CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1.
CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1.
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DOI：
10.1016/j.ebiom.2021.103806
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发表时间：
2022-01
期刊：
影响因子：
11.1
通讯作者：
Maeda Y
中科院分区：
文献类型：
--
作者：
Fink-Baldauf IM;Stuart WD;Brewington JJ;Guo M;Maeda Y
为了确定与新冠肺炎病严重程度相关的寄主遗传变异(SNP)，已经进行了一些全基因组关联研究。由于大多数已识别的变异位于非编码区，这些变异可能会影响邻近基因的表达，从而影响新冠肺炎的病情严重程度。然而，在很大程度上还不清楚哪些基因会受到这样的新冠肺炎基因座的影响。采用CRISPRi(干扰)技术，通过靶向新冠肺炎基因座附近区域(SNPs)的方法筛选肺上皮细胞株中受该基因座调控的基因。使用新冠肺炎收缩的人和猴肺单核/细胞(sn/sc)RNA-seq数据集，研究了CRISPRi识别基因的表达。CRISPRi分析表明，染色体3p21.31上rs11385942(与新冠肺炎疾病严重程度相关的区域)附近的一个区域显著影响了纤毛调节因子LZTFL1的表达(P<；0.05)。位于染色体19p13.2上rs74956615附近的一个区域(位于RAVER1的3‘非翻译外显子区域)影响了RAVER1(P<；0.05)的表达，RAVER1是MDA5的辅助激活因子(IFIH1)，它诱导包括ICAM 1在内的抗病毒反应基因。Sn/scRNA-seq数据集表明，MDA5/RAVER1-ICAM 1通路在新冠肺炎耐药猴的肺上皮细胞中被激活，但在新冠肺炎死亡者的肺上皮细胞中没有激活。携带rs11385942和rs74956615等位基因的患者可能是新冠肺炎危重病的易感基因，部分原因是LZTFL1介导的纤毛发生导致的呼吸道病毒清除减弱，以及MDA5/RAVER1途径导致的抗病毒免疫反应减弱。国家卫生研究院。
To identify host genetic variants (SNPs) associated with COVID-19 disease severity, a number of genome-wide association studies (GWAS) have been conducted. Since most of the identified variants are located at non-coding regions, such variants are presumed to affect the expression of neighbouring genes, thereby influencing COVID-19 disease severity. However, it remains largely unknown which genes are influenced by such COVID-19 GWAS loci. CRISPRi (interference)-mediated gene expression analysis was performed to identify genes functionally regulated by COVID-19 GWAS loci by targeting regions near the loci (SNPs) in lung epithelial cell lines. The expression of CRISPRi-identified genes was investigated using COVID-19-contracted human and monkey lung single-nucleus/cell (sn/sc) RNA-seq datasets. CRISPRi analysis indicated that a region near rs11385942 at chromosome 3p21.31 (locus of highest significance with COVID-19 disease severity at intron 5 of LZTFL1) significantly affected the expression of LZTFL1 (P<0.05), an airway cilia regulator. A region near rs74956615 at chromosome 19p13.2 (locus located at the 3’ untranslated exonic region of RAVER1), which is associated with critical illness in COVID-19, affected the expression of RAVER1 (P<0.05), a coactivator of MDA5 (IFIH1), which induces antiviral response genes, including ICAM1. The sn/scRNA-seq datasets indicated that the MDA5/RAVER1-ICAM1 pathway was activated in lung epithelial cells of COVID-19-resistant monkeys but not those of COVID-19-succumbed humans. Patients with risk alleles of rs11385942 and rs74956615 may be susceptible to critical illness in COVID-19 in part through weakened airway viral clearance via LZTFL1-mediated ciliogenesis and diminished antiviral immune response via the MDA5/RAVER1 pathway, respectively. NIH.
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DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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Casanova JL
影响因子：
64.8
作者：
COVID-19 Host Genetics Initiative
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COVID-19 Host Genetics Initiative
影响因子：
64.8
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Regev A
影响因子：
46.9
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影响因子：
30.8
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