| Genetic predictors of medically refractory ulcerative colitis. | |
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MedLine Citation:
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PMID: 20848476 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Talin Haritunians; Kent D Taylor; Stephan R Targan; Marla Dubinsky; Andrew Ippoliti; Soonil Kwon; Xiuqing Guo; Gil Y Melmed; Dror Berel; Emebet Mengesha; Bruce M Psaty; Nicole L Glazer; Eric A Vasiliauskas; Jerome I Rotter; Phillip R Fleshner; Dermot P B McGovern |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Inflammatory bowel diseases Volume: 16 ISSN: 1536-4844 ISO Abbreviation: Inflamm. Bowel Dis. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-21 Completed Date: 2011-02-11 Revised Date: 2012-04-30 |
Medline Journal Info:
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Nlm Unique ID: 9508162 Medline TA: Inflamm Bowel Dis Country: United States |
Other Details:
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Languages: eng Pagination: 1830-40 Citation Subset: IM |
Affiliation:
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Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Talin.Haritunians@cshs.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Adolescent Adult Cohort Studies Colectomy Colitis, Ulcerative / drug therapy*, genetics*, surgery Female Genetic Loci Genome-Wide Association Study* Humans Major Histocompatibility Complex / genetics* Male Polymorphism, Single Nucleotide Risk Factors Severity of Illness Index Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics Young Adult |
| Grant Support | |
ID/Acronym/Agency:
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DK063491/DK/NIDDK NIH HHS; DK084554/DK/NIDDK NIH HHS; DK76984/DK/NIDDK NIH HHS; M01-RR00425/RR/NCRR NIH HHS; N01 HC-15103/HC/NHLBI NIH HHS; N01 HC-55222/HC/NHLBI NIH HHS; N01-HC-35129/HC/NHLBI NIH HHS; N01-HC-45133/HC/NHLBI NIH HHS; N01-HC-75150/HC/NHLBI NIH HHS; N01-HC-85079/HC/NHLBI NIH HHS; N01-HC-85086/HC/NHLBI NIH HHS; P01 DK046763-080001/DK/NIDDK NIH HHS; P01 DK046763-130001/DK/NIDDK NIH HHS; P01 DK046763-15/DK/NIDDK NIH HHS; P01 DK046763-150001/DK/NIDDK NIH HHS; P01 DK046763-170001/DK/NIDDK NIH HHS; P01-DK046763/DK/NIDDK NIH HHS; P30 DK063491/DK/NIDDK NIH HHS; P30 DK063491-06/DK/NIDDK NIH HHS; R01 DK033651/DK/NIDDK NIH HHS; R01 DK033651-29/DK/NIDDK NIH HHS; R01 DK056328-13/DK/NIDDK NIH HHS; R01 HL087652/HL/NHLBI NIH HHS; R01 HL087652-03/HL/NHLBI NIH HHS; R03 DK076984-02/DK/NIDDK NIH HHS; R21 DK084554-01/DK/NIDDK NIH HHS; U01 HL080295/HL/NHLBI NIH HHS; U01 HL080295-03/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/TNFSF15 protein, human; 0/Tumor Necrosis Factor Ligand Superfamily Member 15 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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