title: Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn's disease is a risk factor for disease relapse in Japanese patients.
abstract: BACKGROUND
  IL12B is a promising candidate for a susceptibility gene in Crohn's disease (CD). The aim of this study was to perform a candidate gene analysis of IL12B in Japanese CD patients, investigate whether the genotype is associated with disease phenotypes, and determine how the risk allele affects susceptibility to CD.
  
  
  METHODS
  Three hundred seventy-five patients with CD, 265 patients with ulcerative colitis, and 463 healthy controls were examined. Ten single-nucleotide polymorphisms (SNPs) around IL12B were genotyped. Case-control and subphenotype (including disease course) analyses were performed. The allelic expression ratio of IL12B messenger RNA (mRNA) was examined by a SNaPshot analysis in lipopolysaccharide-stimulated monocytes.
  
  
  RESULTS
  Four SNPs located upstream of the IL12B gene were significantly associated with CD. A conditional analysis revealed that these associations included two independent signals tagged by IL12B_1 and IL12B_3 (P = 9.42 × 10-6and  1.49 × 10-4respectively). IL12B_3 was also associated with earlier relapse in CD (P = 0.0144). The allelic expression ratios of IL12B mRNA transcribed from the risk haplotype to the protective haplotype tagged by IL12B_3 in lipopolysaccharide-stimulated monocytes from ten healthy controls heterozygous for IL12B_3 were significantly higher than that of the respective genomic DNA (P = 0.00923). No SNP was associated with ulcerative colitis.
  
  
  CONCLUSIONS
  We confirmed the association of SNPs located upstream of IL12B with CD in Japanese patients. The demonstrated allelic expression imbalance supports the idea that the IL12B risk haplotype confers susceptibility not only to CD onset but to also relapse through increased IL12B mRNA expression.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan. ykakuta@med.tohoku.ac.jp.
authors.forename: Yoichi
authors.identifier: http://orcid.org/0000-0002-7042-009X
authors.initials: Y
authors.lastname: Kakuta
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Negoro
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Kuroha
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shiga
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Endo
authors.affiliation: Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kinouchi
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D007564:Japan; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D012307:Risk Factors; D055815:Young Adult
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D012333:RNA, Messenger
keywords: Allelic expression imbalance; Crohn’s disease; IL12B