Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria
Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria
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DOI：
10.1007/s00439-002-0882-4
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发表时间：
2003-04-01
期刊：
影响因子：
5.3
通讯作者：
Kwiatkowski, DP
中科院分区：
文献类型：
--
作者：
Burgner, D;Usen, S;Kwiatkowski, DP
为了评估一氧化氮在脑型疟疾发病机制中起关键作用的假设，我们分析了NOS2A基因近端启动子区域的遗传变异，NOS2A基因编码诱导型一氧化氮合酶。对72条冈比亚染色体进行测序，发现11个2.5 kB的单核苷酸多态性（theta = 8.6 x 10(-4)）。104个核心家族的基因分型鉴定出6种常见的单倍型。通过对334名患病儿童及其父母的传播不平衡检验，发现由NOS2A-1659T等位基因定义的单倍型与脑型疟疾相关（P = 0.02）。来自同一人群的505名不同儿童的独立病例对照研究证实了与脑型疟疾相关的等位基因（优势比：1.31,P = 0.04）。综上所述，这些数据表明NOS2A基因座与脑型疟疾易感性之间存在微弱但显著的关联。尽管在整个研究区域中存在高度的连锁不平衡，但如果没有用于单倍型标记的密集标记集的初始构建，这种关联就不会被检测到。
To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (theta = 8.6 x 10(-4)). Genotyping 104 nuclear families identified six common haplotypes. A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium test of 334 affected children and their parents (P = 0.02). An independent case-control study of 505 different children from the same population replicated the allelic association with cerebral malaria (odds ratio: 1.31, P = 0.04). Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria. Despite high linkage disequilibrium across the region studied, this association would not have been detected without the initial construction of a dense marker set for haplotype tagging.