Glucose-6-phosphate dehydrogenase (G6PD) deficiency in Ethiopia: absence of common African and Mediterranean allelic variants in a nationwide study

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Abstract

Background

Building on the declining trend of malaria in Ethiopia, the Federal Ministry of Health aims to eliminate malaria by 2030. As Plasmodium falciparum and Plasmodium vivax are co-endemic in Ethiopia, the use of primaquine is indicated for both transmission interruption and radical cure, respectively. However, the limited knowledge of the local prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency and its associated variants has hindered the use of primaquine.

Methods

Some 11,138 dried blood spot (DBS) samples were collected in 2011 as part of a national, household Malaria Indicator Survey, a multi-stage nationally representative survey of all malaria-endemic areas of Ethiopia. A randomly selected sub-set of 1414 DBS samples was successfully genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique. Considering the geographical position and ethnic mix of the country, three common variants: G6PD*A (A376G), G6PD*A− (G202A) and Mediterranean (C563T) were investigated.

Results

Of the 1998 randomly selected individuals, 1429 (71.5%) DBS samples were genotyped and merged to the database, of which 53.5% were from females. G6PD*A (A376G) was the only genotype detected. No sample was positive for either G6PD*A− (G202A) or Mediterranean (C563T) variants. The prevalence of G6PD*A (A376G) was 8.9% [95% confidence interval (CI) 6.7–11.2] ranging from 12.2% in the Southern Nations, Nationalities and Peoples’ (95% CI 5.7–18.7) to none in Dire Dawa/Harari Region.

Conclusion

The common G6PD*A− (G202A) or Mediterranean (C563T) variants were not observed in this nationwide study. The observed G6PD*A (A376G) mutation has little or no clinical significance. These findings supported the adoption of primaquine for P. falciparum transmission interruption and radical cure of P. vivax in Ethiopia. As the presence of other clinically important, less common variants cannot be ruled out, the implementation of radical cure will be accompanied by active haematological and adverse events monitoring in Ethiopia.

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Most cited references 21

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G6PD deficiency: global distribution, genetic variants and primaquine therapy.

Simon Hay, Katherine Battle, Ari W Satyagraha … (2012)

Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination. Copyright © 2013 Elsevier Ltd. All rights reserved.

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G6PD deficiency.

E Beutler (1994)

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Spatial distribution of G6PD deficiency variants across malaria-endemic regions

Rosalind E. Howes, Mewahyu Dewi, Frédéric Piel … (2013)

Background Primaquine is essential for malaria control and elimination since it is the only available drug preventing multiple clinical attacks by relapses of Plasmodium vivax. It is also the only therapy against the sexual stages of Plasmodium falciparum infectious to mosquitoes, and is thus useful in preventing malaria transmission. However, the difficulties of diagnosing glucose-6-phosphate dehydrogenase deficiency (G6PDd) greatly hinder primaquine’s widespread use, as this common genetic disorder makes patients susceptible to potentially severe and fatal primaquine-induced haemolysis. The risk of such an outcome varies widely among G6PD gene variants. Methods A literature review was conducted to identify surveys of G6PD variant frequencies among representative population groups. Informative surveys were assembled into two map series: (1) those showing the relative proportions of the different variants among G6PDd individuals; and (2) those showing allele frequencies of G6PD variants based on population surveys without prior G6PDd screening. Results Variants showed conspicuous geographic patterns. A limited repertoire of variants was tested for across sub-Saharan Africa, which nevertheless indicated low genetic heterogeneity predominated by the G6PD A- 202A mutation, though other mutations were common in western Africa. The severe G6PD Mediterranean variant was widespread across western Asia. Further east, a sharp shift in variants was identified, with high variant heterogeneity in the populations of China and the Asia-Pacific where no single variant dominated. Conclusions G6PD variants exhibited distinctive region-specific distributions with important primaquine policy implications. Relative homogeneity in the Americas, Africa, and western Asia contrasted sharply with the heterogeneity of variants in China, Southeast Asia and Oceania. These findings will inform rational risk assessments for primaquine in developing public health strategies for malaria control and elimination, and support the future development of regionally targeted policies. The major knowledge gaps highlighted here strongly advocate for further investigation of G6PD variant diversity and their primaquine-sensitivity phenotypes.

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Author and article information

Contributors

Ashenafi Assefa:

ORCID: http://orcid.org/0000-0001-6093-6685

ashyaega@yahoo.com

Journal

Journal ID (nlm-ta): Malar J

Journal ID (iso-abbrev): Malar. J

Title: Malaria Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2875

Publication date (Electronic): 26 October 2018

Publication date PMC-release: 26 October 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 388

Affiliations

[1 ]GRID grid.452387.f, Ethiopian Public Health Institute, ; Addis Ababa, Ethiopia

[2 ]ISNI 0000 0001 1250 5688, GRID grid.7123.7, Addis Ababa University, ; Addis Ababa, Ethiopia

[3 ]Columbia University ICAP, Addis Ababa, Ethiopia

[4 ]US President’s Malaria Initiative, United States Agency for International Development, Addis Ababa, Ethiopia

[5 ]GRID grid.414835.f, Ethiopian Federal Ministry of Health, ; Addis Ababa, Ethiopia

[6 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, US President’s Malaria Initiative, Malaria Branch, Division of Parasitic Diseases and Malaria, , Centers for Disease Control and Prevention, ; Atlanta, GA USA

[7 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, Malaria Branch, Division of Parasitic Diseases and Malaria, , Centers for Disease Control and Prevention, ; Atlanta, GA USA

[8 ]ISNI 0000000100301493, GRID grid.62562.35, RTI International, ; Washington, DC USA

[9 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Global Health Group, , University of California San Francisco, ; San Francisco, CA USA

Author information

Ashenafi Assefa http://orcid.org/0000-0001-6093-6685

Article

Publisher ID: 2538

DOI: 10.1186/s12936-018-2538-4

PMC ID: 6204031

PubMed ID: 30367627

SO-VID: 177b3e72-d7cf-4286-bbf4-7b17b94d6396

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 June 2018

Date accepted : 20 October 2018

Funding

Funded by: This research was made possible through support provided by the U.S. President’s Malaria Initiative via the Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, U.S. Agency for International Development. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of the Centers for Disease Control and Prevention or the U.S. Agency for International Development. HT and JH receive salary support from the U.S. President’s Malaria Initiative.