A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria
A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria
复制标题
DOI：
10.1038/9649
复制
发表时间：
1999-06-01
期刊：
影响因子：
30.8
通讯作者：
Kwiatkowski, D
中科院分区：
文献类型：
--
作者：
Knight, JC;Udalova, I;Kwiatkowski, D
细胞因子启动子区的遗传变异被认为影响感染的易感性，但这种多态性影响基因调控的分子机制尚不清楚。通过系统的DNA足迹的TNF（编码肿瘤坏死因子，TNF）启动子区域，我们已经确定了一个单核苷酸多态性（SNP），导致螺旋-转角-螺旋转录因子OCT-1结合到一个新的区域的复杂的蛋白质-DNA相互作用，并改变人类单核细胞的基因表达。OCT-1结合基因型，发现在大约5%的非洲人，与四倍增加脑型疟疾的易感性在西非和东非人口的大型病例对照研究，校正其他已知的TNF多态性和相关的HLA等位基因。
Genetic Variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene, regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.