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Genetic predictors of medically refractory ulcerative colitis.
Tuesday,2012-11-06 12:19 America/Los_Angeles — eenright
| Title | Genetic predictors of medically refractory ulcerative colitis. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Haritunians, T, Taylor, KD, Targan, SR, Dubinsky, M, Ippoliti, A, Kwon, S, Guo, X, Melmed, GY, Berel, D, Mengesha, E, Psaty, BM, Glazer, NL, Vasiliauskas, EA, Rotter, JI, Fleshner, PR, McGovern, DPB |
| Journal | Inflamm Bowel Dis |
| Volume | 16 |
| Issue | 11 |
| Pagination | 1830-40 |
| Date Published | 2010 Nov |
| ISSN | 1536-4844 |
| Keywords | Acute Disease, Adolescent, Adult, Cohort Studies, Colectomy, Colitis, Ulcerative, Female, Genetic Loci, Genome-Wide Association Study, Humans, Major Histocompatibility Complex, Male, Polymorphism, Single Nucleotide, Risk Factors, Severity of Illness Index, Tumor Necrosis Factor Ligand Superfamily Member 15, Young Adult |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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)).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1002/ibd.21293 |
| Alternate Journal | Inflamm. Bowel Dis. |
| PubMed ID | 20848476 |
| PubMed Central ID | PMC2959149 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States N01 HC085081 / HC / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States R21 DK084554 / DK / NIDDK NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States N01 HC085083 / HC / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 DK033651 / DK / NIDDK NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States R03 DK076984 / DK / NIDDK NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States P01-DK046763 / DK / NIDDK NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States P01 DK046763 / DK / NIDDK NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States DK084554 / DK / NIDDK NIH HHS / United States R01 DK056328 / DK / NIDDK NIH HHS / United States DK76984 / DK / NIDDK NIH HHS / United States |