KCNN4 Gene Variant Is Associated With Ileal Crohn's Disease in the Australian and New Zealand Population
KCNN4 Gene Variant Is Associated With Ileal Crohn's Disease in the Australian and New Zealand Population
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DOI：
10.1038/ajg.2010.161
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发表时间：
2010-10-01
影响因子：
9.8
通讯作者：
Radford-Smith, Graham L.
中科院分区：
文献类型：
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作者：
Simms, Lisa A.;Doecke, James D.;Radford-Smith, Graham L.
目的：克罗恩病（CD; MIM 266600）是最常见的炎症性肠病（IBD）之一，是发达国家卫生保健的一个重大负担。我们的目的是确定染色体19q13上IBD连锁区域中一个与Paneth细胞分泌和t细胞活化有关的基因是否对CD的发展具有遗传易感性。方法：总共有792例CD病例和1244例澳大利亚裔（高加索人）的对照，在编码中间电导钙活化钾通道蛋白（KCNN4）的基因19q13.2上进行了7个单核苷酸多态性（snp）的基因分型。使用蒙特利尔分类对CD病例进行表型分析。复制组包括额外的326例CD病例和951例基于人群的高加索对照。采用定量逆转录pcr技术对KCNN4 mRNA转录物进行分析。结果：KCNN4 SNP rs2306801与CD相关(主要P=0.0008，优势比（OR）（95%可信区间（CI））： 0.76 (0.65 ~ 0.89)；复制P=0.01, OR (95% CI): 0.77（0.61-0.97）。根据疾病位置分层发现SNP rs2306801与回肠CD之间存在关联（P=0.01）。携带任何常见疾病易感性NOD2变异（R702W、G908R、1007fs）的CD患者的非炎症回肠粘膜KCNN4 mRNA表达水平显著降低（P=0.001）。KCNN4蛋白在Paneth细胞和炎症固有层的T细胞中表达。结论：我们的数据提示KCNN4在回肠CD中的作用。KCNN4在Paneth细胞分泌和t细胞活化中的双重作用以及其作为钾离子通道的性质使其成为一个重要的实用治疗靶点。
OBJECTIVES: Crohn's disease (CD; MIM 266600) is one of the most common forms of inflammatory bowel disease (IBD), and represents a significant burden to health care in developed countries. Our aim was to determine whether a gene in the IBD linkage region on chromosome 19q13, with a role in Paneth cell secretion and T-cell activation, conferred genetic susceptibility to the development of CD.METHODS: In total, 792 CD cases and 1,244 controls of Australian origin (Caucasian) were genotyped for seven single-nucleotide polymorphisms (SNPs) in the gene encoding the intermediate conductance calcium-activated potassium channel protein (KCNN4) at 19q13.2. CD cases were phenotyped using the Montreal classification. The replication set comprised an additional 326 CD cases and 951 population-based Caucasian controls. Analysis of the KCNN4 mRNA transcript was carried out using quantitative reverse transcriptase-PCR.RESULTS: KCNN4 SNP rs2306801 was associated with CD (primary P=0.0008, odds ratio (OR) (95% confidence interval (CI)): 0.76 (0.65-0.89); replication P=0.01, OR (95% CI): 0.77 (0.61-0.97). Stratification by disease location identified the association between SNP rs2306801 and ileal CD (P=0.01). Non-inflamed ileal mucosa from CD patients carrying any of the common disease-predisposing NOD2 variants (R702W, G908R, 1007fs) had significantly reduced levels of KCNN4 mRNA expression (P=0.001). KCNN4 protein expression was detected in Paneth cells, and in T cells in inflamed lamina propria.CONCLUSIONS: Our data implicate the role of KCNN4 in ileal CD. The dual roles of KCNN4 in Paneth cell secretion and T-cell activation and also its nature as a potassium channel make it an important and practical therapeutic target.