G6PD distribution in sub-Saharan Africa and potential risks of using chloroquine/hydroxychloroquine based treatments for COVID-19

  1. Jorge E. B. da Rocha
  2. Houcemeddine Othman
  3. Caroline T. Tiemessen
  4. Gerrit Botha
  5. Michèle Ramsay
  6. Collen Masimirembwa
  7. Clement Adebamowo
  8. Ananyo Choudhury
  9. Jean-Tristan Brandenburg
  10. Mogomotsi Matshaba
  11. Gustave Simo
  12. Francisco-Javier Gamo
  13. Scott Hazelhurst
  14. as members of the H3Africa Consortium
  15. Jorge E. B. da Rocha

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Chloroquine/hydroxychloroquine have been proposed as potential treatments for COVID-19. These drugs have warning labels for use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Analysis of whole genome sequence data of 458 individuals from sub-Saharan Africa showed significant G6PD variation across the continent. We identified nine variants, of which four are potentially deleterious to G6PD function, and one (rs1050828) that is known to cause G6PD deficiency. We supplemented data for the rs1050828 variant with genotype array data from over 11,000 Africans. Although this variant is common in Africans overall, large allele frequency differences exist between sub-populations. African sub-populations in the same country can show significant differences in allele frequency (e.g. 16.0% in Tsonga vs 0.8% in Xhosa, both in South Africa, p  = 2.4 × 10 − 3 ). The high prevalence of variants in the G6PD gene found in this analysis suggests that it may be a significant interaction factor in clinical trials of chloroquine and hydroxychloroquine for treatment of COVID-19 in Africans.

Article activity feed

  1. Version published to 10.1038/s41397-021-00242-8
  2. ScreenIT

    SciScore for 10.1101/2020.05.27.20114066: (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
    Variants were called with Haplotype-Caller in gVCF mode using GATK v.
    GATK
    suggested: (GATK, RRID:SCR_001876)
    4.0.8.1 HAAD gVCFs (along with gVCFs produced with African 1000 Genomes Project data (KGA) [2]) were combined with GATK’s CombineGVCF (v.4.0.8.1), and jointly called with GenotypeGVCFs (v4.1.3.0) and followed GATK’s best practice guidelines.
    1000 Genomes Project
    suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
    The G6PD canonical gene region (chrX:153759606-153775469) was extracted with bcftools v1.9, and variants were annotated (e.g. as missense, intronic etc.) with variant effect predictor (VEP) v92.0 [24] and SNPeff v4.3t [6].
    bcftools
    suggested: (SAMtools/BCFtools, RRID:SCR_005227)
    SNPeff
    suggested: (SnpEff, RRID:SCR_005191)
    Functional annotation for these variants was performed using dbNSFP [15] to retrieve scores for five predictive toolsets (LRT, MutationAssessor, PROVEAN, VEST3 and CADD), which were then used for prediction based on a pharmacogene optimised model [43].
    MutationAssessor
    suggested: (MutationAssessor, RRID:SCR_005762)
    PROVEAN
    suggested: (PROVEAN, RRID:SCR_002182)
    PLINK [4] was used to remove any individuals with more than 1% missingness or genotypes which conflicted with declared sex.
    PLINK
    suggested: (PLINK, RRID:SCR_001757)
    The data was analysed using a custom Python script using the pandas-plink library (https://github.com/limix/pandas-plink).
    Python
    suggested: (IPython, RRID:SCR_001658)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This highlights the limitation of reporting allele frequency by country rather than ethnolinguistic groups. African populations undergoing COVID-19 CQ/HCQ treatment trials may not have the same relative frequency of this allele as others. Thus we urge that models for G6PD related effects based on a single proxy African population are not directly transferable to other Africans, even those close geographically. We observed other potentially deleterious variants in the African populations we studied. For instance, rs34193178 and chrX:g.153762577 A>G, which were not found across all populations, do not have well characterised effects, and are unlikely to be included in assays to type well known G6PD variants. If these have a functional impact on G6DPD, they may add complexities to studies assessing the presence of rs1050828 and rs1050829 alone. The chrX:g.153762577 A>G variant in particular has structural evidence for deleterious functional impact. Although use of either CQ/HCQ is not new in African populations, the dosage and duration of CQ/HCQ treatment for COVID-19 may lead to higher prevalence of adverse effects related to G6PD deficiency. Acute haemolysis has been observed in a G6PD deficient male suspected of carrying the G6PD Mediterranean variant (rs5030868) who was treated with lopinavir and HCQ [8]. Although the Mediterranean variant is known to induce a greater sensitivity to pro-oxidant drugs than the A-variant [43], the observation of haemolytic effects highlights t...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.05.27.20114066v1 on medRxiv