OBJECTIVES: One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS: From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS: From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS: Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.
OBJECTIVES: One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS: From a prospective registry, we characterized the response of 427 CDpatients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS: From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS: Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.
Authors: Matthias Jürgens; Rüdiger P Laubender; Franziska Hartl; Maria Weidinger; Julia Seiderer; Johanna Wagner; Martin Wetzke; Florian Beigel; Simone Pfennig; Johannes Stallhofer; Fabian Schnitzler; Cornelia Tillack; Peter Lohse; Burkhard Göke; Jürgen Glas; Thomas Ochsenkühn; Stephan Brand Journal: Am J Gastroenterol Date: 2010-03-02 Impact factor: 10.864
Authors: Gary Toedter; Katherine Li; Colleen Marano; Keying Ma; Sarah Sague; C Chris Huang; Xiao-Yu Song; Paul Rutgeerts; Frédéric Baribaud Journal: Am J Gastroenterol Date: 2011-03-29 Impact factor: 10.864
Authors: Jean Frédéric Colombel; William J Sandborn; Walter Reinisch; Gerassimos J Mantzaris; Asher Kornbluth; Daniel Rachmilewitz; Simon Lichtiger; Geert D'Haens; Robert H Diamond; Delma L Broussard; Kezhen L Tang; C Janneke van der Woude; Paul Rutgeerts Journal: N Engl J Med Date: 2010-04-15 Impact factor: 91.245
Authors: Elena Urcelay; Juan-Luis Mendoza; Alfonso Martinez; Laura Fernandez; Carlos Taxonera; Manuel Diaz-Rubio; Emilio-G de la Concha Journal: World J Gastroenterol Date: 2005-02-28 Impact factor: 5.742
Authors: V Pittoni; M Bombardieri; F R Spinelli; R Scrivo; C Alessandri; F Conti; A Spadaro; G Valesini Journal: Ann Rheum Dis Date: 2002-08 Impact factor: 19.103
Authors: Jan Hendrik Niess; Jochen Klaus; Johannes Stephani; Carolin Pflüger; Nadine Degenkolb; Ulrike Spaniol; Benjamin Mayer; Georgia Lahr; Georg B T von Boyen Journal: Dig Dis Sci Date: 2011-12-07 Impact factor: 3.199
Authors: Luke Jostins; Stephan Ripke; Rinse K Weersma; Richard H Duerr; Dermot P McGovern; Ken Y Hui; James C Lee; L Philip Schumm; Yashoda Sharma; Carl A Anderson; Jonah Essers; Mitja Mitrovic; Kaida Ning; Isabelle Cleynen; Emilie Theatre; Sarah L Spain; Soumya Raychaudhuri; Philippe Goyette; Zhi Wei; Clara Abraham; Jean-Paul Achkar; Tariq Ahmad; Leila Amininejad; Ashwin N Ananthakrishnan; Vibeke Andersen; Jane M Andrews; Leonard Baidoo; Tobias Balschun; Peter A Bampton; Alain Bitton; Gabrielle Boucher; Stephan Brand; Carsten Büning; Ariella Cohain; Sven Cichon; Mauro D'Amato; Dirk De Jong; Kathy L Devaney; Marla Dubinsky; Cathryn Edwards; David Ellinghaus; Lynnette R Ferguson; Denis Franchimont; Karin Fransen; Richard Gearry; Michel Georges; Christian Gieger; Jürgen Glas; Talin Haritunians; Ailsa Hart; Chris Hawkey; Matija Hedl; Xinli Hu; Tom H Karlsen; Limas Kupcinskas; Subra Kugathasan; Anna Latiano; Debby Laukens; Ian C Lawrance; Charlie W Lees; Edouard Louis; Gillian Mahy; John Mansfield; Angharad R Morgan; Craig Mowat; William Newman; Orazio Palmieri; Cyriel Y Ponsioen; Uros Potocnik; Natalie J Prescott; Miguel Regueiro; Jerome I Rotter; Richard K Russell; Jeremy D Sanderson; Miquel Sans; Jack Satsangi; Stefan Schreiber; Lisa A Simms; Jurgita Sventoraityte; Stephan R Targan; Kent D Taylor; Mark Tremelling; Hein W Verspaget; Martine De Vos; Cisca Wijmenga; David C Wilson; Juliane Winkelmann; Ramnik J Xavier; Sebastian Zeissig; Bin Zhang; Clarence K Zhang; Hongyu Zhao; Mark S Silverberg; Vito Annese; Hakon Hakonarson; Steven R Brant; Graham Radford-Smith; Christopher G Mathew; John D Rioux; Eric E Schadt; Mark J Daly; Andre Franke; Miles Parkes; Severine Vermeire; Jeffrey C Barrett; Judy H Cho Journal: Nature Date: 2012-11-01 Impact factor: 49.962
Authors: Parambir S Dulai; Brigid S Boland; Siddharth Singh; Khadija Chaudrey; Jenna L Koliani-Pace; Gursimran Kochhar; Malav P Parikh; Eugenia Shmidt; Justin Hartke; Prianka Chilukuri; Joseph Meserve; Diana Whitehead; Robert Hirten; Adam C Winters; Leah G Katta; Farhad Peerani; Neeraj Narula; Keith Sultan; Arun Swaminath; Matthew Bohm; Dana Lukin; David Hudesman; John T Chang; Jesus Rivera-Nieves; Vipul Jairath; G Y Zou; Brian G Feagan; Bo Shen; Corey A Siegel; Edward V Loftus; Sunanda Kane; Bruce E Sands; Jean-Frederic Colombel; William J Sandborn; Karen Lasch; Charlie Cao Journal: Gastroenterology Date: 2018-05-30 Impact factor: 22.682
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