Genetic Profiles in Pharmacogenes Indicate Personalized Drug Therapy for COVID-19

  1. Lei-Yun Wang
  2. Jia-Jia Cui
  3. Qian-Ying OuYang
  4. Yan Zhan
  5. Yi-Min Wang
  6. Xiang-Yang Xu
  7. Cheng-Xian Guo
  8. Ji-Ye Yin

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Abstract

Background

The coronavirus disease 2019 (COVID-19) has become a global pandemic currently. Many drugs showed potential for COVID-19 therapy. However, genetic factors which can lead to different drug efficiency and toxicity among populations are still undisclosed in COVID-19 therapy.

Methods

We selected 67 potential drugs for COVID-19 therapy (DCTs) from clinical guideline and clinical trials databases. 313 pharmaco-genes related to these therapeutic drugs were included. Variation information in 125,748 exomes were collected for racial differences analyses. The expression level of pharmaco-genes in single cell resolution was evaluated from single-cell RNA sequencing (scRNA-seq) data of 17 healthy adults.

Results

Pharmacogenes, including CYP3A4, ABCB1, SLCO1B1, ALB, CYP3A5, were involved in the process of more than multi DCTs. 224 potential drug-drug interactions (DDIs) of DCTs were predicted, while 112 of them have been reported. Racial discrepancy of common nonsynonymous mutations was found in pharmacogenes including: VDR, ITPA, G6PD, CYP3A4 and ABCB1 which related to DCTs including ribavirin, α-interferon, chloroquine and lopinavir. Moreover, ACE2, the target of 2019-nCoV, was only found in parts of lung cells, which makes drugs like chloroquine that prevent virus binding to ACE2 more specific than other targeted drugs such as camostat mesylate.

Conclusions

At least 17 drugs for COVID-19 therapy with predictable pharmacogenes should be carefully utilized in risk races which are consisted of more risk allele carriers. At least 29 drugs with potential of DDIs are reported to be affected by other DDIs, they should be replaced by similar drugs without interaction if it is possible. Drugs which specifically targeted to infected cells with ACE2 such as chloroquine are preferred in COVID-19 therapy.

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    SciScore for 10.1101/2020.03.23.20041350: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    , Clinical Trails (https://clinicaltrials.gov) and Chine se Clinical Trail Registry (http://www.chictr.org.cn).
    https://clinicaltrials.gov
    suggested: (ClinicalTrials.gov, RRID:SCR_002309)
    The pharmacogenes related to all drugs were obtained from DrugBank (https://www.drugbank.ca/) and Phar mGKB (https://www.pharmgkb.org/) databases.
    DrugBank
    suggested: (DrugBank, RRID:SCR_002700)
    https://www.pharmgkb.org/
    suggested: (PharmGKB, RRID:SCR_002689)
    Genetic variation data on each of the genes were retrieved from Gnom AD database (http://gnomad.broadinstitute.org/, version: 2.1.1).
    http://gnomad.broadinstitute.org/
    suggested: (Genome Aggregation Database, RRID:SCR_014964)
    Genetic variations annotation and drug-gene network construction: All genetic variations were annotated by allele frequency, location and function in different populations using ANNOVAR (version: 2019Oct24) (Table S1).
    ANNOVAR
    suggested: (ANNOVAR, RRID:SCR_012821)
    Functional nonsynonymous mutations were predicted by PROVEAN (http://provean.jcvi.org/).
    PROVEAN
    suggested: (PROVEAN, RRID:SCR_002182)
    The drug-gene network was constructed by Cytoscape software (version:3.7.1) [10].
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04252664SuspendedA Trial of Remdesivir in Adults With Mild and Moderate COVID…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.03.23.20041350v1 on medRxiv