Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis
Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis
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DOI：
10.1093/hmg/ddh008
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Brant, SR
中科院分区：
文献类型：
--
作者：
Karban, AS;Okazaki, T;Brant, SR
核因子-κ B（NF-κ B）是免疫应答、细胞凋亡和细胞生长控制基因的主要转录调节因子，并且在炎症性肠病（IBD）、溃疡性结肠炎（UC）和克罗恩病中上调。NFKB 1基因编码NF-κ B p105/p50同种型。IBD家族中的全基因组筛选显示在染色体4 q上连锁的证据，其中NFKB 1映射。我们对10例IBD先证者和2例对照者的NFKB 1启动子、外显子1和所有编码外显子进行了测序，并鉴定了6种核苷酸变异，包括一种常见的插入/缺失启动子多态性（-94ins/delATTG）。使用基于家系的传递不平衡检验，我们观察到在235个IBD家系中的131个具有UC后代的IBD家系中，-94delATTG等位基因与UC之间存在独立于连锁的连锁不平衡（LD）的适度证据（P=0.047-0.052）。该等位基因在来自235个IBD家系的156个非犹太UC先证者中也比在149个非犹太对照中更频繁（P=0.015）。在第二组258例无关的非犹太人UC病例和653例新的非犹太人对照中，-94delATTG与UC的相关性得到了重复（P=0.021）。来自正常人结肠组织和结肠细胞系的核蛋白，而不是回肠组织，显示出与含有-94insATTG但不与含有-94delATTG的寡核苷酸显著结合。含有-94delATTG等位基因的NFKB 1启动子/外显子1荧光素酶报告质粒构建体转染到HeLa或HT-29细胞系中，其启动子活性低于含有-94insATTG等位基因的可比较构建体。因此，我们已经确定了第一个潜在的功能多态性NFKB 1，并证明其与人类常见疾病，溃疡性结肠炎的遗传关联。
Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.