title: Genetic predictors of medically refractory ulcerative colitis.
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.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Talin.Haritunians@cshs.org
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Marla
authors.initials: M
authors.lastname: Dubinsky
authors.forename: Andrew
authors.initials: A
authors.lastname: Ippoliti
authors.forename: Soonil
authors.initials: S
authors.lastname: Kwon
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Gil Y
authors.initials: GY
authors.lastname: Melmed
authors.forename: Dror
authors.initials: D
authors.lastname: Berel
authors.forename: Emebet
authors.initials: E
authors.lastname: Mengesha
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glazer
authors.forename: Eric A
authors.initials: EA
authors.lastname: Vasiliauskas
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Fleshner
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D003082:Colectomy; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics; D055815:Young Adult
chemical_list: C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15