{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T22:24:33Z","timestamp":1773527073859,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\/Aga Khan","award":["n\u00ba330842553"],"award-info":[{"award-number":["n\u00ba330842553"]}]},{"name":"FCT\/Aga Khan","award":["UIDB\/05608\/2020"],"award-info":[{"award-number":["UIDB\/05608\/2020"]}]},{"name":"FCT\/Aga Khan","award":["UIDP\/05608\/2020"],"award-info":[{"award-number":["UIDP\/05608\/2020"]}]},{"name":"FCT\/MCTES","award":["n\u00ba330842553"],"award-info":[{"award-number":["n\u00ba330842553"]}]},{"name":"FCT\/MCTES","award":["UIDB\/05608\/2020"],"award-info":[{"award-number":["UIDB\/05608\/2020"]}]},{"name":"FCT\/MCTES","award":["UIDP\/05608\/2020"],"award-info":[{"award-number":["UIDP\/05608\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sickle cell anemia (SCA) is an inherited disease affecting the hemoglobin that is particularly common in sub-Saharan Africa. Although monogenic, phenotypes are markedly heterogeneous in terms of severity and life span. Hydroxyurea is still the most common treatment for these patients, and the response to treatment is highly variable and seems to be an inherited trait. Therefore, identifying the variants that might predict hydroxyurea response is important for identifying patients who will have a poorer or non-response to treatment, and the ones that are more prone to suffer from severe side effects. In the present pharmacogenetic study, we analyzed the exons of 77 genes described in the literature as potentially associated with hydroxyurea metabolism in Angolan children treated with hydroxyurea and evaluated the drug response considering fetal hemoglobin levels, other hematological and biochemical parameters, hemolysis, number of vaso-occlusive crises and hospitalizations. Thirty variants were identified in 18 of those genes as possibly associated with drug response, five of them in gene DCHS2. Other polymorphisms in this gene were also associated with hematological, biochemical and clinical parameters. Further research examining the maximum tolerated dose and fixed dose with a larger sample size is necessary to corroborate these findings.<\/jats:p>","DOI":"10.3390\/ijms24108792","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T02:37:51Z","timestamp":1684204671000},"page":"8792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Are Genetic Modifiers the Answer to Different Responses to Hydroxyurea Treatment?\u2014A Pharmacogenetic Study in Sickle Cell Anemia Angolan Children"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-782X","authenticated-orcid":false,"given":"Catarina","family":"Ginete","sequence":"first","affiliation":[{"name":"H&TRC\u2014Health & Technology Research Center, ESTeSL\u2014Escola Superior de Tecnologia da Sa\u00fade, Instituto Polit\u00e9cnico de Lisboa, 1990-096 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0586-9154","authenticated-orcid":false,"given":"Mariana","family":"Delgadinho","sequence":"additional","affiliation":[{"name":"H&TRC\u2014Health & Technology Research Center, ESTeSL\u2014Escola Superior de Tecnologia da Sa\u00fade, Instituto Polit\u00e9cnico de Lisboa, 1990-096 Lisbon, Portugal"}]},{"given":"Br\u00edgida","family":"Santos","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Angola (CISA), Bengo, Angola"},{"name":"Hospital Pedi\u00e1trico David Bernardino (HPDB), Luanda, Angola"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-5612","authenticated-orcid":false,"given":"Vera","family":"Pinto","sequence":"additional","affiliation":[{"name":"H&TRC\u2014Health & Technology Research Center, ESTeSL\u2014Escola Superior de Tecnologia da Sa\u00fade, Instituto Polit\u00e9cnico de Lisboa, 1990-096 Lisbon, Portugal"},{"name":"Centro de Estat\u00edstica e Aplica\u00e7\u00f5es, Universidade de Lisboa (CEAUL), 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-7935","authenticated-orcid":false,"given":"Carina","family":"Silva","sequence":"additional","affiliation":[{"name":"H&TRC\u2014Health & Technology Research Center, ESTeSL\u2014Escola Superior de Tecnologia da Sa\u00fade, Instituto Polit\u00e9cnico de Lisboa, 1990-096 Lisbon, Portugal"},{"name":"Centro de Estat\u00edstica e Aplica\u00e7\u00f5es, Universidade de Lisboa (CEAUL), 1749-016 Lisbon, Portugal"}]},{"given":"Armandina","family":"Miranda","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge (INSA), 1649-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6394-658X","authenticated-orcid":false,"given":"Miguel","family":"Brito","sequence":"additional","affiliation":[{"name":"H&TRC\u2014Health & Technology Research Center, ESTeSL\u2014Escola Superior de Tecnologia da Sa\u00fade, Instituto Polit\u00e9cnico de Lisboa, 1990-096 Lisbon, Portugal"},{"name":"Centro de Investiga\u00e7\u00e3o em Sa\u00fade de Angola (CISA), Bengo, Angola"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18010","DOI":"10.1038\/nrdp.2018.10","article-title":"Sickle Cell Disease","volume":"4","author":"Kato","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3233\/CH-189004","article-title":"Genetic Modifiers of Severity in Sickle Cell Disease","volume":"68","author":"Chang","year":"2018","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1002\/ajh.23578","article-title":"A Prospective Newborn Screening and Treatment Program for Sickle Cell Anemia in Luanda, Angola","volume":"88","author":"Mcgann","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1016\/S0140-6736(15)01341-0","article-title":"Fetal Haemoglobin in Sickle-Cell Disease: From Genetic Epidemiology to New Therapeutic Strategies","volume":"387","author":"Lettre","year":"2016","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s40291-018-0370-8","article-title":"Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease","volume":"23","author":"Menzel","year":"2019","journal-title":"Mol. Diagn. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e584","DOI":"10.1097\/HS9.0000000000000584","article-title":"Research in Sickle Cell Disease: From Bedside to Bench to Bedside","volume":"5","author":"Thein","year":"2021","journal-title":"HemaSphere"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.exphem.2020.08.008","article-title":"Efficacy and Safety of Recently Approved Drugs for Sickle Cell Disease: A Review of Clinical Trials","volume":"92","author":"Ali","year":"2020","journal-title":"Exp. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40246-021-00329-0","article-title":"Genome-Based Therapeutic Interventions for \u03b2-Type Hemoglobinopathies","volume":"15","author":"Karamperis","year":"2021","journal-title":"Hum. Genom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.bcmd.2017.08.017","article-title":"Real-Life Experience with Hydroxyurea in Sickle Cell Disease: A Multicenter Study in a Cohort of Patients with Heterogeneous Descent","volume":"69","author":"Rigano","year":"2018","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/j.1600-0609.2006.00788.x","article-title":"Therapy with Hydroxyurea Is Associated with Reduced Adhesion Molecule Gene and Protein Expression in Sickle Red Cells with a Concomitant Reduction in Adhesive Properties","volume":"78","author":"Gambero","year":"2007","journal-title":"Eur. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1111\/bjh.17315","article-title":"Blood Plasma Metabolomics of Children and Adolescents with Sickle Cell Anaemia Treated with Hydroxycarbamide: A New Tool for Uncovering Biochemical Alterations","volume":"192","author":"Ribeiro","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1182\/blood-2011-07-364190","article-title":"Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics of Hydroxyurea Treatment for Children with Sickle Cell Anemia","volume":"118","author":"Ware","year":"2011","journal-title":"Blood"},{"key":"ref_13","first-page":"261","article-title":"Pharmacogenomics of Sickle Cell Disease: Steps toward Personalized Medicine","volume":"10","author":"Husain","year":"2017","journal-title":"Pharm. Pers. Med."},{"key":"ref_14","first-page":"386","article-title":"Fetal Hemoglobin in Sickle Cell Anemia: Genetic Determinants of Response to Hydroxyurea","volume":"7","author":"Ma","year":"2007","journal-title":"Pharm. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jmb.2004.01.026","article-title":"Identification of New Human Cadherin Genes Using a Combination of Protein Motif Search and Gene Finding Methods","volume":"337","author":"Ivanov","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sheehan, V.A., Crosby, J.R., Sabo, A., Mortier, N.A., Howard, T.A., Muzny, D.M., Dugan-Perez, S., Aygun, B., Nottage, K.A., and Boerwinkle, E. (2014). Whole Exome Sequencing Identifies Novel Genes for Fetal Hemoglobin Response to Hydroxyurea in Children with Sickle Cell Anemia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110740"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1016\/j.febslet.2009.05.003","article-title":"TTLL10 Can Perform Tubulin Glycylation When Co-Expressed with TTLL8","volume":"583","author":"Ikegami","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.ajhg.2016.07.011","article-title":"Bi-Allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans","volume":"99","author":"Vetrini","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"43924","DOI":"10.1074\/jbc.M203569200","article-title":"The RhoA-Binding Protein, Rhophilin-2, Regulates Actin Cytoskeleton Organization","volume":"277","author":"Peck","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Felipe-Abrio, B., and Carnero, A. (2020). The Tumor Suppressor Roles of MYBBP1A, a Major Contributor to Metabolism Plasticity and Stemness. Cancers, 12.","DOI":"10.3390\/cancers12010254"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2217\/pgs.13.31","article-title":"Genomic Variation in the MAP3K5 Gene Is Associated with \u03b2-Thalassemia Disease Severity and Hydroxyurea Treatment Efficacy","volume":"14","author":"Tafrali","year":"2013","journal-title":"Pharmacogenomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/03630269.2019.1597732","article-title":"Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in \u03b2-Thalassemia Intermedia: A Validation Cohort Study","volume":"43","author":"Kolliopoulou","year":"2019","journal-title":"Hemoglobin"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.clinbiochem.2010.08.006","article-title":"The Effect of UGT1A1 Promoter Polymorphism on Bilirubin Response to Hydroxyurea Therapy in Hemoglobinopathies","volume":"43","author":"Italia","year":"2010","journal-title":"Clin. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/ajh.23457","article-title":"Genetic Modifiers of Sickle Cell Anemia in the Baby Hug Cohort: Influence on Laboratory and Clinical Phenotypes","volume":"88","author":"Sheehan","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1007\/s00277-021-04422-1","article-title":"Influence of UGT1A1 Promoter Polymorphism, \u03b1-Thalassemia and \u0392s Haplotype in Bilirubin Levels and Cholelithiasis in a Large Sickle Cell Anemia Cohort","volume":"100","author":"Batista","year":"2021","journal-title":"Ann. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1182\/blood-2009-08-239517","article-title":"Fetal Hemoglobin in Sickle Cell Anemia: Genome-Wide Association Studies Suggest a Regulatory Region in the 5\u2032 Olfactory Receptor Gene Cluster","volume":"115","author":"Solovieff","year":"2010","journal-title":"Blood"},{"key":"ref_27","first-page":"730","article-title":"Hydroxyurea in the Management of Sickle Cell Disease: Pharmacogenomics and Enzymatic Metabolism","volume":"18","author":"Adorno","year":"2018","journal-title":"Pharm. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e201","DOI":"10.1111\/aos.13519","article-title":"Association between CFH, CFB, ARMS2, SERPINF1, VEGFR1 and VEGF Polymorphisms and Anatomical and Functional Response to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration","volume":"96","author":"Cobos","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bl\u00e1nquez-Mart\u00ednez, D., D\u00edaz-Villamar\u00edn, X., Garc\u00eda-Rodr\u00edguez, S., Ant\u00fanez-Rodr\u00edguez, A., Pozo-Agundo, A., Mart\u00ednez-Gonz\u00e1lez, L.J., Mu\u00f1oz-\u00e1vila, J.I., and D\u00e1vila-Fajardo, C.L. (2022). Genetic Polymorphisms in VEGFR Coding Genes (FLT1\/KDR) on Ranibizumab Response in High Myopia and Choroidal Neovascularization Patients. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14081555"},{"key":"ref_30","first-page":"436","article-title":"Progress of EGFL6 in Angiogenesis and Tumor Development","volume":"15","author":"Su","year":"2022","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00228-020-03058-w","article-title":"The Influence of Recipient SLCO1B1 Rs2291075 Polymorphism on Tacrolimus Dose\u2013Corrected Trough Concentration in the Early Period after Liver Transplantation","volume":"77","author":"Wu","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1002\/cpt.315","article-title":"Inherited Variation in OATP1B1 Is Associated with Treatment Outcome in Acute Myeloid Leukemia","volume":"99","author":"Drenberg","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.exphem.2011.01.004","article-title":"Transcellular Movement of Hydroxyurea Is Mediated by Specific Solute Carrier Transporters","volume":"39","author":"Walker","year":"2011","journal-title":"Exp. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"553064","DOI":"10.3389\/fphar.2020.553064","article-title":"Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response","volume":"11","author":"Neres","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2217\/pgs.16.1","article-title":"Genomic Variants in the ASS1 Gene, Involved in the Nitric Oxide Biosynthesis and Signaling Pathway, Predict Hydroxyurea Treatment Efficacy in Compound Sickle Cell Disease\/\u03b2-Thalassemia Patients","volume":"17","author":"Chalikiopoulou","year":"2016","journal-title":"Pharmacogenomics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1182\/blood.V124.21.4073.4073","article-title":"Are There True Non-Responders to Hydroxyurea in Sickle Cell Disease? A Multiparameter Analysis","volume":"124","author":"Chand","year":"2014","journal-title":"Blood"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8792\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:35:28Z","timestamp":1760124928000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8792"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,15]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108792"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108792","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,15]]}}}