann, C, Laurence, A, Laurence, TA, Lawson, J, Le, HP, Leach, RR, Leal, L, Leatherland, A, LeChien, K, Lechleiter, B, Lee, A, Lee, M, Lee, T, Leeper, RJ, Lefebvre, E, Leidinger, J-P, LeMire, B, Lemke, RW, Lemos, NC, Le Pape, S, Lerche, R, Lerner, S, Letts, S, Levedahl, K, Lewis, T, Li, CK, Li, H, Li, J, Liao, W, Liao, ZM, Liedahl, D, Liebman, J, Lindford, G, Lindman, EL, Lindl, JD, Loey, H, London, RA, Long, F, Loomis, EN, Lopez, FE, Lopez, H, Losbanos, E, Loucks, S, Lowe-Webb, R, Lundgren, E, Ludwigsen, AP, Luo, R, Lusk, J, Lyons, R, Ma, T, Macallop, Y, MacDonald, MJ, MacGowan, BJ, Mack, JM, Mackinnon, AJ, MacLaren, SA, MacPhee, AG, Magelssen, GR, Magoon, J, Malone, RM, Malsbury, T, Managan, R, Mancini, R, Manes, K, Maney, D, Manha, D, Mannion, OM, Manuel, AM, Mapoles, E, Mara, G, Marcotte, T, Marin, E, Marinak, MM, Mariscal, C, Mariscal, DA, Mariscal, EF, Marley, EV, Marozas, JA, Marquez, R, Marshall, CD, Marshall, FJ, Marshall, M, Marshall, S, Marticorena, J, Martinez, D, Maslennikov, I, Mason, D, Mason, RJ, Masse, L, Massey, W, Masson-Laborde, P-E, Masters, ND, Mathisen, D, Mathison, E, Matone, J, Matthews, MJ, Mattoon, C, Mattsson, TR, Matzen, K, Mauche, CW, Mauldin, M, McAbee, T, McBurney, M, Mccarville, T, McCrory, RL, McEvoy, AM, McGuffey, C, Mcinnis, M, McKenty, P, McKinley, MS, McLeod, JB, McPherson, A, Mcquillan, B, Meamber, M, Meaney, KD, Meezan, NB, Meissner, R, Mehlhorn, TA, Mehta, NC, Menapace, J, Merrill, FE, Merritt, BT, Merritt, EC, Meyerhofer, DD, Mezyk, S, Mich, RJ, Michel, PA, Milam, D, Miller, C, Miller, D, Miller, DS, Miller, E, Miller, EK, Miller, J, Miller, M, Miller, PE, Miller, T, Miller, W, Miller-Kamm, V, Millot, M, Milovich, JL, Minner, P, Miquel, J-L, Mitchell, S, Molvig, K, Montesanti, RC, Montgomery, DS, Monticelli, M, Montoya, A, Moody, JD, Moore, AS, Moore, E, Moran, M, Moreno, JC, Moreno, K, Morgan, BE, Morrow, T, Morton, JW, Moses, E, Moy, K, Muir, R, Murillo, MS, Murray, JE, Murray, JR, Munro, DH, Murphy, TJ, Munteanu, FM, Nafziger, J, Nagayama, T, Nagel, SR, Nast, R, Negres, RA, Nelson, A, Nelson, D, Nelson, J, Nelson, S, Nemethy, S, Neumayer, P, Newman, K, Newton, M, Nguyen, H, Di Nicola, J-MG, Di Nicola, P, Niemann, C, Nikroo, A, Nilson, PM, Nobile, A, Noorai, V, Nora, R, Norton, M, Nostrand, M, Note, V, Novell, S, Nowak, PF, Nunez, A, Nyholm, RA, O'Brien, M, Oceguera, A, Oertel, JA, Okui, J, Olejniczak, B, Oliveira, J, Olsen, P, Olson, B, Olson, K, Olson, RE, Opachich, YP, Orsi, N, Orth, CD, Owen, M, Padalino, S, Padilla, E, Paguio, R, Paguio, S, Paisner, J, Pajoom, S, Pak, A, Palaniyappan, S, Palma, K, Pannell, T, Papp, F, Paras, D, Parham, T, Park, H-S, Pasternak, A, Patankar, S, Patel, MV, Patel, PK, Patterson, R, Patterson, S, Paul, B, Paul, M, Pauli, E, Pearce, OT, Pearcy, J, Pedrotti, B, Peer, A, Pelz, LJ, Penetrante, B, Penner, J, Perez, A, Perkins, LJ, Pernice, E, Perry, TS, Person, S, Petersen, D, Petersen, T, Peterson, DL, Peterson, EB, Peterson, JE, Peterson, JL, Peterson, K, Peterson, RR, Petrasso, RD, Philippe, F, Phipps, TJ, Piceno, E, Ping, Y, Pickworth, L, Pino, J, Plummer, R, Pollack, GD, Pollaine, SM, Pollock, BB, Ponce, D, Ponce, J, Pontelandolfo, J, Porter, JL, Post, J, Poujade, O, Powell, C, Powell, H, Power, G, Pozulp, M, Prantil, M, Prasad, M, Pratuch, S, Price, S, Primdahl, K, Prisbrey, S, Procassini, R, Pruyne, A, Pudliner, B, Qiu, SR, Quan, K, Quinn, M, Quintenz, J, Radha, PB, Rainer, F, Ralph, JE, Raman, KS, Raman, R, Rambo, P, Rana, S, Randewich, A, Rardin, D, Ratledge, M, Ravelo, N, Ravizza, F, Rayce, M, Raymond, A, Raymond, B, Reed, B, Reed, C, Regan, S, Reichelt, B, Reis, V, Reisdorf, S, Rekow, V, Remington, BA, Rendon, A, Requieron, W, Rever, M, Reynolds, H, Reynolds, J, Rhodes, J, Rhodes, M, Richardson, MC, Rice, B, Rice, NG, Rieben, R, Rigatti, A, Riggs, S, Rinderknecht, HG, Ring, K, Riordan, B, Riquier, R, Rivers, C, Roberts, D, Roberts, V, Robertson, G, Robey, HF, Robles, J, Rocha, P, Rochau, G, Rodriguez, J, Rodriguez, S, Rosen, M, Rosenberg, M, Ross, G, Ross, JS, Ross, P, Rouse, J, Rovang, D, Rubenchik, AM, Rubery, MS, Ruiz, CL, Rushford, M, Russ, B, Rygg, JR, Ryujin, BS, Sacks, RA, Sacks, RF, Saito, K, Salmon, T, Salmonson, JD, Sanchez, J, Samuelson, S, Sanchez, M, Sangster, C, Saroyan, A, Sater, J, Satsangi, A, Sauers, S, Saunders, R, Sauppe, JP, Sawicki, R, Sayre, D, Scanlan, M, Schaffers, K, Schappert, GT, Schiaffino, S, Schlossberg, DJ, Schmidt, DW, Schmitt, MJ, Schneider, DHG, Schneider, MB, Schneider, R, Schoff, M, Schollmeier, M, Schölmerich, M, Schroeder, CR, Schrauth, SE, Scott, HA, Scott, I, Scott, JM, Scott, RHH, Scullard, CR, Sedillo, T, Seguin, FH, Seka, W, Senecal, J, Sepke, SM, Seppala, L, Sequoia, K, Severyn, J, Sevier, JM, Sewell, N, Seznec, S, Shah, RC, Shamlian, J, Shaughnessy, D, Shaw, M, Shaw, R, Shearer, C, Shelton, R, Shen, N, Sherlock, MW, Shestakov, AI, Shi, EL, Shin, SJ, Shingleton, N, Shmayda, W, Shor, M, Shoup, M, Shuldberg, C, Siegel, L, Silva, FJ, Simakov, AN, Sims, BT, Sinars, D, Singh, P, Sio, H, Skulina, K, Skupsky, S, Slutz, S, Sluyter, M, Smalyuk, VA, Smauley, D, Smeltser, RM, Smith, C, Smith, I, Smith, J, Smith, L, Smith, R, Sohn, R, Sommer, S, Sorce, C, Sorem, M, Soures, JM, Spaeth, ML, Spears, BK, Speas, S, Speck, D, Speck, R, Spears, J, Spinka, T, Springer, PT, Stadermann, M, Stahl, B, Stahoviak, J, Stanton, LG, Steele, R, Steele, W, Steinman, D, Stemke, R, Stephens, R, Sterbenz, S, Sterne, P, Stevens, D, Stevers, J, Still, CB, Stoeckl, C, Stoeffl, W, Stolken, JS, Stolz, C, Storm, E, Stone, G, Stoupin, S, Stout, E, Stowers, I, Strauser, R, Streckart, H, Streit, J, Strozzi, DJ, Suratwala, T, Sutcliffe, G, Suter, LJ, Sutton, SB, Svidzinski, V, Swadling, G, Sweet, W, Szoke, A, Tabak, M, Takagi, M, Tambazidis, A, Tang, V, Taranowski, M, Taylor, LA, Telford, S, Theobald, W, Thi, M, Thomas, A, Thomas, CA, Thomas, I, Thomas, R, Thompson, IJ, Thongstisubskul, A, Thorsness, CB, Tietbohl, G, Tipton, RE, Tobin, M, Tomlin, N, Tommasini, R, Toreja, AJ, Torres, J, Town, RPJ, Townsend, S, Trenholme, J, Trivelpiece, A, Trosseille, C, Truax, H, Trummer, D, Trummer, S, Truong, T, Tubbs, D, Tubman, ER, Tunnell, T, Turnbull, D, Turner, RE, Ulitsky, M, Upadhye, R, Vaher, JL, VanArsdall, P, VanBlarcom, D, Vandenboomgaerde, M, VanQuinlan, R, Van Wonterghem, BM, Varnum, WS, Velikovich, AL, Vella, A, Verdon, CP, Vermillion, B, Vernon, S, Vesey, R, Vickers, J, Vignes, RM, Visosky, M, Vocke, J, Volegov, PL, Vonhof, S, Von Rotz, R, Vu, HX, Vu, M, Wall, D, Wall, J, Wallace, R, Wallin, B, Walmer, D, Walsh, CA, Walters, CF, Waltz, C, Wan, A, Wang, A, Wang, Y, Wark, JS, Warner, BE, Watson, J, Watt, RG, Watts, P, Weaver, J, Weaver, RP, Weaver, S, Weber, CR, Weber, P, Weber, SV, Wegner, P, Welday, B, Welser-Sherrill, L, Weiss, K, Widmann, K, Wheeler, GF, Whistler, W, White, RK, Whitley, HD, Whitman, P, Wickett, ME, Widmayer, C, Wiedwald, J, Wilcox, R, Wilcox, S, Wild, C, Wilde, BH, Wilde, CH, Wilhelmsen, K, Wilke, MD, Wilkens, H, Wilkins, P, Wilks, SC, Williams, EA, Williams, GJ, Williams, W, Williams, WH, Wilson, DC, Wilson, B, Wilson, E, Wilson, R, Winters, S, Wisoff, J, Wittman, M, Wolfe, J, Wong, A, Wong, KW, Wong, L, Wong, N, Wood, R, Woodhouse, D, Woodruff, J, Woods, DT, Woods, S, Woodworth, BN, Wooten, E, Wootton, A, Work, K, Workman, JB, Wright, J, Wu, M, Wuest, C, Wysocki, FJ, Xu, H, Yamaguchi, M, Yang, B, Yang, ST, Yatabe, J, Yeamans, CB, Yee, BC, Yi, SA, Yin, L, Young, B, Young, CS, Young, CV, Young, P, Youngblood, K, Zacharias, R, Zagaris, G, Zaitseva, N, Zaka, F, Ze, F, Zeiger, B, Zika, M, Zimmerman, GB, Zobrist, T, Zuegel, JD, Zylstra, AB, Indirect Drive ICF Collaboration, Collaboration, Indirect Drive ICF, AWE Plc, Lawrence Livermore National Laboratory, and U.S Department of Energy

Subjects
General Physics, 02 Physical Sciences, General Physics and Astronomy, Indirect Drive ICF Collaboration, 01 Mathematical Sciences, 09 Engineering
Abstract

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Published
2022

3. Thromboprophylaxis use in paediatric inflammatory bowel disease: an international RAND appropriateness panel

Author

Torrente F, Meade S, Benchimol EI, de Ridder L, Croft NM, Kammermeier J, Mack DR, Klomberg RCW, Turner D, Wilson DC, Martín-de-Carpi J, Bronsky J, Dias JA, Walker G, van Ommen CH, Powar MP, Burgess N, Irving PM, Samaan MA, and Hansen R

Subjects
inflammatory bowel disease, Paediatric gastroenterology, ulcerative colitis
Abstract

BACKGROUND AND AIMS: Thromboprophylaxis use in paediatric inflammatory bowel disease (IBD) is inconsistent. Current guidelines only support treating children with acute severe colitis with risk factors. We convened an international RAND panel to explore thromboprophylaxis in paediatric IBD inpatients in the context of new evidence. METHODS: We convened a geographically diverse 14-person panel of paediatric gastroenterologists alongside supporting experts. An online survey was sent before an online meeting. Panellists were asked to rate the appropriateness of thromboprophylaxis in hospitalised paediatric IBD patients via 27 scenarios of varying ages, gender, and phenotype, with and without thrombotic risk factors. Anonymised results were presented at the meeting. A second modified survey was distributed to all panellists present at the meeting. Results from the second survey constitute the RAND panel results. The validated RAND disagreement index defined disagreement when =1. RESULTS: The combined outcome of thromboprophylaxis being considered appropriate until discharge and inappropriate to withhold was seen in 20 of 27 scenarios, including all patients with new-onset acute severe colitis; all flares of known ulcerative colitis, irrespective of risk factors except pre-pubescent patients with limited disease and no risk factors; and all Crohn's patients with risk factors. Disagreement was seen in 5 scenarios regarding Crohn's without risk factors where outcomes were already uncertain. CONCLUSIONS: RAND panels are an established method to assess expert opinion in areas of limited evidence. This work therefore constitutes neither a guideline nor a consensus; however, the findings suggest a need to re-evaluate the role of thromboprophylaxis in future guidelines.

Published
2022

9. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease

Author

Uhlig, H, Charbit-Henrion, F, Kotlarz, D, Shouval, D, Schwerd, T, Strisciuglio, C, de Ridder, L, van Limbergen, J, Macchia, L, Snapper, SB, Rummele, FM, Wilson, DC, Travis, SPL, Griffiths, AM, Turner, D, Klein, C, Muise, AM, Russell, RK, and ESPGHAN, Paediatric IBD Porto Group of

Abstract

Background: It is important to identify patients with monogenic IBD since management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. Methods: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). Results: We recommend next-generation DNA sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD onset (infantile IBD, very early onset IBD, paediatric or young adult IBD) and further criteria such as family history, relevant comorbidities and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We develop a diagnostic algorithm that includes a gene panel of seventy-five monogenic IBD genes. Considerations are provided also for low resource countries. Summary: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Published
2021

10. Predicting Outcomes in Pediatric Ulcerative Colitis for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program

Author

Meyer EO, Aardoom M, Ricciuto A, Navon D, Carman N, Aloi M, Bronsky J, Däbritz J, Dubinsky M, Hussey S, Lewindon P, Martín-de-Carpi J, Navas-López VM, Orsi M, Ruemmele FM, Russell RK, Veres G, Walters TD, Wilson DC, Kaiser T, de Ridder L, Griffiths A, and Turner D

Subjects
Prognostic Factors, Acute Severe Colitis, Mortality, Prediction, Colectomy, Pediatric Ulcerative Colitis, Cancer
Abstract

BACKGROUND & AIMS: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms. METHODS: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements. RESULTS: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P 10 years), male sex, and younger age at diagnosis. CONCLUSIONS: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC.

Published
2021

11. Predicting Outcomes in Pediatric Crohn's Disease for Management Optimization: Systematic Review and Consensus Statements From the Pediatric Inflammatory Bowel Disease-Ahead Program

Author

Ricciuto A, Aardoom M, Meyer EO, Navon D, Carman N, Aloi M, Bronsky J, Däbritz J, Dubinsky M, Hussey S, Lewindon P, Martín-de-Carpi J, Navas-López VM, Orsi M, Ruemmele FM, Russell RK, Veres G, Walters TD, Wilson DC, Kaiser T, de Ridder L, Turner D, Griffiths AM, and Pediatric Inflammatory Bowel Disease (PIBD) Ahead Steering Committee

Subjects
NOD2/CARD15, Serology, Complications, Prognostic Factors, ASCA, Structuring or Penetrating Disease, Growth Impairment, Polymorphism
Abstract

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: Asurvey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

Published
2021

20. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

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

Subjects
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.

Published
2018

21. The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study

Author

Saeed, K, Wilson, DC, Bloos, F, Schuetz, P, Does, Yuri, Melander, O, Hausfater, P, Legramante, JM, Claessens, YE, Amin, D, Rosenqvist, M, White, G, Mueller, B, Limper, M, Callejo, CC, Brandi, A, Macchi, MA, Cortes, N, Kutz, A, Patka, Petr, Yanez, MC, Bernardini, S, Beau, N, Dryden, M, van Gorp, Eric, Minieri, M, Chan, L, Rood, Pleunie, del Castillo, JG, Saeed, K, Wilson, DC, Bloos, F, Schuetz, P, Does, Yuri, Melander, O, Hausfater, P, Legramante, JM, Claessens, YE, Amin, D, Rosenqvist, M, White, G, Mueller, B, Limper, M, Callejo, CC, Brandi, A, Macchi, MA, Cortes, N, Kutz, A, Patka, Petr, Yanez, MC, Bernardini, S, Beau, N, Dryden, M, van Gorp, Eric, Minieri, M, Chan, L, Rood, Pleunie, and del Castillo, JG

Published
2019

22. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, WGS500 Consortium, Oxford IBD cohort study investigators, COLORS in IBD group investigators, UK IBD Genetics Consortium, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, INTERVAL Study, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, D Pb, Cho, J, Powrie, F, Li, V Sw, Muise, AM, Uhlig, HH, Parkes, Miles [0000-0002-6467-0631], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Male, Genes, Modifier, Genome, Genotype, Colon, Mutation, Missense, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, digestive system diseases, Mice, Inbred C57BL, Mice, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Animals, Humans, Genetic Predisposition to Disease, Child, Reactive Oxygen Species, Genetic Association Studies
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
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23. Real-Life Anti-Tumour Necrosis Factor Experience in > 500 Paediatric United Kingdom Inflammatory Bowel Disease Patients

Author

Merrick, VM, Mortier, K, Williams, LJ, Muhammed, R, Auth, MK, Elawad, M, Fell, JM, Beattie, RM, Loganathan, S, Torrente, F, Morris, M-A, Charlton, C, Croft, NM, Rodrigues, A, Furman, M, Vadamalayan, B, Jenkins, H, Zamvar, V, Mitton, SG, Chong, S, Cosgrove, M, Akobeng, A, Wilson, DC, and Russell, RK

Abstract

OBJECTIVES: To measure the effectiveness, safety and use of anti-Tumour necrosis Factor (TNF) therapy in paediatric inflammatory bowel disease (PIBD) in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment (PGA) +/or the Paediatric Crohn's Disease Activity Index (PCDAI). RESULTS: 37 centres participated (23 of 25 specialist PIBD sites). 524 patients were included; 429 Crohn's disease (CD), 76 ulcerative colitis (UC), 19 IBD unclassified (IBDU). 87% (488/562) anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (IQR 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by PGA compared to 41% (88/217) by PCDAI; Kappa (Κ) 0.28 = only 'fair agreement' (p

Published
2018

24. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at $\textit{ADCY7}$

Author

Luo, Y, de Lange, KM, Jostins, L, Moutsianas, L, Randall, J, Kennedy, NA, Lamb, CA, McCarthy, S, Ahmad, T, Edwards, C, Serra, EG, Hart, A, Hawkey, C, Mansfield, JC, Mowat, C, Newman, WG, Nichols, S, Pollard, M, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, DC, Lee, JC, Prescott, NJ, Lees, CW, Mathew, CG, Parkes, M, Barrett, JC, Anderson, CA, McCarthy, Shane [0000-0002-2715-4187], Lee, James [0000-0001-5711-9385], Parkes, Miles [0000-0002-6467-0631], and Apollo - University of Cambridge Repository

Subjects
inflammatory bowel disease, genetic association study, DNA sequencing
Abstract

To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn’s disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in $\textit{ADCY7}$ that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn’s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

Published
2017
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25. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Author

De Lange, KM, Moutsianas, L, Lee, JC, Lamb, CA, Luo, Y, Kennedy, NA, Jostins, L, Rice, DL, Gutierrez-Achury, J, Ji, S-G, Heap, G, Nimmo, ER, Edwards, C, Henderson, P, Mowat, C, Sanderson, J, Satsangi, J, Simmons, A, Wilson, DC, Tremelling, M, Hart, A, Mathew, CG, Newman, WG, Parkes, M, Lees, CW, Uhlig, H, Hawkey, C, Prescott, NJ, Ahmad, T, Mansfield, JC, Anderson, CA, and Barrett, JC

Subjects
Inflammation, Integrins, Quantitative Trait Loci, Humans, Genetic Predisposition to Disease, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, Alleles, Genome-Wide Association Study
Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Published
2017
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26. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease

Author

Lee, JC, Biasci, D, Roberts, R, Gearry, RB, Mansfield, JC, Ahmad, T, Prescott, NJ, Satsangi, J, Wilson, DC, Jostins, L, Anderson, CA, UK IBD Genetics Consortium, Traherne, JA, Lyons, PA, Parkes, M, Smith, KGC, Lee, James [0000-0001-5711-9385], Biasci, Daniele [0000-0003-3148-8152], Traherne, James [0000-0002-6003-8559], Lyons, Paul [0000-0001-7035-8997], Parkes, Miles [0000-0002-6467-0631], Smith, Kenneth [0000-0003-3829-4326], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Genotype, Genome-wide association study, Disease, Biology, Bioinformatics, Inflammatory bowel disease, Polymorphism, Single Nucleotide, Article, outcomes research, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Polymorphism (computer science), inflammatory bowel disease, Genetic variation, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Crohn's disease, Genome, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, genome-wide association studies, 030211 gastroenterology & hepatology, Female, Colitis, Ulcerative, Disease Susceptibility, Outcomes research, Genome-Wide Association Study
Abstract

For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis)1,2,3. Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis4,5,6, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants7,8,9,10,11,12,13. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.

Published
2017
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27. Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN

Author

Amil-Dias J, Kolacek S, Turner D, Pærregaard A, Rintala R, Afzal NA, Karolewska-Bochenek K, Bronsky J, Chong S, Fell J, Hojsak I, Hugot JP, Koletzko S, Kumar D, Lazowska-Przeorek I, Lillehei C, Lionetti P, Martín-de-Carpi J, Pakarinen M, Ruemmele FM, Shaoul R, Spray C, Staiano A, Sugarman I, Wilson DC, Winter H, Kolho KL, and IBD Working Group of ESPGHAN (IBD Porto Group)

Subjects
surgery, biologicals, complications, treatment, inflammatory bowel disease, Crohn disease
Abstract

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

Published
2017

28. Global Waste Management Outlook

Author

Wilson, DC, Rodic, L, Modak, P, Soos, R, Carpintero, A, Velis, K, Iyer, M, Simonett, O, and Wilson, DC

Abstract

The Global Waste Management Outlook, a collective effort of the United Nations Environment Programme and the International Waste Management Association, is a pioneering scientific global assessment on the state of waste management and a call for action to the international community. Prepared as a follow up to the Rio+20 Summit and as a response to UNEP Governing Council decision GC 27/12, the document establishes the rationale and the tools for taking a holistic approach towards waste management and recognizing waste and resource management as a significant contributor to sustainable development and climate change mitigation. To complement the Sustainable Development Goals of the Post-2015 Development Agenda, the Outlook sets forth Global Waste Management Goals and a Global Call to Action to achieve those goals.

Published
2015

30. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, primary, Bryant, RV, additional, Pandey, S, additional, Capitani, M, additional, Meran, L, additional, Cazier, J-B, additional, Jung, J, additional, Mondal, K, additional, Parkes, M, additional, Mathew, CG, additional, Fiedler, K, additional, McCarthy, DJ, additional, Sullivan, PB, additional, Rodrigues, A, additional, Travis, SPL, additional, Moore, C, additional, Sambrook, J, additional, Ouwehand, WH, additional, Roberts, DJ, additional, Danesh, J, additional, Russell, RK, additional, Wilson, DC, additional, Kelsen, JR, additional, Cornall, R, additional, Denson, LA, additional, Kugathasan, S, additional, Knaus, UG, additional, Serra, EG, additional, Anderson, CA, additional, Duerr, RH, additional, McGovern, DPB, additional, Cho, J, additional, Powrie, F, additional, Li, VSW, additional, Muise, AM, additional, and Uhlig, HH, additional

Published
2018
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31. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes:a genetic association study

Author

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)

Subjects
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).

Published
2016

35. Genetic sharing and heritability of paediatric age of onset autoimmune diseases

Author

Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, Hakonarson, H, Li, YR, Zhao, SD, Li, J, Bradfield, JP, Mohebnasab, M, Steel, L, Kobie, J, Abrams, DJ, Mentch, FD, Glessner, JT, Guo, Y, Wei, Z, Connolly, JJ, Cardinale, CJ, Bakay, M, Li, D, Maggadottir, SM, Thomas, KA, Qui, H, Chiavacci, RM, Kim, CE, Wang, F, Snyder, J, Flato, B, Forre, O, Denson, LA, Thompson, SD, Becker, ML, Guthery, SL, Latiano, A, Perez, E, Resnick, E, Strisciuglio, C, Staiano, A, Miele, E, Silverberg, MS, Lie, BA, Punaro, M, Russell, RK, Wilson, DC, Dubinsky, MC, Monos, DS, Annese, V, Munro, JE, Wise, C, Chapel, H, Cunningham-Rundles, C, Orange, JS, Behrens, EM, Sullivan, KE, Kugathasan, S, Griffiths, AM, Satsangi, J, Grant, SFA, Sleiman, PMA, Finkel, TH, Polychronakos, C, Baldassano, RN, Prak, ETL, Ellis, JA, Li, H, Keating, BJ, and Hakonarson, H

Abstract

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Published
2015

36. Anorexia nervosa with special regard to insulin therapy

Author

Rymarkiewiczowa D, Wilson Dc, and White Wm

Subjects
Pediatrics, medicine.medical_specialty, Anorexia Nervosa, business.industry, Insulin, medicine.medical_treatment, Appetite, General Medicine, Feeding and Eating Disorders, Anorexia nervosa (differential diagnoses), medicine, Humans, business
Published
2010

39. Hydropic changes in pancreatic ductules and islets in alloxan diabetes in the rabbit

Author

Wilson Dc, Gardner C. McMillan, and Duff Gl

Subjects
endocrine system, medicine.medical_specialty, endocrine system diseases, medicine.medical_treatment, Alpha (ethology), General Biochemistry, Genetics and Molecular Biology, Hydropic degeneration, Diabetes Mellitus, Experimental, chemistry.chemical_compound, Alloxan, Internal medicine, Diabetes mellitus, medicine, Diabetes Mellitus, Animals, Fasting blood sugar, Pancreas, geography, geography.geographical_feature_category, business.industry, Insulin, Pancreatic Ducts, Islet, medicine.disease, Endocrinology, chemistry, Alloxan diabetes, Rabbits, business
Abstract

SummaryModerate to extreme hydropic degeneration of the pancreatic ductules and islets was observed in rabbits rendered diabetic by alloxan when the diabetic state had persisted for several months. Such changes have not hitherto been described in alloxan diabetes in the rabbit. The earliest appearance of these alterations was at the end of 45 days after the injection of alloxan and hydropic changes were never absent after 90 days providing that the average fasting blood sugar level during the experiment had been 303 mg per 100 cc, or higher. The hydropic state of the ductules and islets persisted without histological evidence of any further change in association with more or less severe diabetes lasting for periods up to one year. The alpha cells of the islets remained histologically normal but appeared to be increased in number. Preliminary observations demonstrated that the hydropic degeneration of both ductules and islets is reversible by adequate treatment of the diabetic state with insulin. The rever...

Published
2010

40. Two-stage genome-wide methylation profiling in childhood-onset Crohn's disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci

Author

Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, O'Leary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, Nimmo, ER, Hold, GL, Satsangi, J, Adams, AT, Kennedy, NA, Hansen, R, Ventham, NT, O'Leary, KR, Drummond, HE, Noble, CL, El-Omar, E, Russell, RK, Wilson, DC, Nimmo, ER, Hold, GL, and Satsangi, J

Abstract

Background: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease. Methods: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa. Results: We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10-7), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10-7), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10-15) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10-5, n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10-6, n = 99). Conclusions: We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.

Published
2014

47. NOX1loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, DPB, Cho, J, Powrie, F, Li, VSW, Muise, AM, and Uhlig, HH

Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivocolonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
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48. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author

Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, Rioux, JD, Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, and Rioux, JD

Abstract

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Published
2011

49. Management of obesity:summary of SIGN guideline

Author

Logue, J, Thompson, L, Romanes, F, Wilson, DC, Thompson, J, Sattar, N, Group, Guideline Development, Logue, J, Thompson, L, Romanes, F, Wilson, DC, Thompson, J, Sattar, N, and Group, Guideline Development

Published
2010

50. Common variants at five new loci associated with early-onset inflammatory bowel disease.

Author

Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, Dewit, Olivier, Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, and Dewit, Olivier

Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2009

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