title: Smoking behaviour modifies IL23r-associated disease risk in patients with Crohn's disease.
abstract: OBJECTIVE
  The etiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behavior is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of CD, and to investigate the interactions between IL23R variants, smoking behavior, and CD-associated genes, NOD2 and ATG16L1.
  
  
  METHODS
  Ten IL23R single-nucleotide polymorphisms (SNPs) were genotyped in 675 CD cases, and 1255 controls from Brisbane, Australia (dataset 1). Six of these SNPs were genotyped in 318 CD cases and 533 controls from Canterbury, New Zealand (dataset 2). Case-control analysis of genotype and allele frequencies, and haplotype analysis for all SNPs was conducted.
  
  
  RESULTS
  We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking. Ileal involvement was a consistent marker of strong SNP-CD association (P ≤ 0.001), while the lowest minor allele frequencies for location were found in those with colonic CD (L2). Three haplotype blocks were identified across the 10 IL23R SNPs conferring different risk of CD. Haplotypes conferred no further risk of CD when compared with single SNP analyses.
  
  
  CONCLUSIONS
  IL23R gene variants determine CD susceptibility in the Australian and New Zealand population, particularly ileal CD. A strong additive interaction exists between IL23R SNPs and smoking behavior resulting in a dramatic increase in disease risk depending upon specific genetic background.
authors.affiliation: CSIRO Computational Informatics/Australian E-Health Research Centre, Royal Brisbane and Women's Hospital, Brisbane, Victoria, Australia; Preventative Health Flagship, Melbourne, Victoria, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.forename: Zhen Zhen
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Fowler
authors.forename: Anthony
authors.initials: A
authors.lastname: Croft
authors.forename: Angela
authors.initials: A
authors.lastname: Lin
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Florin
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D001315:Australia; D016022:Case-Control Studies; D015331:Cohort Studies; D003424:Crohn Disease / Q000209:etiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009520:New Zealand; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult
chemical_list: C515500:IL23R protein, human; D018123:Receptors, Interleukin
keywords: ATG16L1; Crohn's disease; IL23R; NOD2; interleukin 23 receptor; smoking