McGuire W, Hill A V, Allsopp C E, Greenwood B M, Kwiatkowski D
Department of Paediatrics, John Radcliffe Hospital, Oxford, UK.
Nature. 1994 Oct 6;371(6497):508-10. doi: 10.1038/371508a0.
Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage.
肿瘤坏死因子-α（TNF-α）被认为在严重传染病的发病机制中起重要作用，而致命性脑型疟疾与这种细胞因子的高循环水平相关。在一项针对冈比亚儿童的大型病例对照研究中，我们发现TNF2等位基因（TNF-α基因启动子区域的一个变体）的纯合子因脑型疟疾导致死亡或严重神经后遗症的相对风险为7。尽管TNF2等位基因与几个相邻的HLA等位基因处于连锁不平衡状态，但我们表明这种疾病关联独立于HLA I类和II类变异。这些数据表明细胞因子基因的调控多态性可影响严重感染的结局。TNF2等位基因在冈比亚以0.16的基因频率维持，这意味着纯合子中脑型疟疾风险的增加被某种生物学优势所抵消。
