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Genetic predictors of medically refractory ulcerative colitis

Haritunians, Talin PhD1,*; Taylor, Kent D. PhD1; Targan, Stephan R. MD2; Dubinsky, Marla MD2; Ippoliti, Andrew MD2; Kwon, Soonil PhD1; Guo, Xiuqing PhD1; Melmed, Gil Y. MD2; Berel, Dror PhD2,3; Mengesha, Emebet BS1; Psaty, Bruce M. MD, PhD4; Glazer, Nicole L. PhD4; Vasiliauskas, Eric A. MD2; Rotter, Jerome I. MD1; Fleshner, Phillip R. MD2; McGovern, Dermot P.B. MD, PhD2

Inflammatory Bowel Diseases:
doi: 10.1002/ibd.21293
Original Basic Science Articles
Abstract

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. (Inflamm Bowel Dis 2010)

Author Information

1Medical Genetics Institute, Cedars‐Sinai Medical Center, Los Angeles, CA; 2Inflammatory Bowel and Immunobiology Research Institute, Cedars‐Sinai Medical Center, Los Angeles, CA; 3Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center, Los Angeles, CA; 4Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, & Health Services, University of Washington, and Center for Health Studies, Group Health, Seattle, WA

*Reprints: Medical Genetics Institute, Cedars‐Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048

Email: Talin.Haritunians@cshs.org

Received 10 February 2010; Accepted 18 February 2010

Supported in part by NCRR grant M01‐RR00425 to the Cedars‐Sinai General Research Center Genotyping core; NIH/NIDDK grant P01‐DK046763; the Southern California Diabetes Endocrinology Research Center grant, DK063491; Cedars‐Sinai Medical Center Inflammatory Bowel Disease Research Funds; The Feintech Family Chair in IBD (S.R.T.); The Abe and Claire Levine Chair in Pediatric IBD (M.D.) and The Cedars‐Sinai Board of Governors' Chair in Medical Genetics (J.I.R.). Additional funding through grants DK76984 (M.D.) and DK084554 (M.D. and D.P.B.M). The CHS research reported in this article was supported by contract numbers N01‐HC‐85079 through N01‐HC‐85086, N01‐HC‐35129, N01 HC‐15103, N01 HC‐55222, N01‐HC‐75150, N01‐HC‐45133; grant numbers U01 HL080295 and R01 HL087652 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs‐nhlbi.org/pi.htm

Supported by the NCRR M01‐RR00425; NIH/NIDDK P01‐DK046763; Southern California Diabetes Endocrinology Research Center DK063491; Cedars‐Sinai Medical Center Inflammatory Bowel Disease Research Funds; The Feintech Family Chair in IBD; The Abe and Claire Levine Chair in Pediatric IBD; The Cedars‐Sinai Board of Governors' Chair in Medical Genetics DK76984 and DK084554; Unknown funding agency N01‐HC‐85079 and N01‐HC‐85086 and N01‐HC‐35129 and N01 HC‐15103 and N01 HC‐55222 and N01‐HC‐75150 and N01‐HC‐45133; NHLBI U01 HL080295 and R01 HL087652.

Published online 18 May 2010 in Wiley Online Library (wileyonlinelibrary.com).

Additional supporting information may be found in the online version of this article.

© Crohn's & Colitis Foundation of America, Inc.

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