PDF(Pubmed)
Abstract：
Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.
摘要：
感染拉沙病毒（LASV）可引起拉沙热，出血性疾病，估计死亡率为29.7%，但对许多人没有或轻微的症状。这里,为了研究人类遗传变异是否是LASV感染异质性的基础，我们进行了全基因组关联研究（GWAS）以及血清阳性率调查，人类白细胞抗原分型和高通量变异功能鉴定试验。我们分析了尼日利亚和塞拉利昂在7年内招募的533例拉沙热病例和1,986名人口对照组的拉沙热易感性和致命结局。我们在尼日利亚队列中的GRM7和LIF附近检测到了与拉沙热致命结局相关的全基因组显著变异。我们还表明，具有阳性选择和重叠LARGE1特征的单倍型，这是必需的LASV进入因子，在尼日利亚队列中与拉沙热风险降低相关,但在塞拉利昂队列中与拉沙热风险降低相关.总的来说,我们确定了可能影响严重拉沙热风险的变异和基因，证明GWAS如何提供对病毒发病机制的见解。
