炎症性肠病与一种肿瘤坏死因子（TNF）多态性相关，这种多态性会影响有机阳离子转运体1（OCT1）与核因子-κB（NF-κB）转录因子之间的相互作用。
Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors.
作者信息
van Heel David A, Udalova Irina A, De Silva Arjuna P, McGovern Dermot P, Kinouchi Yoshitaka, Hull Jeremy, Lench Nicholas J, Cardon Lon R, Carey Alisoun H, Jewell Derek P, Kwiatkowski Dominic
机构信息
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
出版信息
Hum Mol Genet. 2002 May 15;11(11):1281-9. doi: 10.1093/hmg/11.11.1281.
Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.
肿瘤坏死因子-α（TNF）在炎症性肠病（IBD）中表达增加，且TNF定位于IBD3易感基因座。在两个独立的白种人队列中进行的传递不平衡和病例对照分析显示，TNF（-857C）启动子多态性与IBD存在新的关联（在587个IBD家族中总体P = 0.001）。在溃疡性结肠炎和克罗恩病中观察到TNF（-857C）与IBD亚表型有进一步的遗传关联，但仅在未携带常见NOD2突变的患者中出现。遗传数据提示为隐性遗传模式，并且我们观察到健康的TNF（-857C）纯合子中，体外脂多糖刺激的全血TNF产生更高。我们发现转录因子OCT1可结合TNF（-857T）而非TNF（-857C），并在体外和体内与促炎的NF（-κ）B转录因子p65亚基在相邻结合位点相互作用。除了对该基因密集区域进行进一步的遗传定位外，对肠道巨噬细胞中这些相互作用进行详细的功能分析，对于理解所观察到的TNF（-857C）与IBD关联的意义至关重要。
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