OBJECTIVES: Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS: We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied. RESULTS: We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS: We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.
OBJECTIVES:Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS: We performed a large replication study in 2,731 Dutch and Belgian IBDpatients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied. RESULTS: We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS: We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.
Authors: Matti Waterman; Wei Xu; Joanne M Stempak; Raquel Milgrom; Charles N Bernstein; Anne M Griffiths; Gordon R Greenberg; A Hillary Steinhart; Mark S Silverberg Journal: Inflamm Bowel Dis Date: 2010-12-10 Impact factor: 5.325
Authors: Nora Meggyesi; Lajos S Kiss; Magdalena Koszarska; Martin Bortlik; Dana Duricova; Laszlo Lakatos; Tamas Molnar; Martin Leniček; Libor Vítek; Istvan Altorjay; Maria Papp; Zsolt Tulassay; Pal Miheller; Janos Papp; Attila Tordai; Hajnalka Andrikovics; Milan Lukas; Peter Laszlo Lakatos Journal: World J Gastroenterol Date: 2010-11-07 Impact factor: 5.742
Authors: Long Zhang; Fangfang Zhou; Yihao Li; Yvette Drabsch; Juan Zhang; Hans van Dam; Peter ten Dijke Journal: J Biol Chem Date: 2012-06-22 Impact factor: 5.157
Authors: Josef Wagner; Winnie H Sim; Justine A Ellis; Eng K Ong; Anthony G Catto-Smith; Donald J S Cameron; Ruth F Bishop; Carl D Kirkwood Journal: PLoS One Date: 2010-11-08 Impact factor: 3.240
Authors: Natalie J Prescott; Katherine M Dominy; Michiaki Kubo; Cathryn M Lewis; Sheila A Fisher; Richard Redon; Ni Huang; Barbara E Stranger; Katarzyna Blaszczyk; Barry Hudspith; Gareth Parkes; Naoya Hosono; Keiko Yamazaki; Clive M Onnie; Alastair Forbes; Emmanouil T Dermitzakis; Yusuke Nakamura; John C Mansfield; Jeremy Sanderson; Matthew E Hurles; Roland G Roberts; Christopher G Mathew Journal: Hum Mol Genet Date: 2010-01-27 Impact factor: 6.150