A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya
A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya
复制标题
DOI：
10.1093/hmg/6.8.1357
复制
发表时间：
1997-08-01
影响因子：
3.5
通讯作者：
Newbold, CI
中科院分区：
文献类型：
--
作者：
FernandezReyes, D;Craig, AG;Newbold, CI
疟疾寄生虫恶性疟原虫（Plasmodium falciparum）在人类基因组上起着强有力的选择力的作用，这种生物体的特定毒力被认为是由于寄生的红细胞通过几种受体（包括CD 36、血小板反应蛋白和细胞间粘附分子1）粘附到小血管内皮上免疫组织化学研究表明ICAM-1在脑型疟疾的发病机制中具有潜在的重要性，这使我们推断，如果任何单一受体参与脑型疟疾的发展，那么鉴于该并发症的高死亡率，自然选择应该产生结合能力降低的变体，因此，我们对一些非洲人的ICAM-1的N-末端结构域进行了测序，发现了一个高频率的单一突变，从一个病例的样本中提取的基因型-对照研究表明，多态性与临床疟疾的严重程度相关，因此突变纯合子的个体对疟疾的易感性增加。这些违反直觉的结果对疟疾发病机制、对其他感染因子的抗性和移植免疫学具有意义。
The malarial parasite Plasmodium falciparum has acted as a potent selective force on the human genome, The particular virulence of this organism is thought to be due to the adherence of parasitised red blood cells to small vessel endothelium through several receptors, including CD36, thrombospondin and intercellular adhesion molecule 1 (ICAM-1, CD54), and parasite isolates differ in their ability to bind to each, Immunohistochemical studies have implicated ICAM-1 as of potential importance in the pathogenesis of cerebral malaria, leading us to reason that if any single receptor were involved in the development of cerebral malaria, then in view of the high mortality of that complication, natural selection should have produced variants with reduced binding capacity, We therefore sequenced the N-terminal domain of ICAM-1 from a number of Africans and discovered a single mutation present at high frequency, Genotypes at this locus from samples from a case-control study indicated an association of the polymorphism with the severity of clinical malaria such that individuals homozygous for the mutation have increased susceptibility to cerebral malaria with a relative risk of two, These counterintuitive results have implications for the mechanism of malaria pathogenesis, resistance to other infectious agents and transplantation immunology.