State Key Laboratory of Pathogen and Bio-Security, Beijing Institute of Biotechnology, Beijing, China.
PLoS One. 2011;6(8):e23730. doi: 10.1371/journal.pone.0023730. Epub 2011 Aug 17.
Genetic background may play an important role in the process of SARS-CoV infection and SARS development. We found several proteins that could interact with the nucleocapsid protein of the SARS coronavirus (SARS-CoV). α-2-Heremans-Schmid Glycoprotein (AHSG), which is required for macrophage deactivation by endogenous cations, is associated with inflammatory regulation. Cytochrome P450 Family 3A (CYP4F3A) is an ω-oxidase that inactivates Leukotriene B4 (LTB4) in human neutrophils and the liver. We investigated the association between the polymorphisms of these two inflammation-associated genes and SARS development. The linkage disequilibrium (LD) maps of these two genes were built with Haploview using data on CHB+JPT (version 2) from the HapMap. A total of ten tag SNPs were selected and genotyped. In the Guangzhou cohort study, after adjusting for age and sex, two AHSG SNPs and one CYP4F3 SNP were found to be associated with SARS susceptibility: rs2248690 (adjusted odds ratio [AOR] 2.42; 95% confidence interval [CI] 1.30-4.51); rs4917 (AOR 1.84; 95% CI 1.02-3.34); and rs3794987 (AOR 2.01; 95% CI 1.10-3.68). To further validate the association, the ten tag SNPs were genotyped in the Beijing cohort. After adjusting for age and sex, only rs2248690 (AOR, 1.63; 95% CI, 1.30-2.04) was found to be associated with SARS susceptibility. The combined analysis of the two studies confirmed tag SNP rs2248690 in AHSG as a susceptibility variant (AOR 1.70; 95% CI 1.37-2.09). The statistical analysis of the rs2248690 genotype data among the patients and healthy controls in the HCW cohort, who were all similarly exposed to the SARS virus, also supported the findings. Further, the SNP rs2248690 affected the transcriptional activity of the AHSG promoter and thus regulated the AHSG serum level. Therefore, our study has demonstrated that the AA genotype of rs2268690, which leads to a higher AHSG serum concentration, was significantly associated with protection against SARS development.
遗传背景可能在 SARS-CoV 感染和 SARS 发展过程中发挥重要作用。我们发现了几种可能与 SARS 冠状病毒（SARS-CoV）核衣壳蛋白相互作用的蛋白质。α-2-赫姆斯-施密特糖蛋白（AHSG）是一种内源性阳离子使巨噬细胞失活所必需的蛋白，与炎症调节有关。细胞色素 P450 家族 3A（CYP4F3A）是一种 ω-氧化酶，可使人类中性粒细胞和肝脏中的白三烯 B4（LTB4）失活。我们研究了这两个与炎症相关的基因的多态性与 SARS 发展之间的关系。使用来自 HapMap 的 CHB+JPT（版本 2）的数据，使用 Haploview 构建了这两个基因的连锁不平衡（LD）图谱。共选择了 10 个标记 SNP 并进行了基因分型。在广州队列研究中，在调整年龄和性别后，发现两个 AHSG SNP 和一个 CYP4F3 SNP 与 SARS 易感性相关：rs2248690（调整后的优势比 [AOR] 2.42；95%置信区间 [CI] 1.30-4.51）；rs4917（AOR 1.84；95% CI 1.02-3.34）；和 rs3794987（AOR 2.01；95% CI 1.10-3.68）。为了进一步验证相关性，对北京队列中的 10 个标记 SNP 进行了基因分型。在调整年龄和性别后，仅发现 rs2248690（AOR，1.63；95% CI，1.30-2.04）与 SARS 易感性相关。两项研究的综合分析证实，AHSG 中的标记 SNP rs2248690 是一个易感变异（AOR 1.70；95% CI 1.37-2.09）。在 SARS 病毒暴露情况相似的 HCW 队列中，对患者和健康对照者的 rs2248690 基因型数据进行的统计分析也支持了这一发现。此外，SNP rs2248690 影响 AHSG 启动子的转录活性，从而调节 AHSG 血清水平。因此，我们的研究表明，rs2268690 的 AA 基因型导致 AHSG 血清浓度升高，与 SARS 发展的保护作用显著相关。
