{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T08:01:21Z","timestamp":1768809681012,"version":"3.49.0"},"reference-count":51,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n<jats:p>Malaria remains an important public health problem despite efforts to control it. Besides active transmission, relapsing malaria caused by dormant liver stages of <jats:italic>Plasmodium vivax<\/jats:italic> and <jats:italic>Plasmodium ovale<\/jats:italic> hypnozoites is a major hurdle in malaria control and elimination programs. Primaquine (PQ) is the most widely used drug for radical cure of malaria. Due to its anti-hypnozoite and gametocidal activity, PQ plays a key role in malaria relapse and transmission. The human enzyme glucose-6-phosphate dehydrogenase (G6PD) is crucial in determining the safety of PQ because G6PD-deficient individuals are prone to hemolysis if treated with PQ. Therefore, there is a need to study the prevalence of G6PD-deficient genetic variants in endemic populations to assess the risk of PQ treatment and the necessity to develop alternative treatments. In this work, we discuss the common G6PD variants, their varying enzymatic activity, and their distribution on the three-dimensional structure of G6PD. Our work highlights the important G6PD variants and the need for large-scale G6PD gene polymorphism studies to predict populations at risk of PQ-induced toxicity.<\/jats:p>","DOI":"10.4269\/ajtmh.22-0468","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T15:35:45Z","timestamp":1675697745000},"page":"470-476","source":"Crossref","is-referenced-by-count":1,"title":["Single-Nucleotide Polymorphisms in Glucose-6-Phosphate Dehydrogenase and their Relevance for the Deployment of Primaquine as a Radical Cure for Malaria"],"prefix":"10.4269","volume":"108","author":[{"given":"Minu","family":"Nain","sequence":"first","affiliation":[{"name":"ICMR-National Institute of Malaria Research, New Delhi, India;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmita","family":"Gill","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Malaria Research, New Delhi, India;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mradul","family":"Mohan","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Malaria Research, New Delhi, India;"},{"name":"Academy of Scientific and Innovative Research, Ghaziabad, India;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Sharma","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Malaria Research, New Delhi, India;"},{"name":"Academy of Scientific and Innovative Research, Ghaziabad, India;"},{"name":"Molecular Medicine, International Centre for Genetic Engineering and Biotechnology, New Delhi, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2795","reference":[{"key":"b1","series-title":"World Malaria Report 2021","year":"2021"},{"key":"b2","series-title":"J Infect","first-page":"231","article-title":"Epidemiology and clinical outcomes of severe Plasmodium vivax malaria in India","volume":"82","author":"Kojom Foko","year":"2021"},{"key":"b3","series-title":"Malar J","first-page":"141","article-title":"Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group","volume":"16","author":"Thriemer","year":"2017"},{"key":"b4","series-title":"IJMS","first-page":"2069","article-title":"Glucose-6-phosphate dehydrogenase: update and analysis of new mutations around the world","volume":"17","author":"G\u00f3mez-Manzo","year":"2016"},{"key":"b5","series-title":"Indian J Hematol Blood Transfus","first-page":"349","article-title":"Molecular characterization of G6PD deficiency: report of three novel G6PD variants","volume":"36","author":"Arunachalam","year":"2020"},{"key":"b6","series-title":"Blood","first-page":"1225","article-title":"Glucose-6-phosphate dehydrogenase deficiency","volume":"136","author":"Luzzatto","year":"2020"},{"key":"b7","series-title":"Infect Genet Evol","first-page":"1228","article-title":"A large, systematic molecular-genetic study of G6PD in Indian populations identifies a new non-synonymous variant and supports recent positive selection","volume":"10","author":"Sarkar","year":"2010"},{"key":"b8","series-title":"J Pediatr Genet","first-page":"47","article-title":"Prevalence and genetic characterization of glucose-6-phosphate dehydrogenase deficiency in anemic subjects from Uttar Pradesh, India","volume":"8","author":"Tripathi","year":"2019"},{"key":"b9","series-title":"Infect Genet Evol","first-page":"104597","article-title":"Prevalence and spectrum of mutations causing G6PD deficiency in Indian populations","volume":"86","author":"Devendra","year":"2020"},{"key":"b10","series-title":"Ann Hum Biol","first-page":"55","article-title":"G6PD A- is the major cause of G6PD deficiency among the Siddis of Karnataka, India","volume":"47","author":"Devendra","year":"2020"},{"key":"b11","series-title":"J Trop Med","first-page":"5194287","article-title":"Molecular characterization of glucose-6-phosphate dehydrogenase: do single nucleotide polymorphisms affect hematological parameters in HIV-positive patients?","volume":"2020","author":"Danquah","year":"2020"},{"key":"b12","series-title":"Malar J","first-page":"418","article-title":"Spatial distribution of G6PD deficiency variants across malaria-endemic regions","volume":"12","author":"Howes","year":"2013"},{"key":"b13","series-title":"PLoS Med","first-page":"e1001339","article-title":"G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map","volume":"9","author":"Howes","year":"2012"},{"key":"b14","series-title":"Clin Pharmacol Ther","first-page":"376","article-title":"Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update","volume":"95","author":"Crews","year":"2014"},{"key":"b15","series-title":"Pathog Glob Health","first-page":"93","article-title":"Origins and implications of neglect of G6PD deficiency and primaquine toxicity in Plasmodium vivax malaria","volume":"109","author":"Baird","year":"2015"},{"key":"b16","series-title":"eLife","first-page":"e62448","article-title":"Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria","volume":"10","author":"Awab","year":"2021"},{"key":"b17","series-title":"Infect Genet Evol","first-page":"103980","article-title":"The glucose-6-phosphate dehydrogenase Mahidol variant protects against uncomplicated Plasmodium vivax infection and reduces disease severity in a Kachin population from northeast Myanmar","volume":"75","author":"Yi","year":"2019"},{"key":"b18","series-title":"Sci Rep","first-page":"45963","article-title":"Association of glucose-6-phosphate dehydrogenase deficiency and malaria: a systematic review and meta-analysis","volume":"7","author":"Mbanefo","year":"2017"},{"key":"b19","author":"Awab","year":"2021"},{"key":"b20","series-title":"Br J Haematol","first-page":"469","article-title":"G6PD deficiency: a classic example of pharmacogenetics with on\u2010going clinical implications","volume":"164","author":"Luzzatto","year":"2014"},{"key":"b21","series-title":"IJMS","first-page":"21179","article-title":"The stability of G6PD is affected by mutations with different clinical phenotypes","volume":"15","author":"G\u00f3mez-Manzo","year":"2014"},{"key":"b22","series-title":"Clin Microbiol Rev","first-page":"e00011","article-title":"8-Aminoquinoline therapy for latent malaria","volume":"32","author":"Baird","year":"2019"},{"key":"b23","series-title":"Best Pract Res Clin Haematol","first-page":"39","article-title":"Chronic non-spherocytic haemolytic disorders associated with glucose-6-phosphate dehydrogenase variants","volume":"13","author":"Fiorelli","year":"2000"},{"key":"b24","series-title":"Front Pharmacol","first-page":"638885","article-title":"G6PD variants and haemolytic sensitivity to primaquine and other drugs","volume":"12","author":"Bancone","year":"2021"},{"key":"b25","series-title":"J Med Genet","first-page":"191","article-title":"G6PD (Dublin): chronic non-spherocytic haemolytic anaemia resulting from glucose-6-phosphate dehydrogenase deficiency in an Irish kindred","volume":"17","author":"McCann","year":"1980"},{"key":"b26","series-title":"Hum Genet","first-page":"560","article-title":"A novel single-base mutation in the glucose 6-phosphate dehydrogenase gene is associated with chronic non-spherocytic haemolytic anaemia","volume":"94","author":"Filosa","year":"1994"},{"key":"b27","series-title":"Clin Genet","first-page":"357","article-title":"Molecular characterisation of an Italian G6PD variant responsible for chronic non-spherocytic haemolytic anaemia","volume":"46","author":"Montemuros","year":"2008"},{"key":"b28","series-title":"Br J Haematol","first-page":"66","article-title":"Molecular genetics of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Spain: identification of two new point mutations in the G6PD gene","volume":"91","author":"Rovira","year":"1995"},{"key":"b29","series-title":"Br J Haematol","first-page":"111","article-title":"Molecular basis of chronic non-spherocytic haemolytic anaemia: a new G6PD variant (393 Arg\u2192His) with abnormal KmG6P and marked in\u00a0vivo instability","volume":"80","author":"Filosa","year":"1992"},{"key":"b30","series-title":"Acta Crystallogr D Biol Crystallogr","first-page":"495","article-title":"Structural studies of glucose-6-phosphate and NADP+ binding to human glucose-6-phosphate dehydrogenase","volume":"61","author":"Kotaka","year":"2005"},{"key":"b31","series-title":"Protein Sci","first-page":"1403","article-title":"What is the role of the second \u201cstructural\u201d NADP+-binding site in human glucose 6-phosphate dehydrogenase?","volume":"17","author":"Wang","year":"2008"},{"key":"b32","series-title":"Catalysts","first-page":"135","article-title":"Functional and biochemical analysis of glucose-6-phosphate dehydrogenase (G6PD) variants: elucidating the molecular basis of G6PD deficiency","volume":"7","author":"G\u00f3mez-Manzo","year":"2017"},{"key":"b33","series-title":"Proc Natl Acad Sci USA","first-page":"e2022790118","article-title":"Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency","volume":"118","author":"Horikoshi","year":"2021"},{"key":"b34","series-title":"BMJ Glob Health","first-page":"e004558","article-title":"Relapses of Plasmodium vivax malaria threaten disease elimination: time to deploy tafenoquine in India?","volume":"6","author":"Ahmad","year":"2021"},{"key":"b35","series-title":"eLife","first-page":"e23061","article-title":"Modelling primaquine-induced haemolysis in G6PD deficiency","volume":"6","author":"Watson","year":"2017"},{"key":"b36","series-title":"Hematol Oncol Clin North Am","first-page":"373","article-title":"Glucose-6-phosphate dehydrogenase deficiency","volume":"30","author":"Luzzatto","year":"2016"},{"key":"b37","series-title":"J Pharmacol Exp Ther","first-page":"838","article-title":"Primaquine-induced hemolytic anemia: role of membrane lipid peroxidation and cytoskeletal protein alterations in the hemotoxicity of 5-hydroxyprimaquine","volume":"314","author":"Bowman","year":"2005"},{"key":"b38","series-title":"Proc Natl Acad Sci USA","first-page":"697","article-title":"Unstable hemoglobins: the role of heme loss in Heinz body formation","volume":"65","author":"Jacob","year":"1970"},{"key":"b39","series-title":"Nature","first-page":"665","article-title":"Mechanism of induction of haemolytic anaemia by phenylhydrazine","volume":"256","author":"Itano","year":"1975"},{"key":"b40","series-title":"Br J Haematol","first-page":"99","article-title":"Induction of haemolytic anaemia by substituted phenylhydrazines","volume":"32","author":"Itano","year":"1976"},{"key":"b41","series-title":"Proc Natl Acad Sci USA","first-page":"2556","article-title":"Ligands and oxidants in ferrihemochrome formation and oxidative hemolysis","volume":"74","author":"Itano","year":"1977"},{"key":"b42","series-title":"BMC Med","first-page":"203","article-title":"Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency","volume":"13","author":"Kheng","year":"2015"},{"key":"b43","series-title":"PLoS Negl Trop Dis","first-page":"e0006230","article-title":"Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: divergent policies and practices in malaria endemic countries","volume":"12","author":"Recht","year":"2018"},{"key":"b44","series-title":"IUBMB Life","first-page":"27","article-title":"Glucose-6-phosphate dehydrogenase laboratory assay: how, when, and why?","volume":"61","author":"Minucci","year":"2009"},{"key":"b45","series-title":"PLoS Med","first-page":"e1002992","article-title":"Performance of the Access Bio\/CareStart rapid diagnostic test for the detection of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis","volume":"16","author":"Ley","year":"2019"},{"key":"b46","series-title":"PLoS Negl Trop Dis","first-page":"e0009415","article-title":"Real-life implementation of a G6PD deficiency screening qualitative test into routine vivax malaria diagnostic units in the Brazilian Amazon (SAFEPRIM study)","volume":"15","author":"Brito-Sousa","year":"2021"},{"key":"b47","series-title":"Malar J","first-page":"101","article-title":"Primaquine-induced haemolysis in females heterozygous for G6PD deficiency","volume":"17","author":"Chu","year":"2018"},{"key":"b48","series-title":"PLoS Negl Trop Dis","first-page":"e0009610","article-title":"Genotypes and phenotypes of G6PD deficiency among Indonesian females across diagnostic thresholds of G6PD activity guiding safe primaquine therapy of latent malaria","volume":"15","author":"Satyagraha","year":"2021"},{"key":"b49","series-title":"Malar J","first-page":"120","article-title":"Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa","volume":"17","author":"Awandu","year":"2018"},{"key":"b50","series-title":"PLoS Negl Trop Dis","first-page":"e0006230","article-title":"Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: divergent policies and practices in malaria endemic countries","volume":"12","author":"Recht","year":"2018"},{"key":"b51","series-title":"Trop Med Health","first-page":"97","article-title":"Distribution of G6PD deficiency genotypes among Southeast Asian populations","volume":"49","author":"Tantular","year":"2021"}],"container-title":["The American Journal of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/108\/3\/article-p470.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/108\/3\/article-p470.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/108\/3\/article-p470.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T14:01:58Z","timestamp":1677679318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/108\/3\/article-p470.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,1]]},"references-count":51,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.22-0468","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,1]]}}}