Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease

Inflamm Bowel Dis. 2013 Jul;19(8):1662-70. doi: 10.1097/MIB.0b013e318281f275.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Crohn Disease / genetics*
  • Crohn Disease / mortality
  • Crohn Disease / surgery
  • Female
  • Follow-Up Studies
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Infant
  • Interleukin-12 Subunit p40 / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Risk Assessment
  • Survival Rate
  • Time Factors
  • Young Adult

Substances

  • IL12B protein, human
  • Interleukin-12 Subunit p40