Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan.
Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan.
J Gastroenterol. 2017 Dec;52(12):1230-1239. doi: 10.1007/s00535-017-1322-5. Epub 2017 Feb 22.
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.
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.
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 and 1.49 × 10 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.
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.
IL12B 是克罗恩病（CD）易感基因的候选基因。本研究旨在对日本 CD 患者的 IL12B 进行候选基因分析，探讨基因型是否与疾病表型相关，并确定风险等位基因如何影响 CD 的易感性。
检查了 375 例 CD 患者、265 例溃疡性结肠炎患者和 463 名健康对照者。对 IL12B 周围的 10 个单核苷酸多态性（SNP）进行基因分型。进行病例对照和亚表型（包括疾病病程）分析。通过脂多糖刺激的单核细胞中的 SNaPshot 分析检查 IL12B 信使 RNA（mRNA）的等位基因表达比。
IL12B 基因上游的 4 个 SNP 与 CD 显著相关。条件分析表明，这些关联包括由 IL12B_1 和 IL12B_3 标记的两个独立信号（分别为 P = 9.42×10 和 1.49×10）。IL12B_3 也与 CD 的早期复发相关（P = 0.0144）。在 10 名 IL12B_3 杂合的健康对照者的脂多糖刺激的单核细胞中，从 IL12B_3 标记的风险单倍型转录的 IL12B mRNA 的等位基因表达比与相应的基因组 DNA 明显更高（P = 0.00923）。没有 SNP 与溃疡性结肠炎相关。
我们在日本患者中证实了位于 IL12B 上游的 SNP 与 CD 的关联。表现出的等位基因表达失衡支持这样一种观点，即 IL12B 风险单倍型不仅通过增加 IL12B mRNA 表达赋予 CD 发病易感性，而且赋予复发易感性。
