Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa
Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa
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DOI：
10.1016/j.humimm.2011.03.023
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发表时间：
2011-07-01
期刊：
影响因子：
2.7
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Arai, Takashi;Kakuta, Yoichi;Shimosegawa, Tooru
NKX2.3是炎症性肠病（IBD）易感基因的一个有希望的候选基因。本研究的目的是在日本IBD中进行NKX2.3的候选基因分析，并使用NKX2.3 mRNA在所涉及的结肠粘膜中的等位基因表达比率来研究风险等位基因（单倍型）如何影响IBD的易感性。共有344例克罗恩病（CD）患者，253例溃疡性结肠炎（UC）患者和243例健康对照（HC）进行了NKX2.3附近3个标签单核苷酸多态性（SNP; rs 10883365，rs 888208和rs 11596008）的基因分型。以rs 888208为等位基因（单倍型）标记，采用TaqMan法检测NKX2.3-mRNA的等位基因表达率。两个snp（rs 10883365和rs 888208）与UC显著相关（p = 7.79 x 10（-4），比值比[OR] = 1.54 [95%置信区间（95% CI）1.20-1.99]，p = 7.70 x 10（-3），OR = 1.41 [95% CI 1.10-1.811，1个SNP（rs 10883365）与CD相关（p = 0.0366，OR = 1.29 [95%CI 1.02-1.63]）。由3个SNP形成的单倍型B与UC显著相关（p = 6.11 x 10（-4），OR = 1.56 [95%CI 1.21-2.00]）。亚组分析表明，rs 10883365主要与结肠CD显著相关（p = 1.99 x 10（-3），OR = 1.91 [95% CI 1.27-2.88]，vs HC）。在10例IBD患者的受累粘膜中，从单倍型B（风险单倍型）到单倍型A（非风险单倍型）转录的NKX2.3 mRNA的等位基因表达比率显著高于各自基因组DNA的等位基因比率（p = 0.00195）。我们证实了位于NKX2.3 5'侧翼区的SNP rs 10883365与日本UC和结肠CD的相关性，并确定了UC的风险单倍型（单倍型B）。已证实的等位基因表达不平衡支持NKX2.3风险单倍型通过增加结肠粘膜中NKX2.3 mRNA的表达而赋予UC易感性的观点。(C)2011年美国组织相容性和免疫遗传学学会。爱思唯尔公司出版All rights reserved.
NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 x 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 x 10(-3), OR = 1.41 [95% CI 1.10-1.811, respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 x 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 x 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2.3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa. (C) 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.