G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials
Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature Plasmodium falciparum gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in ind...
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Frontiers Media S.A.
2021-04-01
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| author | Nuno Sepúlveda Nuno Sepúlveda Lynn Grignard Jonathan Curry Laleta Mahey Guido J. H. Bastiaens Alfred B. Tiono Joseph Okebe Sam A. Coulibaly Bronner P. Gonçalves Bronner P. Gonçalves Muna Affara Alphonse Ouédraogo Edith C. Bougouma Guillaume S. Sanou Issa Nébié Kjerstin Lanke Sodiomon B. Sirima Alassane Dicko Umberto d’Alessandro Umberto d’Alessandro Taane G. Clark Taane G. Clark Susana Campino Ingrid Chen Alice C. Eziefula Alice C. Eziefula Roly Gosling Teun Bousema Teun Bousema Chris Drakeley |
| author_facet | Nuno Sepúlveda Nuno Sepúlveda Lynn Grignard Jonathan Curry Laleta Mahey Guido J. H. Bastiaens Alfred B. Tiono Joseph Okebe Sam A. Coulibaly Bronner P. Gonçalves Bronner P. Gonçalves Muna Affara Alphonse Ouédraogo Edith C. Bougouma Guillaume S. Sanou Issa Nébié Kjerstin Lanke Sodiomon B. Sirima Alassane Dicko Umberto d’Alessandro Umberto d’Alessandro Taane G. Clark Taane G. Clark Susana Campino Ingrid Chen Alice C. Eziefula Alice C. Eziefula Roly Gosling Teun Bousema Teun Bousema Chris Drakeley |
| author_sort | Nuno Sepúlveda |
| collection | DOAJ |
| description | Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature Plasmodium falciparum gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked G6PD gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [−log10(p-value) = 2.44] and two less-known SNPs, rs2230037 [−log10(p-value] = 2.60), and rs28470352 [−log10(p-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other (R2 = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ. |
| first_indexed | 2024-12-24T11:11:12Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-24T11:11:12Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-6bc0084ed7fc40678dd9adc28f1490fb2022-12-21T16:58:31ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-04-011210.3389/fgene.2021.645688645688G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical TrialsNuno Sepúlveda0Nuno Sepúlveda1Lynn Grignard2Jonathan Curry3Laleta Mahey4Guido J. H. Bastiaens5Alfred B. Tiono6Joseph Okebe7Sam A. Coulibaly8Bronner P. Gonçalves9Bronner P. Gonçalves10Muna Affara11Alphonse Ouédraogo12Edith C. Bougouma13Guillaume S. Sanou14Issa Nébié15Kjerstin Lanke16Sodiomon B. Sirima17Alassane Dicko18Umberto d’Alessandro19Umberto d’Alessandro20Taane G. Clark21Taane G. Clark22Susana Campino23Ingrid Chen24Alice C. Eziefula25Alice C. Eziefula26Roly Gosling27Teun Bousema28Teun Bousema29Chris Drakeley30Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomCEAUL – Centro de Estatística e Aplicações da Universidade de Lisboa, Lisbon, PortugalDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomLGC Genomics, Hertfordshire, United KingdomLGC Genomics, Hertfordshire, United KingdomDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of International Public Health, Liverpool School of Tropical Medicine, Liverpool, United KingdomDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomDepartment of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United KingdomMRC Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, GambiaDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Public Health, Centre National de Recherche et de Formation sur le Paludisme & Institut National de Santé Publique, Ouagadougou, Burkina FasoMalaria Research and Training Centre, Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technology of Bamako, Bamako, MaliMRC Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, Gambia0Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United KingdomDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomDepartment of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United KingdomDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom1Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom2Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom1Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United KingdomPrimaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature Plasmodium falciparum gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked G6PD gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [−log10(p-value) = 2.44] and two less-known SNPs, rs2230037 [−log10(p-value] = 2.60), and rs28470352 [−log10(p-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other (R2 = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ.https://www.frontiersin.org/articles/10.3389/fgene.2021.645688/fullgenetic association studyclinical trialsmalariadrug safetyhemoglobin |
| spellingShingle | Nuno Sepúlveda Nuno Sepúlveda Lynn Grignard Jonathan Curry Laleta Mahey Guido J. H. Bastiaens Alfred B. Tiono Joseph Okebe Sam A. Coulibaly Bronner P. Gonçalves Bronner P. Gonçalves Muna Affara Alphonse Ouédraogo Edith C. Bougouma Guillaume S. Sanou Issa Nébié Kjerstin Lanke Sodiomon B. Sirima Alassane Dicko Umberto d’Alessandro Umberto d’Alessandro Taane G. Clark Taane G. Clark Susana Campino Ingrid Chen Alice C. Eziefula Alice C. Eziefula Roly Gosling Teun Bousema Teun Bousema Chris Drakeley G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials Frontiers in Genetics genetic association study clinical trials malaria drug safety hemoglobin |
| title | G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials |
| title_full | G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials |
| title_fullStr | G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials |
| title_full_unstemmed | G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials |
| title_short | G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials |
| title_sort | g6pd polymorphisms and hemolysis after antimalarial treatment with low single dose primaquine a pooled analysis of six african clinical trials |
| topic | genetic association study clinical trials malaria drug safety hemoglobin |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.645688/full |
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