1. Epidemiology and Global Health
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Protective effect of Mediterranean type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

  1. Ghulam R Awab
  2. Fahima Aaram
  3. Natsuda Jamornthanyawat
  4. Kanokon Suwannasin
  5. Watcharee Pagornrat
  6. James A Watson
  7. Charles J Woodrow
  8. Arjen M Dondorp
  9. Nicholas PJ Day
  10. Mallika Imwong
  11. Nicholas J White  Is a corresponding author
  1. Nangarhar Medical Faculty, Afghanistan
  2. Kabul Medical University, Afghanistan
  3. Mahidol University, Thailand
  4. Mahidol Oxford Tropical Medicine Research Unit, Thailand
  5. Mahidol-Oxford Tropical Medicine Research Unit, Thailand
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Cite this article as: eLife 2021;10:e62448 doi: 10.7554/eLife.62448

Abstract

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% CI 58-88) in hemizygous males and homozygous females combined, and 55% (95% CI 38-68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.

Data availability

All data used in the analysis are available along with the code which is given in the supplementary materials.

Article and author information

Author details

  1. Ghulam R Awab

    Nangarhar Medical Faculty, Jalalabad, Afghanistan
    Competing interests
    The authors declare that no competing interests exist.
  2. Fahima Aaram

    Medicine, Kabul Medical University, Kabul, Afghanistan
    Competing interests
    The authors declare that no competing interests exist.
  3. Natsuda Jamornthanyawat

    Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  4. Kanokon Suwannasin

    Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  5. Watcharee Pagornrat

    Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  6. James A Watson

    Nuffield Department of Medicine, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  7. Charles J Woodrow

    Faculty of Medicine, Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  8. Arjen M Dondorp

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5190-2395
  9. Nicholas PJ Day

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  10. Mallika Imwong

    Department of Molecular Tropical Medicine and Genetics, Mahidol University, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
  11. Nicholas J White

    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    For correspondence
    nickw@tropmedres.ac
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978

Funding

Wellcome Trust: Principle Fellowship of NJ White (093956/Z/10/Z)

  • Ghulam R Awab

Wellcome Trust: Major Overseas Programme-Thailand Unit Core Grant (093956/Z/10/Z)

  • Kanokon Suwannasin

Wellcome Trust: Training Fellowship (107548Z/15/Z)

  • Ghulam R Awab

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The clinical studies were approved by the Institutional Review Board of the Afghan Public Health Institute, Ministry of Public Health, Afghanistan, the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, Thailand, and the Oxford Tropical Research Ethics Committee, Oxford University, UK.

Reviewing Editor

  1. Amy Wesolowski, Johns Hopkins Bloomberg School of Public Health, United States

Publication history

  1. Received: August 25, 2020
  2. Accepted: February 3, 2021
  3. Accepted Manuscript published: February 5, 2021 (version 1)
  4. Version of Record published: February 15, 2021 (version 2)

Copyright

© 2021, Awab et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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    Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.

    Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10-year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.

    Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR <0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47% decrease to a 118% increase. Mediation analyses revealed 28.5% of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7% (P = 0.003) via systolic blood pressure and 6.4% (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.

    Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and BP-related pathways to CHD risk.

    Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key and Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).