ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility.
ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility.
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DOI：
10.3389/fgene.2021.698033
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发表时间：
2021
影响因子：
3.7
通讯作者：
Polimanti R
中科院分区：
文献类型：
--
作者：
Pathak GA;Wendt FR;Goswami A;Koller D;De Angelis F;COVID-19 Host Genetics Initiative;Polimanti R
血管紧张素转换酶-2（ACE 2）受体已被确定为SARS-CoV-2传播的关键粘附分子。然而，没有证据表明ACE 2的人类遗传变异是COVID-19易感性的唯一原因。因此，我们对与ACE 2相互作用的基因（ACE 2-gene network）进行了综合性多水平表征，以获得COVID-19背景下统计学上丰富的生物学特性。包括ACE 2在内的51个基因与4，756个性状（分为26个表型类别）的全表型关联显示了免疫、呼吸、环境、骨骼、皮肤和代谢领域的富集（p <4 e-4）。ACE 2基因网络的转录组调控在肾脏、小肠和结肠中因组织特异性而富集（p < 4.7e-4）。利用药物-基因相互作用数据库，我们确定了47种药物，包括地塞米松和螺内酯等。考虑到ACE 2网络基因± 10 kb内的遗传变异，我们鉴定出了可能因遗传变异而改变结合位点的miRNA。鉴定的miRNAs揭示了炎症、衰老、糖尿病和心脏病的统计学过度表达。在COVID-19易感性的全基因组关联研究（GWAS）中观察到RORA、SLC 12 A6和SLC 6A 19基因的遗传变异关联。我们还报道了在3p21.31位点的GWAS鉴定的变异体，作为RORA和RORC基因的反式QTL。总体而言，ACE 2基因网络的功能特征突出了COVID-19易感性的几种潜在机制。这些数据也可以在https://gpwhiz.github.io/ACE2Netlas/上获得。
Angiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p < 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p < 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within ± 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in RORA, SLC12A6, and SLC6A19 genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for RORA and RORC genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/.
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