title: Early-onset Crohn disease is associated with male sex and a polymorphism in the IL-6 promoter.
abstract: OBJECTIVE
  Pediatric onset of Crohn disease (CD) is characterized by male sex predominance while adult-onset disease demonstrates female sex predominance. It has been postulated that this phenomenon may be genetically determined or due to an effect of estrogen on age of onset. Interleukin (IL)-6 modulates the TH17 pathway, and the IL-6 promoter is modulated by estrogen, possibly linking genetically determined inflammation and the presence of estrogen. The aim of our study was to investigate whether differences in IL-6 promoter genotype could explain male sex in earlier disease onset.
  
  
  METHODS
  We genotyped 333 patients with CD and 100 controls, 162 pediatric-onset patients (age of onset 18 years and younger) for the IL-6-174 polymorphic site. Genotype, sex, and age of onset were compared.
  
  
  RESULTS
  Males with IL-6-174GG genotype (the wild-type allele) had an increased risk for a younger age of onset compared to males with IL-6-174GC or CC genotype (G --> C genotype), hazard ratio (HR) 1.49, P = 0.02, 95% confidence interval (CI) 1.07-2.09. Females with GG genotype were not found to have an increased risk for a younger age of onset compared with females with G --> C genotype, HR 1.01, P = 0.96, 95% CI 0.72-1.41.
  
  
  CONCLUSIONS
  Males with IL-6-174GG genotype are prone to develop CD at a younger age than males with the IL-6-174G --> C genotype. Our study suggests that age of onset may be modified by the IL-6-174GG genotype and this modification is sex dependent. This may be due to increased transcription of IL-6, an effect that may be repressed by estrogen in females.
authors.affiliation: Pediatric Gastroenterology Unit, Wolfson Medical Center, Holon Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Sagiv-Friedgut
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Batya
authors.initials: B
authors.lastname: Weiss
authors.forename: Ron
authors.initials: R
authors.lastname: Shaoul
authors.forename: Raanan
authors.initials: R
authors.lastname: Shamir
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bujanover
authors.forename: Shimon
authors.initials: S
authors.lastname: Reif
authors.forename: Mona
authors.initials: M
authors.lastname: Boaz
authors.forename: Inbar
authors.initials: I
authors.lastname: Shani
authors.forename: Arie
authors.initials: A
authors.lastname: Levine
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D003424:Crohn Disease / Q000235:genetics*; D004967:Estrogens; D005260:Female; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D055815:Young Adult
chemical_list: D004967:Estrogens; D015850:Interleukin-6