Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines
Abstract Background It was hypothesized that glucose-6-phosphate dehydrogenase (G6PD) deficiency confers a protective effect against malaria infection, however, safety concerns have been raised regarding haemolytic toxicity caused by radical cure with 8-aminoquinolines in G6PD-deficient individuals....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Malaria Journal |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12936-024-04864-8 |
| _version_ | 1827328535777247232 |
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| author | Usa Boonyuen Beatriz Aira C. Jacob Jutamas Wongwigkan Kamonwan Chamchoy Natsamon Singha-art Natnicha Pengsuk Duantida Songdej Emily R. Adams Thomas Edwards Supat Chamnanchanunt Syazwani Itri Amran Nurriza Ab Latif Naveen Eugene Louis Shamini Chandran |
| author_facet | Usa Boonyuen Beatriz Aira C. Jacob Jutamas Wongwigkan Kamonwan Chamchoy Natsamon Singha-art Natnicha Pengsuk Duantida Songdej Emily R. Adams Thomas Edwards Supat Chamnanchanunt Syazwani Itri Amran Nurriza Ab Latif Naveen Eugene Louis Shamini Chandran |
| author_sort | Usa Boonyuen |
| collection | DOAJ |
| description | Abstract Background It was hypothesized that glucose-6-phosphate dehydrogenase (G6PD) deficiency confers a protective effect against malaria infection, however, safety concerns have been raised regarding haemolytic toxicity caused by radical cure with 8-aminoquinolines in G6PD-deficient individuals. Malaria elimination and control are also complicated by the high prevalence of G6PD deficiency in malaria-endemic areas. Hence, accurate identification of G6PD deficiency is required to identify those who are eligible for malaria treatment using 8-aminoquinolines. Methods The prevalence of G6PD deficiency among 408 Thai participants diagnosed with malaria by microscopy (71), and malaria-negative controls (337), was assessed using a phenotypic test based on water-soluble tetrazolium salts. High-resolution melting (HRM) curve analysis was developed from a previous study to enable the detection of 15 common missense, synonymous and intronic G6PD mutations in Asian populations. The identified mutations were subjected to biochemical and structural characterisation to understand the molecular mechanisms underlying enzyme deficiency. Results Based on phenotypic testing, the prevalence of G6PD deficiency (< 30% activity) was 6.13% (25/408) and intermediate deficiency (30–70% activity) was found in 15.20% (62/408) of participants. Several G6PD genotypes with newly discovered double missense variants were identified by HRM assays, including G6PD Gaohe + Viangchan, G6PD Valladolid + Viangchan and G6PD Canton + Viangchan. A significantly high frequency of synonymous (c.1311C>T) and intronic (c.1365-13T>C and c.486-34delT) mutations was detected with intermediate to normal enzyme activity. The double missense mutations were less catalytically active than their corresponding single missense mutations, resulting in severe enzyme deficiency. While the mutations had a minor effect on binding affinity, structural instability was a key contributor to the enzyme deficiency observed in G6PD-deficient individuals. Conclusions With varying degrees of enzyme deficiency, G6PD genotyping can be used as a complement to phenotypic screening to identify those who are eligible for 8-aminoquinolines. The information gained from this study could be useful for management and treatment of malaria, as well as for the prevention of unanticipated reactions to certain medications and foods in the studied population. |
| first_indexed | 2024-03-07T15:19:07Z |
| format | Article |
| id | doaj.art-8d6ac690322f4154b192ebeed6d537c9 |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-03-07T15:19:07Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-8d6ac690322f4154b192ebeed6d537c92024-03-05T17:45:16ZengBMCMalaria Journal1475-28752024-02-0123111710.1186/s12936-024-04864-8Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolinesUsa Boonyuen0Beatriz Aira C. Jacob1Jutamas Wongwigkan2Kamonwan Chamchoy3Natsamon Singha-art4Natnicha Pengsuk5Duantida Songdej6Emily R. Adams7Thomas Edwards8Supat Chamnanchanunt9Syazwani Itri Amran10Nurriza Ab Latif11Naveen Eugene Louis12Shamini Chandran13Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol UniversityDepartment of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol UniversityDepartment of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol UniversityPrincess Srisavangavadhana College of Medicine, Chulabhorn Royal AcademyDepartment of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol UniversityDepartment of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol UniversityDepartment of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversityCentre for Drugs and Diagnostics Research, Liverpool School of Tropical MedicineCentre for Drugs and Diagnostics Research, Liverpool School of Tropical MedicineDepartment of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol UniversityDepartment of Bioscience, Faculty of Science, Universiti Teknologi MalaysiaDepartment of Bioscience, Faculty of Science, Universiti Teknologi MalaysiaDepartment of Bioscience, Faculty of Science, Universiti Teknologi MalaysiaDepartment of Bioscience, Faculty of Science, Universiti Teknologi MalaysiaAbstract Background It was hypothesized that glucose-6-phosphate dehydrogenase (G6PD) deficiency confers a protective effect against malaria infection, however, safety concerns have been raised regarding haemolytic toxicity caused by radical cure with 8-aminoquinolines in G6PD-deficient individuals. Malaria elimination and control are also complicated by the high prevalence of G6PD deficiency in malaria-endemic areas. Hence, accurate identification of G6PD deficiency is required to identify those who are eligible for malaria treatment using 8-aminoquinolines. Methods The prevalence of G6PD deficiency among 408 Thai participants diagnosed with malaria by microscopy (71), and malaria-negative controls (337), was assessed using a phenotypic test based on water-soluble tetrazolium salts. High-resolution melting (HRM) curve analysis was developed from a previous study to enable the detection of 15 common missense, synonymous and intronic G6PD mutations in Asian populations. The identified mutations were subjected to biochemical and structural characterisation to understand the molecular mechanisms underlying enzyme deficiency. Results Based on phenotypic testing, the prevalence of G6PD deficiency (< 30% activity) was 6.13% (25/408) and intermediate deficiency (30–70% activity) was found in 15.20% (62/408) of participants. Several G6PD genotypes with newly discovered double missense variants were identified by HRM assays, including G6PD Gaohe + Viangchan, G6PD Valladolid + Viangchan and G6PD Canton + Viangchan. A significantly high frequency of synonymous (c.1311C>T) and intronic (c.1365-13T>C and c.486-34delT) mutations was detected with intermediate to normal enzyme activity. The double missense mutations were less catalytically active than their corresponding single missense mutations, resulting in severe enzyme deficiency. While the mutations had a minor effect on binding affinity, structural instability was a key contributor to the enzyme deficiency observed in G6PD-deficient individuals. Conclusions With varying degrees of enzyme deficiency, G6PD genotyping can be used as a complement to phenotypic screening to identify those who are eligible for 8-aminoquinolines. The information gained from this study could be useful for management and treatment of malaria, as well as for the prevention of unanticipated reactions to certain medications and foods in the studied population.https://doi.org/10.1186/s12936-024-04864-8G6PD deficiencyMalariaG6PD mutationsG6PD genotypingSynonymous mutationsStability |
| spellingShingle | Usa Boonyuen Beatriz Aira C. Jacob Jutamas Wongwigkan Kamonwan Chamchoy Natsamon Singha-art Natnicha Pengsuk Duantida Songdej Emily R. Adams Thomas Edwards Supat Chamnanchanunt Syazwani Itri Amran Nurriza Ab Latif Naveen Eugene Louis Shamini Chandran Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines Malaria Journal G6PD deficiency Malaria G6PD mutations G6PD genotyping Synonymous mutations Stability |
| title | Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines |
| title_full | Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines |
| title_fullStr | Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines |
| title_full_unstemmed | Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines |
| title_short | Genetic analysis and molecular basis of G6PD deficiency among malaria patients in Thailand: implications for safe use of 8-aminoquinolines |
| title_sort | genetic analysis and molecular basis of g6pd deficiency among malaria patients in thailand implications for safe use of 8 aminoquinolines |
| topic | G6PD deficiency Malaria G6PD mutations G6PD genotyping Synonymous mutations Stability |
| url | https://doi.org/10.1186/s12936-024-04864-8 |
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