Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.

中文翻译：

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染色体 21q22.1 疟疾易感位点的正复制和连锁不平衡作图。


四个细胞因子受体基因位于 Chr21q22.11 上，编码干扰素 α 受体的 α 和 β 亚基（IFNAR1 和 IFNAR2）、白细胞介素 10 受体的 β 亚基（IL10RB）和干扰素 γ 受体的第二亚基(IFNGR2)。我们之前报道过 IFNAR1 的两种变异与冈比亚人对疟疾的易感性有关。现在，我们利用从公共数据库获得的 45 个额外遗传标记，并对 24 名冈比亚儿童（12 例/12 名对照）的 IFNAR1 基因内部和周围的 44 kb 区域进行测序，对相关区域进行了广泛的精细绘图。在 IFNAR1 基因中，新研究的 C --> G 单核苷酸多态性（IFNAR1 272354c-g）位于相对于转录起始位置的 -576 位置，被发现与严重疟疾的易感性更为密切相关。在三个人群中观察到关联：冈比亚（P=0.002）、肯尼亚（P=0.022）和越南（P=0.005）病例对照研究。当使用 Mantel-Haenszel 检验将所有三项研究合并时，IFNAR1 -576G 的存在与严重疟疾风险显着升高相关（N=2444，OR=1.38，95% CI：1.17-1.64；P=1.7 x 10(-4))。这项研究以之前的工作为基础，进一步强调了 I 型干扰素通路在疟疾易感性中的重要性，并说明了在多个人群的高度连锁不平衡区域内对 SNP 进行分型以确认初始正相关的效用。