BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC. METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls. RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)). CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC. METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls. RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)). CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.
Authors: L P Fried; N O Borhani; P Enright; C D Furberg; J M Gardin; R A Kronmal; L H Kuller; T A Manolio; M B Mittelmark; A Newman Journal: Ann Epidemiol Date: 1991-02 Impact factor: 3.797
Authors: M Roussomoustakaki; J Satsangi; K Welsh; E Louis; G Fanning; S Targan; C Landers; D P Jewell Journal: Gastroenterology Date: 1997-06 Impact factor: 22.682
Authors: John L Prehn; Shahab Mehdizadeh; Carol J Landers; Xia Luo; Stephanie C Cha; Ping Wei; Stephan R Targan Journal: Clin Immunol Date: 2004-07 Impact factor: 3.969
Authors: Steven R Brant; Carolien I M Panhuysen; Dan Nicolae; Deepthi M Reddy; Denise K Bonen; Reda Karaliukas; Leilei Zhang; Eric Swanson; Lisa W Datta; Thomas Moran; Geoffrey Ravenhill; Richard H Duerr; Jean-Paul Achkar; Amir S Karban; Judy H Cho Journal: Am J Hum Genet Date: 2003-11-07 Impact factor: 11.025
Authors: Jeffrey S Hyams; Sonia Davis Thomas; Nathan Gotman; Yael Haberman; Rebekah Karns; Melanie Schirmer; Angela Mo; David R Mack; Brendan Boyle; Anne M Griffiths; Neal S LeLeiko; Cary G Sauer; David J Keljo; James Markowitz; Susan S Baker; Joel Rosh; Robert N Baldassano; Ashish Patel; Marian Pfefferkorn; Anthony Otley; Melvin Heyman; Joshua Noe; Maria Oliva-Hemker; Paul A Rufo; Jennifer Strople; David Ziring; Stephen L Guthery; Boris Sudel; Keith Benkov; Prateek Wali; Dedrick Moulton; Jonathan Evans; Michael D Kappelman; M Alison Marquis; Francisco A Sylvester; Margaret H Collins; Suresh Venkateswaran; Marla Dubinsky; Vin Tangpricha; Krista L Spada; Bradley Saul; Jessie Wang; Jose Serrano; Kevin Hommel; Urko M Marigorta; Greg Gibson; Ramnik J Xavier; Subra Kugathasan; Thomas Walters; Lee A Denson Journal: Lancet Date: 2019-03-29 Impact factor: 79.321
Authors: Paulo Freire; Ricardo Cardoso; Pedro Figueiredo; Maria M Donato; Manuela Ferreira; Sofia Mendes; Ana Margarida Ferreira; Helena Vasconcelos; Francisco Portela; Carlos Sofia Journal: Int J Colorectal Dis Date: 2014-03-22 Impact factor: 2.571
Authors: Matti Waterman; Jo Knight; Amreen Dinani; Wei Xu; Joanne M Stempak; Kenneth Croitoru; Geoffrey C Nguyen; Zane Cohen; Robin S McLeod; Gordon R Greenberg; A Hillary Steinhart; Mark S Silverberg Journal: Inflamm Bowel Dis Date: 2015-09 Impact factor: 5.325
Authors: Uri Kopylov; Gabrielle Boucher; Matti Waterman; Claudia R Rivers; Mohini Patel; Judy H Cho; Jean F Colombel; Richard H Duerr; David Binion; Dermot P B McGovern; Phillip P Schumm; Steven R Brant; Mark S Silverberg; John D Rioux; Alain Bitton Journal: Inflamm Bowel Dis Date: 2016-10 Impact factor: 5.325