Fernandez-Reyes D, Craig A G, Kyes S A, Peshu N, Snow R W, Berendt A R, Marsh K, Newbold C I
Institute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
Hum Mol Genet. 1997 Aug;6(8):1357-60. doi: 10.1093/hmg/6.8.1357.
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.
疟原虫恶性疟原虫对人类基因组施加了强大的选择压力。这种生物体的特殊毒力被认为是由于被寄生的红细胞通过几种受体（包括CD36、血小板反应蛋白和细胞间粘附分子1（ICAM-1，CD54））与小血管内皮细胞粘附，并且不同的寄生虫分离株与每种受体结合的能力有所不同。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，我们对许多非洲人的ICAM-1 N末端结构域进行了测序，发现了一个高频出现的单一突变。病例对照研究样本中该位点的基因型表明该多态性与临床疟疾的严重程度相关，即该突变的纯合个体对脑型疟疾的易感性增加，相对风险为2。这些与直觉相反的结果对疟疾发病机制、对其他感染因子的抗性以及移植免疫学的机制具有启示意义。
