BACKGROUND: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
BACKGROUND: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
Authors: Julia Seiderer; Stephan Brand; Karin A Herrmann; Fabian Schnitzler; Rudolf Hatz; Alexander Crispin; Simone Pfennig; Stefan O Schoenberg; Burkhard Göke; Peter Lohse; Thomas Ochsenkuhn Journal: Inflamm Bowel Dis Date: 2006-12 Impact factor: 5.325
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Kai Wang; Haitao Zhang; Subra Kugathasan; Vito Annese; Jonathan P Bradfield; Richard K Russell; Patrick M A Sleiman; Marcin Imielinski; Joseph Glessner; Cuiping Hou; David C Wilson; Thomas Walters; Cecilia Kim; Edward C Frackelton; Paolo Lionetti; Arrigo Barabino; Johan Van Limbergen; Stephen Guthery; Lee Denson; David Piccoli; Mingyao Li; Marla Dubinsky; Mark Silverberg; Anne Griffiths; Struan F A Grant; Jack Satsangi; Robert Baldassano; Hakon Hakonarson Journal: Am J Hum Genet Date: 2009-02-26 Impact factor: 11.025
Authors: Jeffrey C Barrett; Sarah Hansoul; Dan L Nicolae; Judy H Cho; Richard H Duerr; John D Rioux; Steven R Brant; Mark S Silverberg; Kent D Taylor; M Michael Barmada; Alain Bitton; Themistocles Dassopoulos; Lisa Wu Datta; Todd Green; Anne M Griffiths; Emily O Kistner; Michael T Murtha; Miguel D Regueiro; Jerome I Rotter; L Philip Schumm; A Hillary Steinhart; Stephan R Targan; Ramnik J Xavier; Cécile Libioulle; Cynthia Sandor; Mark Lathrop; Jacques Belaiche; Olivier Dewit; Ivo Gut; Simon Heath; Debby Laukens; Myriam Mni; Paul Rutgeerts; André Van Gossum; Diana Zelenika; Denis Franchimont; Jean-Pierre Hugot; Martine de Vos; Severine Vermeire; Edouard Louis; Lon R Cardon; Carl A Anderson; Hazel Drummond; Elaine Nimmo; Tariq Ahmad; Natalie J Prescott; Clive M Onnie; Sheila A Fisher; Jonathan Marchini; Jilur Ghori; Suzannah Bumpstead; Rhian Gwilliam; Mark Tremelling; Panos Deloukas; John Mansfield; Derek Jewell; Jack Satsangi; Christopher G Mathew; Miles Parkes; Michel Georges; Mark J Daly Journal: Nat Genet Date: 2008-06-29 Impact factor: 38.330
Authors: Marla C Dubinsky; Ying-Chao Lin; Debra Dutridge; Yoana Picornell; Carol J Landers; Sharmayne Farrior; Iwona Wrobel; Antonio Quiros; Eric A Vasiliauskas; Bruce Grill; David Israel; Ron Bahar; Dennis Christie; Ghassan Wahbeh; Gary Silber; Saied Dallazadeh; Praful Shah; Danny Thomas; Drew Kelts; Robert M Hershberg; Charles O Elson; Stephan R Targan; Kent D Taylor; Jerome I Rotter; Huiying Yang Journal: Am J Gastroenterol Date: 2006-02 Impact factor: 10.864
Authors: Marc Ferrante; Liesbet Henckaerts; Marie Joossens; Marie Pierik; Sofie Joossens; Nir Dotan; Gary L Norman; Rom T Altstock; Kristel Van Steen; Paul Rutgeerts; Gert Van Assche; Séverine Vermeire Journal: Gut Date: 2007-04-24 Impact factor: 23.059
Authors: Marla C Dubinsky; Subra Kugathasan; Ling Mei; Yoana Picornell; Justin Nebel; Iwona Wrobel; Antonio Quiros; Gary Silber; Ghassan Wahbeh; Lirona Katzir; Eric Vasiliauskas; Ron Bahar; Anthony Otley; David Mack; Jonathan Evans; Joel Rosh; Maria Oliva Hemker; Neal Leleiko; Wallace Crandall; Christine Langton; Carol Landers; Kent D Taylor; Stephan R Targan; Jerome I Rotter; James Markowitz; Jeffrey Hyams Journal: Clin Gastroenterol Hepatol Date: 2008-07-10 Impact factor: 11.382
Authors: Mirna Šimurina; Noortje de Haan; Frano Vučković; Nicholas A Kennedy; Jerko Štambuk; David Falck; Irena Trbojević-Akmačić; Florent Clerc; Genadij Razdorov; Anna Khon; Anna Latiano; Renata D'Incà; Silvio Danese; Stephan Targan; Carol Landers; Marla Dubinsky; Dermot P B McGovern; Vito Annese; Manfred Wuhrer; Gordan Lauc Journal: Gastroenterology Date: 2018-01-06 Impact factor: 22.682