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Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn’s disease is a risk factor for disease relapse in Japanese patients

  • Original Article—Alimentary Tract
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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 × 10−6 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.

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.

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Acknowledgements

We thank past and present members of the IBD Group for fruitful discussions and scientific contributions. This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Numbers JP26460959, JP15H04805, and JP15K15284.

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    Authors and Affiliations

    1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan

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

    2. Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan

      Yoshitaka Kinouchi

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    1. Yoichi Kakuta
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    Correspondence to Yoichi Kakuta.

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    Yoichi Kakuta and Tomoya Kimura contributed equally to this work.

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    535_2017_1322_MOESM1_ESM.pptx

    Fig. S1. The calibration curve to measure the IL12B mRNA allelic expression ratio. The regression line was obtained with use of standard mixtures of DNA from two individuals homozygous for the IL12B_10 C and A alleles. The signal intensity (peak height) from SNaPshot was plotted against known ratios in mixed standard samples. The peak height ratios are mean values from three duplicate experiments (PPTX 45 kb)

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    Kakuta, Y., Kimura, T., Negoro, K. et al. Increased expression of IL12B mRNA transcribed from the risk haplotype for Crohn’s disease is a risk factor for disease relapse in Japanese patients. J Gastroenterol 52, 1230–1239 (2017). https://doi.org/10.1007/s00535-017-1322-5

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    • DOI: https://doi.org/10.1007/s00535-017-1322-5

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