title: Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease.
abstract: BACKGROUND
  The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables.
  
  
  METHODS
  Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery.
  
  
  RESULTS
  Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups.
  
  
  CONCLUSIONS
  Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.
authors.affiliation: Departments of Pediatrics, Pediatric Inflammatory Bowel Disease Center and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. dubinskym@csmc.edu
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: Soonil
authors.initials: S
authors.lastname: Kwon
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Iwona
authors.initials: I
authors.lastname: Wrobel
authors.forename: Ghassan
authors.initials: G
authors.lastname: Wahbeh
authors.forename: Antonio
authors.initials: A
authors.lastname: Quiros
authors.forename: Ron
authors.initials: R
authors.lastname: Bahar
authors.forename: Gary
authors.initials: G
authors.lastname: Silber
authors.forename: Sharmayne
authors.initials: S
authors.lastname: Farrior
authors.forename: Michael
authors.initials: M
authors.lastname: Stephens
authors.forename: Nick
authors.initials: N
authors.lastname: Teleten
authors.forename: Deepa
authors.initials: D
authors.lastname: Panikkath
authors.forename: Andrew
authors.initials: A
authors.lastname: Ippoliti
authors.forename: Eric
authors.initials: E
authors.lastname: Vasiliauskas
authors.forename: Phillip
authors.initials: P
authors.lastname: Fleshner
authors.forename: Chadwick
authors.initials: C
authors.lastname: Williams
authors.forename: Carol
authors.initials: C
authors.lastname: Landers
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003424:Crohn Disease / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D018570:Risk Assessment; D015996:Survival Rate; D013997:Time Factors; D055815:Young Adult
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40