Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn’s disease is a risk factor for disease relapse ... View Full Text


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Article Info

DATE

2017-02-22

AUTHORS

Yoichi Kakuta, Tomoya Kimura, Kenichi Negoro, Masatake Kuroha, Hisashi Shiga, Katsuya Endo, Yoshitaka Kinouchi, Tooru Shimosegawa

ABSTRACT

BackgroundIL12B 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.MethodsThree 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.ResultsFour 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 × 10−6 and 1.49 × 10−4 respectively). 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.ConclusionsWe 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. More... »

PAGES

1230-1239

References to SciGraph publications

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  • 2005-04-28. Taq-I polymorphism in 3′UTR of the IL-12B and association with IL-12p40 production from human PBMC in GENES & IMMUNITY
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  • 2008-06-29. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease in NATURE GENETICS
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  • 2002-11-01. A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion in GENES & IMMUNITY
  • 2001-11-01. Identification of missense mutation in the IL12B gene: lack of association between IL12B polymorphisms and asthma and allergic rhinitis in the Japanese population in GENES & IMMUNITY
  • 2009-10-18. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis in NATURE GENETICS
  • 2015-07-20. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations in NATURE GENETICS
  • 2002-03-23. Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools in HUMAN GENETICS
  • 2010-11-21. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci in NATURE GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00535-017-1322-5

    DOI

    http://dx.doi.org/10.1007/s00535-017-1322-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1083859417

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28229296


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        "description": "BackgroundIL12B is a promising candidate for a susceptibility gene in Crohn\u2019s 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.MethodsThree 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\u2013control 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.ResultsFour 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\u00a0=\u00a09.42\u00a0\u00d7\u00a010\u22126 and \u00a01.49\u00a0\u00d7\u00a010\u22124 respectively). IL12B_3 was also associated with earlier relapse in CD (P\u00a0=\u00a00.0144). 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\u00a0=\u00a00.00923). No SNP was associated with ulcerative colitis.ConclusionsWe 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.", 
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    41 schema:description BackgroundIL12B 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.MethodsThree 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.ResultsFour 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 × 10−6 and  1.49 × 10−4 respectively). 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.ConclusionsWe 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.
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    49 CD patients
    50 ConclusionsWe
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    55 Japanese CD patients
    56 Japanese patients
    57 MethodsThree hundred seventy
    58 RNA
    59 aim
    60 alleles
    61 allelic expression imbalance
    62 allelic expression ratios
    63 analysis
    64 association
    65 association of SNPs
    66 candidate gene analysis
    67 candidates
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    88 lipopolysaccharide-stimulated monocytes
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    104 seventies
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    106 single nucleotide polymorphisms
    107 snapshot analysis
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