Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada)
ilustraciones, mapas
- Autores:
-
Rodríguez Vallejo, Luisa Fernanda
- Tipo de recurso:
- Fecha de publicación:
- 2023
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/84164
- Palabra clave:
- 610 - Medicina y salud::615 - Farmacología y terapéutica
570 - Biología::576 - Genética y evolución
Farmacología
Alelos
Frecuencia de los genes
Pharmacology
Gene Frequency
Alleles
ABCB1
DCK
CDA
GSTT1
GSTM1
Citarabina
Antraciclinas
Población colombiana
farmacogenetica
ABCB1
DCK
CDA
GSTT1
GSTM1
Cytarabine
Anthracyclines
Colombian population
pharmacogenetic
- Rights
- openAccess
- License
- Atribución-NoComercial 4.0 Internacional
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oai:repositorio.unal.edu.co:unal/84164 |
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UNACIONAL2 |
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Universidad Nacional de Colombia |
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| dc.title.spa.fl_str_mv |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| dc.title.translated.eng.fl_str_mv |
Determination of allele and genotypic frequencies of 8 variants in the DCK, CDA, ABCB1, GSTT1 and GSTM1 genes in a Colombian population sample of three ethnic origins (Afro-descendant, Native American and mixed Colombian) |
| title |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| spellingShingle |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) 610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución Farmacología Alelos Frecuencia de los genes Pharmacology Gene Frequency Alleles ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas Población colombiana farmacogenetica ABCB1 DCK CDA GSTT1 GSTM1 Cytarabine Anthracyclines Colombian population pharmacogenetic |
| title_short |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| title_full |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| title_fullStr |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| title_full_unstemmed |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| title_sort |
Determinación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada) |
| dc.creator.fl_str_mv |
Rodríguez Vallejo, Luisa Fernanda |
| dc.contributor.advisor.none.fl_str_mv |
Yunis, Juan José Yunis, Luz Karime |
| dc.contributor.author.none.fl_str_mv |
Rodríguez Vallejo, Luisa Fernanda |
| dc.contributor.orcid.spa.fl_str_mv |
Rodriguez Vallejo, Luisa Fernanda [0000-0001-9223-9083] |
| dc.contributor.cvlac.spa.fl_str_mv |
Rodriguez Vallejo, Luisa Fernanda [0000-0001-9223-9083] |
| dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución |
| topic |
610 - Medicina y salud::615 - Farmacología y terapéutica 570 - Biología::576 - Genética y evolución Farmacología Alelos Frecuencia de los genes Pharmacology Gene Frequency Alleles ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas Población colombiana farmacogenetica ABCB1 DCK CDA GSTT1 GSTM1 Cytarabine Anthracyclines Colombian population pharmacogenetic |
| dc.subject.decs.spa.fl_str_mv |
Farmacología Alelos Frecuencia de los genes |
| dc.subject.decs.eng.fl_str_mv |
Pharmacology Gene Frequency |
| dc.subject.decs.end.fl_str_mv |
Alleles |
| dc.subject.proposal.spa.fl_str_mv |
ABCB1 DCK CDA GSTT1 GSTM1 Citarabina Antraciclinas Población colombiana farmacogenetica |
| dc.subject.proposal.eng.fl_str_mv |
ABCB1 DCK CDA GSTT1 GSTM1 Cytarabine Anthracyclines Colombian population pharmacogenetic |
| description |
ilustraciones, mapas |
| publishDate |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2023-07-07T15:27:10Z |
| dc.date.available.none.fl_str_mv |
2023-07-07T15:27:10Z |
| dc.date.issued.none.fl_str_mv |
2023-06-21 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
DataPaper |
| dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/84164 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/84164 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
Meyer UA. Pharmacogenetics and adverse drug reactions. THE LANCET. 2000;356:1667–71 Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, et al. Integrating common and rare genetic variation in diverse human populations. Nature [Internet]. 2010;467(7311):52–8. Available from: https://doi.org/10.1038/nature09298 Kufe DW, Munroe D, Herrick D, Egan E, Spriggs D. Effects of 1-beta-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function. Mol Pharmacol. 1984 Jul;26(1):128–34. Falk IJ, Fyrberg A, Paul E, Nahi H, Hermanson M, Rosenquist R, et al. Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5’-nucleotidase. Am J Hematol. 2013 Dec;88(12):1001–6. Abraham A, Devasia AJ, Varatharajan S, Karathedath S, Balasubramanian P, Mathews V. Effect of cytosine arabinoside metabolizing enzyme expression on drug toxicity in acute myeloid leukemia. Ann Hematol [Internet]. 2014/11/13. 2015 May;94(5):883–5. Available from: https://pubmed.ncbi.nlm.nih.gov/25391240 Lamba JK, Crews K, Pounds S, Schuetz EG, Gresham J, Gandhi V, et al. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007 Dec;323(3):935–45. Sierra YQ, Padrón CH, González AR, Concepción Fernández Y, Pérez IM, Moreno DL, et al. Incorporación de las altas dosis de antraciclina en el tratamiento de la leucemia mieloide aguda del adulto. 2019 Mar 1;35. Rondón González F, Guillermo B. Estructura genética, ancestralidad y su relación con los estudios en salud humana . Vol. 26, Medicas UIS . scieloco ; 2013. p. 37–43. Yunis J, Yunis E. Mitochondrial DNA (mtDNA) haplogroups in 1526 unrelated individuals from 11 Departments of Colombia. Genet Mol Biol. 2013 Sep 1;36:329–35. Yunis JJ, Yunis EJ, Yunis E. MHC Class II haplotypes of Colombian Amerindian tribes. Genet Mol Biol. 2013 Jul;36(2):158–66. Hicks J, McLeod H. Pharmacogenetics and Pharmacogenomics. In: Genomic and Precision Medicine: Primary Care: Third Edition. 2017. p. 89–107. Evans WE, McLeod HL. Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects. New England Journal of Medicine [Internet]. 2003 Feb 6;348(6):538–49. Available from: https://doi.org/10.1056/NEJMra020526 Feero WG, Guttmacher AE, Collins FS. Genomic Medicine — An Updated Primer. New England Journal of Medicine [Internet]. 2010 May 21;362(21):2001–11. Available from: https://doi.org/10.1056/NEJMra0907175 Durbin RM, Altshuler D, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, et al. A map of human genome variation from population-scale sequencing. Nature [Internet]. 2010;467(7319):1061–73. Available from: https://doi.org/10.1038/nature09534 Bhasin MK, Walter H. Genetic Markers in Human Blood. Journal of Life Sciences [Internet]. 2013 Dec 1;5(2):71–121. Available from: https://doi.org/10.1080/09751270.2013.11885217 Hernandez W, Gamazon ER, Aquino-Michaels K, Patel S, O’Brien TJ, Harralson AF, et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans. Pharmacogenomics J [Internet]. 2013/09/10. 2014 Jun;14(3):223–8. Available from: https://pubmed.ncbi.nlm.nih.gov/24018621 Nagar SD, Moreno AM, Norris ET, Rishishwar L, Conley AB, O’Neal KL, et al. Population Pharmacogenomics for Precision Public Health in Colombia [Internet]. Vol. 10, Frontiers in Genetics . 2019. p. 241. Available from: https://www.frontiersin.org/article/10.3389/fgene.2019.00241 Bonifaz-Peña V, Contreras A v, Struchiner CJ, Roela RA, Furuya-Mazzotti TK, Chammas R, et al. Exploring the Distribution of Genetic Markers of Pharmacogenomics Relevance in Brazilian and Mexican Populations. PLoS One [Internet]. 2014 Nov 24;9(11):e112640. Available from: https://doi.org/10.1371/journal.pone.0112640 Suarez-Kurtz G, Parra EJ. Population Diversity in Pharmacogenetics: A Latin American Perspective. In: Advances in pharmacology (San Diego, Calif). United States; 2018. p. 133–54. Yunis JJ, Acevedo LE, Campo DS, Yunis EJ. Population data of Y-STR minimal haplotypes in a sample of Caucasian-Mestizo and African descent individuals of Colombia. Forensic Sci Int. 2005 Jul;151(2–3):307–13. Yunis JJ, Garcia O, Baena A, Arboleda G, Uriarte I, Yunis E. Population frequency for the short tandem repeat loci D18S849, D3S1744, and D12S1090 in Caucasian-Mestizo and African descent populations of Colombia. J Forensic Sci. 2000 Mar;45(2):429–31. Norris ET, Rishishwar L, Wang L, Conley AB, Chande AT, Dabrowski AM, et al. Assortative Mating on Ancestry-Variant Traits in Admixed Latin American Populations [Internet]. Vol. 10, Frontiers in Genetics . 2019. p. 359. Available from: https://www.frontiersin.org/article/10.3389/fgene.2019.00359 Yunis JJ, Baena A, Garcia O, Uriarte I, Yunis EJ. Population data of F13AO1, FES/FPS, VWA, CSF1PO, TPOX and THO1 short tandem repeat loci in a sample of African descent individuals of Colombia. Forensic Sci Int. 2001 Apr;117(3):235–6. Builes JJ, Bravo ML, Gomez C, Espinal C, Aguirre D, Gomez A, et al. Y-chromosome STRs in an Antioquian (Colombia) population sample. Forensic Sci Int. 2006 Dec;164(1):79–86. CÓRDOBA L, GARCÍA JJ, HOYOS LUZS, DUQUE C, ROJAS W, CARVAJAL S, et al. COMPOSICIÓN GENÉTICA DE UNA POBLACIÓN DEL SUROCCIDENTE DE COLOMBIA . Vol. 48, Revista Colombiana de Antropología . scieloco ; 2012. p. 21–48. Megias-Vericat JE, Montesinos P, Herrero MJ, Moscardo F, Boso V, Rojas L, et al. Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia. Leuk Lymphoma. 2017 May;58(5):1197–206. Lizaraso-Caparó F, Ruiz-Mori E. Medicina de precisión, un avance necesario . Vol. 18, Horizonte Médico (Lima) . scielo ; 2018. p. 4–5. Patrinos GP. Sketching the prevalence of pharmacogenomic biomarkers among populations for clinical pharmacogenomics. European Journal of Human Genetics [Internet]. 2020;28(1):1–3. Available from: https://doi.org/10.1038/s41431-019-0499-x Jakobsson M, Scholz SW, Scheet P, Gibbs JR, VanLiere JM, Fung HC, et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature [Internet]. 2008;451(7181):998–1003. Available from: https://doi.org/10.1038/nature06742 Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, et al. Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation. Science (1979) [Internet]. 2008 Feb 22;319(5866):1100 LP – 1104. Available from: http://science.sciencemag.org/content/319/5866/1100.abstract WRIGHT S. The genetical structure of populations. Ann Eugen. 1951 Mar;15(4):323–54. Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. Natural selection has driven population differentiation in modern humans. Nat Genet [Internet]. 2008;40(3):340–5. Available from: https://doi.org/10.1038/ng.78 Chen J, Teo YY, Toh DSL, Sung C. Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory assessments. Pharmacogenomics [Internet]. 2010 Aug 1;11(8):1077–94. Available from: https://doi.org/10.2217/pgs.10.79 Tang H, Quertermous T, Rodriguez B, Kardia SLR, Zhu X, Brown A, et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet [Internet]. 2004/12/29. 2005 Feb;76(2):268–75. Available from: https://pubmed.ncbi.nlm.nih.gov/15625622 Kozyra M, Ingelman-Sundberg M, Lauschke VM. Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response. Genetics in Medicine [Internet]. 2017;19(1):20–9. Available from: https://doi.org/10.1038/gim.2016.33 Bowcock AM, Ruiz-Linares A, Tomfohrde J, Minch E, Kidd JR, Cavalli-Sforza LL. High resolution of human evolutionary trees with polymorphic microsatellites. Nature. 1994 Mar;368(6470):455–7. Calafell F, Shuster A, Speed WC, Kidd JR, Kidd KK. Short tandem repeat polymorphism evolution in humans. Eur J Hum Genet. 1998 Jan;6(1):38–49. Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, et al. Genetic structure of human populations. Science. 2002 Dec;298(5602):2381–5. Yunis J, Acevedo L, Campo D, Yunis E. Geno-geographic origin of Y-specific STR haplotypes in a sample of Caucasian-Mestizo and African-descent male individuals from Colombia. Biomedica. 2013 Sep 1;33:459–67. DANE. POBLACIÓN NEGRA, AFROCOLOMBIANA, RAIZAL Y PALENQUERA. RESULTADOS DEL CENSO NACIONAL DE POBLACIÓN Y VIVIENDA 2018. 2019. DANE-DCD. CNPV 2018. POBLACIÓN INDÍGENA DE COLOMBIA [Internet]. 2019. Available from: https://www.dane.gov.co/files/investigaciones/boletines/grupos-etnicos/presentacion-grupos-etnicos-2019.pdf Vogel Friedrich. Moderne probleme der Humangenetik. Ergeb Inn Med Kinderheild. 1959;12:52±125. Pirmohamed M. Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol. 2001;52:345±347. Ortega-Mata M. Farmacogenética, farmacogenómica y proteómica en la Medicina personalizada. [Internet]. 2001. Available from: www.ranf.com Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogenomics J [Internet]. 2006;6(3):162–5. Available from: https://doi.org/10.1038/sj.tpj.6500361 dbSNP’s human build 150 has doubled the amount of RefSNP records! [Internet]. 2017. Available from: https://ncbiinsights.ncbi.nlm.nih.gov/2017/05/08/dbsnps-human-build-150-has-doubled-the-amount-of-refsnp-records/ Consortium 1000 Genomes Project, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature [Internet]. 2015 Oct 1;526(7571):68–74. Available from: https://pubmed.ncbi.nlm.nih.gov/26432245 Vogenberg FR, Isaacson Barash C, Pursel M. Personalized medicine: part 1: evolution and development into theranostics. P T [Internet]. 2010 Oct;35(10):560–76. Available from: https://pubmed.ncbi.nlm.nih.gov/21037908 Lee J.W., Aminkeng F., Bhavsar A.P., Shaw K., Carleton B.C. H, M.R. RCJD. The emerging era of pharmacogenomics: current successes, future potential, and challenges. Clin Genet. 2014;86:21–8. Quiñones L, Lavanderos M, Cayun J, Garcia-Martin E, Agúndez J, Caceres D, et al. Perception of the Usefulness of Drug/Gene Pairs and Barriers for Pharmacogenomics in Latin America. Curr Drug Metab. 2014 Feb 2;15. ARNOLD J, ALVING AS, HOCKWALD RS, CLAYMAN CB, DERN RJ, BEUTLER E, et al. The effect of continuous and intermittent primaquine therapy on the relapse rate of Chesson strain vivax malaria. J Lab Clin Med. 1954 Sep;44(3):429–38. KALOW W, STARON N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. Can J Biochem Physiol. 1957 Dec;35(12):1305–20. Administration USFAD. Table of Pharmacogenomic Biomarkers in Drug Labeling [Internet]. 2020. Available from: https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling Castell JV. El metabolismo de fármacos, generación de metabolitos reactivos y su papel en el origen de las reacciones inmunológicas a fármacos. In: Absorciòn, distribuciòn y eliminaciòn de los fàrmacos. Valencia; 2018. p. 95–123. Pestaña M. Metabolización de un fármaco: estudio analítico a través de la orina [Internet]. Universidad de Jaèn; 2017. Available from: http://tauja.ujaen.es/bitstream/10953.1/6539/1/TFG_Blanca_Pestana_Maria_Dolores.pdf Sistonen J, Fuselli S, Palo JU, Chauhan N, Padh H, Sajantila A. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics. 2009 Feb;19(2):170–9. Ray B, Ozcagli E, Sadee W, Wang D. CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele): implications for CYP2D6 genotyping panels. Pharmacogenet Genomics. 2019 Feb;29(2):39–47. Balyan R, Mecoli M, Venkatasubramanian R, Chidambaran V, Kamos N, Clay S, et al. CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics. 2017 Mar;18(4):337–48. Severino G, del Zompo M. Adverse drug reactions: role of pharmacogenomics. Pharmacol Res. 2004 Apr;49(4):363–73 Dickins M, Tucker G. Drug disposition: To phenotype or genotype. International Journal of Pharmaceutical Medicine. 2001 Jan 1;15:70–3. Ahmed S, Zhou Z, Zhou J, Chen SQ. c Oct;14(5):298–313. ESE IN de C. Análisis de Situación del Cáncer en Colombia 2015. 2017. Payami H. The emerging science of precision medicine and pharmacogenomics for Parkinson’s disease. Mov Disord. 2017 Aug;32(8):1139–46. Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol [Internet]. 2018 Oct 1;93(10):1267–91. Available from: https://doi.org/10.1002/ajh.25214 Colombia IN de CE. Guía de Práctica Clínica para la detección, tratamiento y seguimiento de leucemias linfoblástica y mieloide en población mayor de 18 años. 2017. Indicadores de gestiòn del riesgo en adultos con leucemia linfoide aguda y leucemia mieloide aguda en Colombia. [Internet]. Costo, Fondo Colombiano de Enfermedades de Alto. 2018. Available from: https://www.cuentadealtocosto.org/site/images/Publicacio [Internet]. Costo, Fondo Colombiano de Enfermedades de Alto. 2018. Available from: https://www.cuentadealtocosto.org/site/images/Publicaciones/2018/Libro_Consenso_Leucemias_2018.pdf Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive Postremission Chemotherapy in Adults with Acute Myeloid Leukemia. New England Journal of Medicine [Internet]. 1994 Oct 6;331(14):896–903. Available from: https://doi.org/10.1056/NEJM199410063311402 Society AC. How Is Acute Myeloid Leukemia Diagnosed? [Internet]. 2014. Available from: https://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/how-diagnosed.html Elgarten CW, Aplenc R. Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy. Curr Opin Pediatr [Internet]. 2020;32(1). Available from: https://journals.lww.com/co-pediatrics/Fulltext/2020/02000/Pediatric_acute_myeloid_leukemia__updates_on.9.aspx Zuckerman T, Ganzel C, Tallman MS, Rowe JM. How I treat hematologic emergencies in adults with acute leukemia. Blood [Internet]. 2012 Sep 6;120(10):1993–2002. Available from: https://doi.org/10.1182/blood-2012-04-424440 Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol [Internet]. 2002 Jul 1;3(7):415–24. Available from: https://doi.org/10.1016/S1470-2045(02)00788-X Löwenberg B. Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety. Hematology [Internet]. 2008 Jan 1;2008(1):1–11. Available from: https://doi.org/10.1182/asheducation-2008.1.1 Megias-Vericat JE, Montesinos P, Herrero MJ, Moscardo F, Boso V, Martinez-Cuadron D, et al. Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment. Leuk Lymphoma. 2017 Dec;58(12):2880–94. Megias-Vericat JE, Martinez-Cuadron D, Herrero MJ, Alino SF, Poveda JL, Sanz MA, et al. Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia. Curr Drug Metab. 2017;19(1):55–74. Maring JG, Groen HJM, Wachters FM, Uges DRA, de Vries EGE. Genetic factors influencing Pyrimidine-antagonist chemotherapy. Pharmacogenomics J [Internet]. 2005;5(4):226–43. Available from: https://doi.org/10.1038/sj.tpj.6500320 Lamba JK. Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657–74. Li Z, Guo JR, Chen QQ, Wang CY, Zhang WJ, Yao MC, et al. Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells. Molecules. 2017 Mar;22(3). Emadi, A., & Karp JE. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. Pharmacogenomics. 2012;13(11):1257–1269. Edwardson DW, Narendrula R, Chewchuk S, Mispel-Beyer K, Mapletoft JPJ, Parissenti AM. Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines. Curr Drug Metab [Internet]. 2015;16(6):412–26. Available from: https://pubmed.ncbi.nlm.nih.gov/26321196 Emadi A, Karp JE. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. Pharmacogenomics. 2012 Aug;13(11):1257–69. Beretta G, Zunino F. Molecular Mechanisms of Anthracycline Activity. Top Curr Chem. 2008 Jan 1;283:1–19. Amaki J, Onizuka M, Ohmachi K, Aoyama Y, Hara R, Ichiki A, et al. Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. Int J Hematol. 2015 Jun;101(6):543–53 Instituto Europeo de Bioinformática (EBI), Instituto Suizo de Bioinformática (SIB) PIR (PIR) [Internet]. UniProtKB [Internet]. P32320 (CDD_HUMAN). 2020 [cited 2020 May 10]. p. 1. Available from: https://www.uniprot.org/uniprot/P32320 Medina-Sanson A, Ramirez-Pacheco A, Moreno-Guerrero SS, Dorantes-Acosta EM, Sanchez-Preza M, Reyes-Lopez A. Role of Genetic Polymorphisms of Deoxycytidine Kinase and Cytidine Deaminase to Predict Risk of Death in Children with Acute Myeloid Leukemia. Biomed Res Int. 2015;2015:309491. Shi JY, Shi Z, Zhang SJ, Zhu YM, Gu BW, Li G, et al. Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. Pharmacogenet Genomics. 2004 Nov 1;14:759–68. Saito Y. CDA (Cytidine Deaminase). Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):673–5. Parmar S, Seeringer A, Denich D, Gärtner F, Pitterle K, Syrovets T, et al. Variability in transport and biotransformation of cytarabine is associated with its toxicity in peripheral blood mononuclear cells. Pharmacogenomics. 2011 Apr;12(4):503–14. Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, et al. SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia. 2009 Oct 21;23(10):1929–32. Li W, Zhang H, Assaraf YG, Zhao K, Xu X, Xie J, et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resistance Updates [Internet]. 2016;27:14–29. Available from: http://www.sciencedirect.com/science/article/pii/S1368764616300127 Fletcher JI, Williams RT, Henderson MJ, Norris MD, Haber M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug Resistance Updates [Internet]. 2016;26:1–9. Available from: http://www.sciencedirect.com/science/article/pii/S1368764616000200 Genovese I, Ilari A, Assaraf YG, Fazi F, Colotti G. Not only P-glycoprotein: Amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins. Drug Resistance Updates. 2017; Kim R B, Leake B F, Choo E F, Dresser G K, Kubba S V, Schwarz U I, Taylor A, Xie H G, McKinsey J, Zhou S, Lan L B, Schuetz J D, Schuetz E G WGR. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70(2):189–99. de Kouchkovsky I, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update.’ Blood Cancer J [Internet]. 2016;6(7):e441–e441. Available from: https://doi.org/10.1038/bcj.2016.50 Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003 Aug;13(8):481–94. Ayala EV, Carbajal PM, Coelho EB, Sandoval JS, Granara AS. Geographic distribution of the 3435C>T polymorphism of the MDR1 gene in Peruvian populations. Drug Metab Pers Ther [Internet]. 2019;34(3):20180041. Available from: https://www.degruyter.com/view/journals/dmdi/34/3/article-20180041.xml Lamba J, Strom S, Venkataramanan R, Thummel KE, Lin YS, Liu W, et al. MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin Pharmacol Ther. 2006 Apr;79(4):325–38. Seedhouse CH, Grundy M, White P, Li Y, Fisher J, Yakunina D, et al. Sequential influences of leukemia-specific and genetic factors on p-glycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials. Clin Cancer Res. 2007 Dec;13(23):7059–66. Xiao Q, Zhou Y, Lauschke VM. Ethnogeographic and inter-individual variability of human ABC transporters. Hum Genet. 2020 May;139(5):623–46. van den Heuvel-Eibrink MM, Wiemer EA, de Boevere MJ, van der Holt B, Vossebeld PJ, Pieters R, et al. MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood. 2001 Jun;97(11):3605–11. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002 Sep;62(17):4955–62. Kim DH, Park JY, Sohn SK, Lee NY, Baek JH, Jeon SB, et al. Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer. 2006 May;118(9):2195–201. Piacentini S, Polimanti R, Porreca F, Martínez-Labarga C, de Stefano GF, Fuciarelli M. GSTT1 and GSTM1 gene polymorphisms in European and African populations. Mol Biol Rep [Internet]. 2011;38(2):1225–30. Available from: https://doi.org/10.1007/s11033-010-0221-0 Frova C. Glutathione transferases in the genomics era: New insights and perspectives. Biomol Eng [Internet]. 2006;23(4):149–69. Available from: http://www.sciencedirect.com/science/article/pii/S1389034406000414 Xu S, Wang Y, Roe B, Pearson WR. Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion. J Biol Chem. 1998 Feb;273(6):3517–27. Weiss JR, Kopecky KJ, Godwin J, Anderson J, Willman CL, Moysich KB, et al. Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials. Vol. 20, Leukemia. England; 2006. p. 2169–71. Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res. 2000 Oct;463(3):247–83. Coggan M, Whitbread L, Whittington A, Board P. Structure and organization of the human theta-class glutathione S-transferase and D-dopachrome tautomerase gene complex. Biochem J. 1998 Sep;334 ( Pt 3(Pt 3):617–23. Parl FF. Glutathione S-transferase genotypes and cancer risk. Cancer Lett [Internet]. 2005;221(2):123–9. Available from: http://www.sciencedirect.com/science/article/pii/S0304383504004628 Sprenger R, Schlagenhaufer R, Kerb R, Bruhn C, Brockmöller J, Roots I, et al. Characterization of the glutathione S-transferase GSTT1 deletion: discrimination of all genotypes by polymerase chain reaction indicates a trimodular genotype–phenotype correlation. Pharmacogenet Genomics [Internet]. 2000;10(6). Available from: https://journals.lww.com/jpharmacogenetics/Fulltext/2000/08000/Characterization_of_the_glutathione_S_transferase.9.aspx Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997 Sep;6(9):733–43. Palma-Cano LE, Córdova EJ, Orozco L, Martínez-Hernández A, Cid M, Leal-Berumen I, et al. GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review. Genet Mol Biol. 2017 Nov 6;40(4):727–35. Ramírez B, Niño-Orrego MJ, Cárdenas D, Ariza KE, Quintero K, Contreras Bravo NC, et al. Copy number variation profiling in pharmacogenetics CYP-450 and GST genes in Colombian population. BMC Med Genomics [Internet]. 2019;12(1):110. Available from: https://doi.org/10.1186/s12920-019-0556-x Yunis JJ, Yunis EJ, Yunis E. Genetic relationship of the Guambino, Paez, and Ingano Amerindians of Southwest Colombia using major histocompatibility complex class II haplotypes and blood groups. Hum Immunol. 2001 Sep;62(9):970–8. Usme-Romero S, Alonso M, Hernandez-Cuervo H, Yunis EJ, Yunis JJ. Genetic differences between Chibcha and Non-Chibcha speaking tribes based on mitochondrial DNA (mtDNA) haplogroups from 21 Amerindian tribes from Colombia. Genet Mol Biol. 2013 Mar 5;36(2):149–57. Mehta B, Daniel R, Phillips C, Mcnevin D. Forensically relevant SNaPshot(®) assays for human DNA SNP analysis: a review. Int J Legal Med. 2016 Nov 14;131. Lindblad-Toh K, Winchester E, Daly MJ, Wang DG, Hirschhorn JN, Laviolette JP, et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat Genet. 2000 Apr;24(4):381–6. Stanford University. PHARMGKB [Internet]. 2019. Available from: http://www.pharmgkb.org/ Rodrigues JCG, Fernandes MR, Guerreiro JF, da Silva AL da C, Ribeiro-dos-Santos Â, Santos S, et al. Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians. Sci Rep. 2019 Dec 10;9(1):7201. Gregers J, Gréen H, Christensen IJ, Dalhoff K, Schroeder H, Carlsen N, et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2015 Aug 13;15(4):372–9. Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein*. Clin Pharmacol Ther. 2002 Aug;72(2):209–19. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BHc. Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males. Pharmacogenomics. 2009 Nov;10(11):1743–51. Yang HC, Chen CW, Lin YT, Chu SK. Genetic ancestry plays a central role in population pharmacogenomics. Commun Biol. 2021 Dec 5;4(1):171. Dessilly G, Panin N, Elens L, Haufroid V, Demoulin JB. Impact of ABCB1 1236C > T-2677G > T-3435C > T polymorphisms on the anti-proliferative activity of imatinib, nilotinib, dasatinib and ponatinib. Sci Rep. 2016 Jul 12;6(1):29559. Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, et al. SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia. 2009 Oct 21;23(10):1929–32. Schroder JK, Kirch C, Seeber S, Schutte J. Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br J Haematol. 1998 Dec;103(4):1096–103. Abraham A, Varatharajan S, Karathedath S, Philip C, Lakshmi KM, Jayavelu AK, et al. RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. Pharmacogenomics. 2015 Jul;16(8):877–90. Abraham A, Varatharajan S, Abbas S, Zhang W, Shaji R v, Ahmed R, et al. Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics. 2012 Feb;13(3):269–82. Carpi FM, Vincenzetti S, Ubaldi J, Pucciarelli S, Polzonetti V, Micozzi D, et al. CDA gene polymorphisms and enzyme activity: genotype-phenotype relationship in an Italian-Caucasian population. Pharmacogenomics. 2013 May;14(7):769–81. Hyo Kim L, Sub Cheong H, Koh Y, Ahn KS, Lee C, Kim HL, et al. Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML. J Hum Genet. 2015 Dec;60(12):749–54. Pinto-Merino Á, Labrador J, Zubiaur P, Alcaraz R, Herrero MJ, Montesinos P, et al. Role of Pharmacogenetics in the Treatment of Acute Myeloid Leukemia: Systematic Review and Future Perspectives. Pharmaceutics. 2023 Mar 3;14(3):559. Burmester JK, Sedova M, Shapero MH, Mansfield E. DMETTM Microarray Technology for Pharmacogenomics-Based Personalized Medicine BT - Microarray Methods for Drug Discovery. In: Chittur S v, editor. Totowa, NJ: Humana Press; 2010. p. 99–124. Available from: https://doi.org/10.1007/978-1-60761-663-4_7 Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther [Internet]. 2017 Oct 1;102(4):688–700. Available from: https://doi.org/10.1002/cpt.690 Schärfe CPI, Tremmel R, Schwab M, Kohlbacher O, Marks DS. Genetic variation in human drug-related genes. Genome Med [Internet]. 2017;9(1):117. Available from: https://doi.org/10.1186/s13073-017-0502-5 Hovelson DH, Xue Z, Zawistowski M, Ehm MG, Harris EC, Stocker SL, et al. Characterization of ADME gene variation in 21 populations by exome sequencing. Pharmacogenet Genomics [Internet]. 2017 Mar;27(3):89–100. Available from: https://pubmed.ncbi.nlm.nih.gov/27984508 Tafazoli A, Guchelaar HJ, Miltyk W, Kretowski AJ, Swen JJ. Applying Next-Generation Sequencing Platforms for Pharmacogenomic Testing in Clinical Practice. Front Pharmacol. 2021 Aug 25;12. Clinical Pharmacogenetics Implementation Consortium [Internet]. CPIC . 2021 [citado 27 octubre 2023]. Disponible en: https://cpicpgx.org/. |
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Universidad Nacional de Colombia |
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Bogotá - Medicina - Maestría en Genética Humana |
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Facultad de Medicina |
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Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Yunis, Juan José98abcaf43212fff33e12065dff8fe674Yunis, Luz Karime02b19ea3c147345dedd51bcea3c01831Rodríguez Vallejo, Luisa Fernanda9e59f4570608358c5eeae0b1a448f0dcRodriguez Vallejo, Luisa Fernanda [0000-0001-9223-9083]Rodriguez Vallejo, Luisa Fernanda [0000-0001-9223-9083]2023-07-07T15:27:10Z2023-07-07T15:27:10Z2023-06-21https://repositorio.unal.edu.co/handle/unal/84164Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, mapasColombia es un país multiétnico donde la población con mezcla europea (AE) predominó después del descubrimiento de América en 1942. Sin embargo, una gran proporción de la población son afrodescendientes (AD) con 6.8% y habitan las costas pacífica y caribe de Colombia, adicionalmente amerindios (Am) con 4.4% de la población con más de 80 tribus distribuidas a través del territorio. En este país, las leucemias son el 5° cáncer más prevalente y la leucemia mieloide aguda tiene una incidencia general de 2 – 3 casos por 100.000 hab. La tasa de mortalidad en pacientes jóvenes ha caído en los últimos años, pero la quimioterapia intensiva se ha asociado con mayores tasas de mortalidad asociada con la terapia (TRM) y recaídas. Para esta condición el tratamiento está basado en citarabina y antraciclinas y por esta razón quisimos conocer la distribución de 8 variantes que han sido asociadas con modificaciones de la respuesta a estos tratamientos, dentro de las tres principales poblaciones de nuestro país. Nosotros analizamos las frecuencias alélicas y genotípicas de los genes ABCB1, rs1045642 (3435C>T), rs1128503 (1236T>C), rs2032582 (2677T>G/A); CDA, rs2072671 (79A>C), rs532545 (-451C>T); DCK, rs2306744 (-201C>A) por medio de un ensayo de SNaPshot y la presencia o ausencia de los alelos GSTT1 y GSTM1 en una muestra de población colombiana mezclada, afrodescendientes y amerindios de Colombia con el fin de caracterizar estas variantes genéticas a nivel poblacional, como también estimar las frecuencias relativas de genotipos de riesgo para citarabina y antraciclinas. Frecuencias alélicas y genotípicas, desviación del equilibrio de Hardy–Weinberg, heterocigosis observadas y esperadas y análisis pareado de Fst fueron calculados, sin encontrar desviaciones significativas del HWE o subestructura genética en los grupos de población analizados. Adicionalmente, se encontraron diferencias estadísticas entre las frecuencias alélicas y genotípicas de estas variantes (P=0.05) en los tres grupos de población. En general, altas frecuencias para genotipos de riesgo fueron encontradas entre la población afrodescendiente, seguido de la colombiana con mezcla y amerindia, estableciendo diferentes perfiles farmacogenéticos para cada población de nuestro país. Nuestros resultados resaltan la importancia de establecer el patrón de ancestría de poblaciones analizadas en estudios farmacogenéticos, al mismo tiempo, reflejan la relevancia de caracterizar la población colombiana que se caracteriza por una alto nivel de mezcla, para correlacionar genotipos asociados con toxicidad cuando estos individuos requieren alguna terapia farmacológica. (Texto tomado de la fuente)Colombia is a multi-ethnic country where the European-admix (AE) population predominate after the arrival of Europeans in what is now known as the Americas in 1492. However, a considerable proportion of the population are African descent (AD) (6.8%) that inhabit the Pacific and Caribbean coast and amerindians (Am) with 4.4% of population and more than eighty different tribes distributed throughout the territory. In this country leukemias are the fifth most prevalent cancer, and acute myeloid leukemia have a general incidence to 2 -3 cases per 100.000 hab. The mortality rate in young patients has dropped in recent years but the intensive chemotherapy has been associated with higher rates of mortality related to therapy (TRM) and relapse. For this disease, the treatment is based in cytarabine and anthracyclines and for this reason we wanted to know the distribution of 8 polymorphisms within the three main populations of our country, which have been associated with modifications in response to this treatment. In this work we analyzed the genotype and allele frequencies of ABCB1 gene, rs1045642 (3435C>T), rs1128503 (1236T>C), rs2032582 (2677T>G/A); CDA gene, rs2072671 (79A>C), rs532545 (-451C>T); DCK gene, rs2306744 (-201C>A) by a SNaPshot assay, and the presence/absence of the GSTT1 and GSTM1 alleles in a sample of AE, AD and Am of Colombia, in order to characterize these gene variants at the population level, as well as, to estimate relative frequencies of cytarabine and anthracycline risk genotypes. Allelic and genotype frequencies, deviations from Hardy–Weinberg equilibrium, observed and expected heterozygosities, and pairwise FST values were calculated and do not deviate significantly from HWE was found or genetic substructure in the population groups studied, in addition significantly different allele and genotype frequencies were found for these gene variants in the three main ethnic groups that compose the Colombian population, with level of statistical significance to P< 0.05. In general, higher frequencies for risk genotypes where were find among AD followed by EA and Am Populations, establishing different pharmacogenetic profile for each population in our country. Our results highlight the importance of setting up the ancestry pattern of population analysis in pharmacogenetics studies, at the same time reflect the relevance of characterize the population that inhabit our country. Our results highlight the importance of analyzing pharmacogenetic gene variants in highly admix populations to correlate genotypes associated with toxicity outcomes when these individuals need drug therapies.MaestríaGenetistaSe diseñó un estudio de tipo transversal, analítico, que pretende estimar la frecuencia de las variantes alélicas rs2306744, en el gen DCK; rs2072671, rs532545 en el gen CDA; rs1045642, rs1128503, rs2032582 en el gen ABCB1 y deleciones de los genes GSTT1, GSTM1, en tres grupos étnicos de Colombia (afrodescendientes, amerindios y colombiana con mezcla).Leucemia Mieloide Aguda en Población Colombiana (COLMA)108 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en Genética HumanaFacultad de MedicinaBogotá,ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéutica570 - Biología::576 - Genética y evoluciónFarmacologíaAlelosFrecuencia de los genesPharmacologyGene FrequencyAllelesABCB1DCKCDAGSTT1GSTM1CitarabinaAntraciclinasPoblación colombianafarmacogeneticaABCB1DCKCDAGSTT1GSTM1CytarabineAnthracyclinesColombian populationpharmacogeneticDeterminación de las frecuencias alélicas y genotípicas de 8 variantes en los genes DCK, CDA, ABCB1, GSTT1 y GSTM1 en una muestra de población colombiana de tres orígenes étnicos (afrodescendientes, nativo americanos y población colombiana mezclada)Determination of allele and genotypic frequencies of 8 variants in the DCK, CDA, ABCB1, GSTT1 and GSTM1 genes in a Colombian population sample of three ethnic origins (Afro-descendant, Native American and mixed Colombian)Trabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionDataPaperhttp://purl.org/redcol/resource_type/TMColombiaMeyer UA. Pharmacogenetics and adverse drug reactions. THE LANCET. 2000;356:1667–71Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, et al. Integrating common and rare genetic variation in diverse human populations. Nature [Internet]. 2010;467(7311):52–8. Available from: https://doi.org/10.1038/nature09298Kufe DW, Munroe D, Herrick D, Egan E, Spriggs D. Effects of 1-beta-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function. Mol Pharmacol. 1984 Jul;26(1):128–34.Falk IJ, Fyrberg A, Paul E, Nahi H, Hermanson M, Rosenquist R, et al. Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5’-nucleotidase. Am J Hematol. 2013 Dec;88(12):1001–6.Abraham A, Devasia AJ, Varatharajan S, Karathedath S, Balasubramanian P, Mathews V. Effect of cytosine arabinoside metabolizing enzyme expression on drug toxicity in acute myeloid leukemia. Ann Hematol [Internet]. 2014/11/13. 2015 May;94(5):883–5. Available from: https://pubmed.ncbi.nlm.nih.gov/25391240Lamba JK, Crews K, Pounds S, Schuetz EG, Gresham J, Gandhi V, et al. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007 Dec;323(3):935–45.Sierra YQ, Padrón CH, González AR, Concepción Fernández Y, Pérez IM, Moreno DL, et al. Incorporación de las altas dosis de antraciclina en el tratamiento de la leucemia mieloide aguda del adulto. 2019 Mar 1;35.Rondón González F, Guillermo B. Estructura genética, ancestralidad y su relación con los estudios en salud humana . Vol. 26, Medicas UIS . scieloco ; 2013. p. 37–43.Yunis J, Yunis E. Mitochondrial DNA (mtDNA) haplogroups in 1526 unrelated individuals from 11 Departments of Colombia. Genet Mol Biol. 2013 Sep 1;36:329–35.Yunis JJ, Yunis EJ, Yunis E. MHC Class II haplotypes of Colombian Amerindian tribes. Genet Mol Biol. 2013 Jul;36(2):158–66.Hicks J, McLeod H. Pharmacogenetics and Pharmacogenomics. In: Genomic and Precision Medicine: Primary Care: Third Edition. 2017. p. 89–107.Evans WE, McLeod HL. Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects. New England Journal of Medicine [Internet]. 2003 Feb 6;348(6):538–49. Available from: https://doi.org/10.1056/NEJMra020526Feero WG, Guttmacher AE, Collins FS. Genomic Medicine — An Updated Primer. New England Journal of Medicine [Internet]. 2010 May 21;362(21):2001–11. Available from: https://doi.org/10.1056/NEJMra0907175Durbin RM, Altshuler D, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, et al. A map of human genome variation from population-scale sequencing. Nature [Internet]. 2010;467(7319):1061–73. Available from: https://doi.org/10.1038/nature09534Bhasin MK, Walter H. Genetic Markers in Human Blood. Journal of Life Sciences [Internet]. 2013 Dec 1;5(2):71–121. Available from: https://doi.org/10.1080/09751270.2013.11885217Hernandez W, Gamazon ER, Aquino-Michaels K, Patel S, O’Brien TJ, Harralson AF, et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans. Pharmacogenomics J [Internet]. 2013/09/10. 2014 Jun;14(3):223–8. Available from: https://pubmed.ncbi.nlm.nih.gov/24018621Nagar SD, Moreno AM, Norris ET, Rishishwar L, Conley AB, O’Neal KL, et al. Population Pharmacogenomics for Precision Public Health in Colombia [Internet]. Vol. 10, Frontiers in Genetics . 2019. p. 241. Available from: https://www.frontiersin.org/article/10.3389/fgene.2019.00241Bonifaz-Peña V, Contreras A v, Struchiner CJ, Roela RA, Furuya-Mazzotti TK, Chammas R, et al. Exploring the Distribution of Genetic Markers of Pharmacogenomics Relevance in Brazilian and Mexican Populations. PLoS One [Internet]. 2014 Nov 24;9(11):e112640. Available from: https://doi.org/10.1371/journal.pone.0112640Suarez-Kurtz G, Parra EJ. Population Diversity in Pharmacogenetics: A Latin American Perspective. In: Advances in pharmacology (San Diego, Calif). United States; 2018. p. 133–54.Yunis JJ, Acevedo LE, Campo DS, Yunis EJ. Population data of Y-STR minimal haplotypes in a sample of Caucasian-Mestizo and African descent individuals of Colombia. Forensic Sci Int. 2005 Jul;151(2–3):307–13.Yunis JJ, Garcia O, Baena A, Arboleda G, Uriarte I, Yunis E. Population frequency for the short tandem repeat loci D18S849, D3S1744, and D12S1090 in Caucasian-Mestizo and African descent populations of Colombia. J Forensic Sci. 2000 Mar;45(2):429–31.Norris ET, Rishishwar L, Wang L, Conley AB, Chande AT, Dabrowski AM, et al. Assortative Mating on Ancestry-Variant Traits in Admixed Latin American Populations [Internet]. Vol. 10, Frontiers in Genetics . 2019. p. 359. Available from: https://www.frontiersin.org/article/10.3389/fgene.2019.00359Yunis JJ, Baena A, Garcia O, Uriarte I, Yunis EJ. Population data of F13AO1, FES/FPS, VWA, CSF1PO, TPOX and THO1 short tandem repeat loci in a sample of African descent individuals of Colombia. Forensic Sci Int. 2001 Apr;117(3):235–6.Builes JJ, Bravo ML, Gomez C, Espinal C, Aguirre D, Gomez A, et al. Y-chromosome STRs in an Antioquian (Colombia) population sample. Forensic Sci Int. 2006 Dec;164(1):79–86.CÓRDOBA L, GARCÍA JJ, HOYOS LUZS, DUQUE C, ROJAS W, CARVAJAL S, et al. COMPOSICIÓN GENÉTICA DE UNA POBLACIÓN DEL SUROCCIDENTE DE COLOMBIA . Vol. 48, Revista Colombiana de Antropología . scieloco ; 2012. p. 21–48.Megias-Vericat JE, Montesinos P, Herrero MJ, Moscardo F, Boso V, Rojas L, et al. Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia. Leuk Lymphoma. 2017 May;58(5):1197–206.Lizaraso-Caparó F, Ruiz-Mori E. Medicina de precisión, un avance necesario . Vol. 18, Horizonte Médico (Lima) . scielo ; 2018. p. 4–5.Patrinos GP. Sketching the prevalence of pharmacogenomic biomarkers among populations for clinical pharmacogenomics. European Journal of Human Genetics [Internet]. 2020;28(1):1–3. Available from: https://doi.org/10.1038/s41431-019-0499-xJakobsson M, Scholz SW, Scheet P, Gibbs JR, VanLiere JM, Fung HC, et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature [Internet]. 2008;451(7181):998–1003. Available from: https://doi.org/10.1038/nature06742Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, et al. Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation. Science (1979) [Internet]. 2008 Feb 22;319(5866):1100 LP – 1104. Available from: http://science.sciencemag.org/content/319/5866/1100.abstractWRIGHT S. The genetical structure of populations. Ann Eugen. 1951 Mar;15(4):323–54.Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. Natural selection has driven population differentiation in modern humans. Nat Genet [Internet]. 2008;40(3):340–5. Available from: https://doi.org/10.1038/ng.78Chen J, Teo YY, Toh DSL, Sung C. Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory assessments. Pharmacogenomics [Internet]. 2010 Aug 1;11(8):1077–94. Available from: https://doi.org/10.2217/pgs.10.79Tang H, Quertermous T, Rodriguez B, Kardia SLR, Zhu X, Brown A, et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet [Internet]. 2004/12/29. 2005 Feb;76(2):268–75. Available from: https://pubmed.ncbi.nlm.nih.gov/15625622Kozyra M, Ingelman-Sundberg M, Lauschke VM. Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response. Genetics in Medicine [Internet]. 2017;19(1):20–9. Available from: https://doi.org/10.1038/gim.2016.33Bowcock AM, Ruiz-Linares A, Tomfohrde J, Minch E, Kidd JR, Cavalli-Sforza LL. High resolution of human evolutionary trees with polymorphic microsatellites. Nature. 1994 Mar;368(6470):455–7.Calafell F, Shuster A, Speed WC, Kidd JR, Kidd KK. Short tandem repeat polymorphism evolution in humans. Eur J Hum Genet. 1998 Jan;6(1):38–49.Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, et al. Genetic structure of human populations. Science. 2002 Dec;298(5602):2381–5.Yunis J, Acevedo L, Campo D, Yunis E. Geno-geographic origin of Y-specific STR haplotypes in a sample of Caucasian-Mestizo and African-descent male individuals from Colombia. Biomedica. 2013 Sep 1;33:459–67.DANE. POBLACIÓN NEGRA, AFROCOLOMBIANA, RAIZAL Y PALENQUERA. RESULTADOS DEL CENSO NACIONAL DE POBLACIÓN Y VIVIENDA 2018. 2019.DANE-DCD. CNPV 2018. POBLACIÓN INDÍGENA DE COLOMBIA [Internet]. 2019. Available from: https://www.dane.gov.co/files/investigaciones/boletines/grupos-etnicos/presentacion-grupos-etnicos-2019.pdfVogel Friedrich. Moderne probleme der Humangenetik. Ergeb Inn Med Kinderheild. 1959;12:52±125.Pirmohamed M. Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol. 2001;52:345±347.Ortega-Mata M. Farmacogenética, farmacogenómica y proteómica en la Medicina personalizada. [Internet]. 2001. Available from: www.ranf.comKalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogenomics J [Internet]. 2006;6(3):162–5. Available from: https://doi.org/10.1038/sj.tpj.6500361dbSNP’s human build 150 has doubled the amount of RefSNP records! [Internet]. 2017. Available from: https://ncbiinsights.ncbi.nlm.nih.gov/2017/05/08/dbsnps-human-build-150-has-doubled-the-amount-of-refsnp-records/Consortium 1000 Genomes Project, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature [Internet]. 2015 Oct 1;526(7571):68–74. Available from: https://pubmed.ncbi.nlm.nih.gov/26432245Vogenberg FR, Isaacson Barash C, Pursel M. Personalized medicine: part 1: evolution and development into theranostics. P T [Internet]. 2010 Oct;35(10):560–76. Available from: https://pubmed.ncbi.nlm.nih.gov/21037908Lee J.W., Aminkeng F., Bhavsar A.P., Shaw K., Carleton B.C. H, M.R. RCJD. The emerging era of pharmacogenomics: current successes, future potential, and challenges. Clin Genet. 2014;86:21–8.Quiñones L, Lavanderos M, Cayun J, Garcia-Martin E, Agúndez J, Caceres D, et al. Perception of the Usefulness of Drug/Gene Pairs and Barriers for Pharmacogenomics in Latin America. Curr Drug Metab. 2014 Feb 2;15.ARNOLD J, ALVING AS, HOCKWALD RS, CLAYMAN CB, DERN RJ, BEUTLER E, et al. The effect of continuous and intermittent primaquine therapy on the relapse rate of Chesson strain vivax malaria. J Lab Clin Med. 1954 Sep;44(3):429–38.KALOW W, STARON N. On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. Can J Biochem Physiol. 1957 Dec;35(12):1305–20.Administration USFAD. Table of Pharmacogenomic Biomarkers in Drug Labeling [Internet]. 2020. Available from: https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labelingCastell JV. El metabolismo de fármacos, generación de metabolitos reactivos y su papel en el origen de las reacciones inmunológicas a fármacos. In: Absorciòn, distribuciòn y eliminaciòn de los fàrmacos. Valencia; 2018. p. 95–123.Pestaña M. Metabolización de un fármaco: estudio analítico a través de la orina [Internet]. Universidad de Jaèn; 2017. Available from: http://tauja.ujaen.es/bitstream/10953.1/6539/1/TFG_Blanca_Pestana_Maria_Dolores.pdfSistonen J, Fuselli S, Palo JU, Chauhan N, Padh H, Sajantila A. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics. 2009 Feb;19(2):170–9.Ray B, Ozcagli E, Sadee W, Wang D. CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele): implications for CYP2D6 genotyping panels. Pharmacogenet Genomics. 2019 Feb;29(2):39–47.Balyan R, Mecoli M, Venkatasubramanian R, Chidambaran V, Kamos N, Clay S, et al. CYP2D6 pharmacogenetic and oxycodone pharmacokinetic association study in pediatric surgical patients. Pharmacogenomics. 2017 Mar;18(4):337–48.Severino G, del Zompo M. Adverse drug reactions: role of pharmacogenomics. Pharmacol Res. 2004 Apr;49(4):363–73Dickins M, Tucker G. Drug disposition: To phenotype or genotype. International Journal of Pharmaceutical Medicine. 2001 Jan 1;15:70–3.Ahmed S, Zhou Z, Zhou J, Chen SQ. c Oct;14(5):298–313.ESE IN de C. Análisis de Situación del Cáncer en Colombia 2015. 2017.Payami H. The emerging science of precision medicine and pharmacogenomics for Parkinson’s disease. Mov Disord. 2017 Aug;32(8):1139–46.Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol [Internet]. 2018 Oct 1;93(10):1267–91. Available from: https://doi.org/10.1002/ajh.25214Colombia IN de CE. Guía de Práctica Clínica para la detección, tratamiento y seguimiento de leucemias linfoblástica y mieloide en población mayor de 18 años. 2017.Indicadores de gestiòn del riesgo en adultos con leucemia linfoide aguda y leucemia mieloide aguda en Colombia. [Internet]. Costo, Fondo Colombiano de Enfermedades de Alto. 2018. Available from: https://www.cuentadealtocosto.org/site/images/Publicacio [Internet]. Costo, Fondo Colombiano de Enfermedades de Alto. 2018. Available from: https://www.cuentadealtocosto.org/site/images/Publicaciones/2018/Libro_Consenso_Leucemias_2018.pdfMayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive Postremission Chemotherapy in Adults with Acute Myeloid Leukemia. New England Journal of Medicine [Internet]. 1994 Oct 6;331(14):896–903. Available from: https://doi.org/10.1056/NEJM199410063311402Society AC. How Is Acute Myeloid Leukemia Diagnosed? [Internet]. 2014. Available from: https://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/how-diagnosed.htmlElgarten CW, Aplenc R. Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy. Curr Opin Pediatr [Internet]. 2020;32(1). Available from: https://journals.lww.com/co-pediatrics/Fulltext/2020/02000/Pediatric_acute_myeloid_leukemia__updates_on.9.aspxZuckerman T, Ganzel C, Tallman MS, Rowe JM. How I treat hematologic emergencies in adults with acute leukemia. Blood [Internet]. 2012 Sep 6;120(10):1993–2002. Available from: https://doi.org/10.1182/blood-2012-04-424440Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol [Internet]. 2002 Jul 1;3(7):415–24. Available from: https://doi.org/10.1016/S1470-2045(02)00788-XLöwenberg B. Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety. Hematology [Internet]. 2008 Jan 1;2008(1):1–11. Available from: https://doi.org/10.1182/asheducation-2008.1.1Megias-Vericat JE, Montesinos P, Herrero MJ, Moscardo F, Boso V, Martinez-Cuadron D, et al. Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment. Leuk Lymphoma. 2017 Dec;58(12):2880–94.Megias-Vericat JE, Martinez-Cuadron D, Herrero MJ, Alino SF, Poveda JL, Sanz MA, et al. Pharmacogenetics of Metabolic Genes of Anthracyclines in Acute Myeloid Leukemia. Curr Drug Metab. 2017;19(1):55–74.Maring JG, Groen HJM, Wachters FM, Uges DRA, de Vries EGE. Genetic factors influencing Pyrimidine-antagonist chemotherapy. Pharmacogenomics J [Internet]. 2005;5(4):226–43. Available from: https://doi.org/10.1038/sj.tpj.6500320Lamba JK. Genetic factors influencing cytarabine therapy. Pharmacogenomics. 2009 Oct;10(10):1657–74.Li Z, Guo JR, Chen QQ, Wang CY, Zhang WJ, Yao MC, et al. Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells. Molecules. 2017 Mar;22(3).Emadi, A., & Karp JE. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. Pharmacogenomics. 2012;13(11):1257–1269.Edwardson DW, Narendrula R, Chewchuk S, Mispel-Beyer K, Mapletoft JPJ, Parissenti AM. Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines. Curr Drug Metab [Internet]. 2015;16(6):412–26. Available from: https://pubmed.ncbi.nlm.nih.gov/26321196Emadi A, Karp JE. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. Pharmacogenomics. 2012 Aug;13(11):1257–69.Beretta G, Zunino F. Molecular Mechanisms of Anthracycline Activity. Top Curr Chem. 2008 Jan 1;283:1–19.Amaki J, Onizuka M, Ohmachi K, Aoyama Y, Hara R, Ichiki A, et al. Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. Int J Hematol. 2015 Jun;101(6):543–53Instituto Europeo de Bioinformática (EBI), Instituto Suizo de Bioinformática (SIB) PIR (PIR) [Internet]. UniProtKB [Internet]. P32320 (CDD_HUMAN). 2020 [cited 2020 May 10]. p. 1. Available from: https://www.uniprot.org/uniprot/P32320Medina-Sanson A, Ramirez-Pacheco A, Moreno-Guerrero SS, Dorantes-Acosta EM, Sanchez-Preza M, Reyes-Lopez A. Role of Genetic Polymorphisms of Deoxycytidine Kinase and Cytidine Deaminase to Predict Risk of Death in Children with Acute Myeloid Leukemia. Biomed Res Int. 2015;2015:309491.Shi JY, Shi Z, Zhang SJ, Zhu YM, Gu BW, Li G, et al. Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients. Pharmacogenet Genomics. 2004 Nov 1;14:759–68.Saito Y. CDA (Cytidine Deaminase). Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):673–5.Parmar S, Seeringer A, Denich D, Gärtner F, Pitterle K, Syrovets T, et al. Variability in transport and biotransformation of cytarabine is associated with its toxicity in peripheral blood mononuclear cells. Pharmacogenomics. 2011 Apr;12(4):503–14.Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, et al. SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia. 2009 Oct 21;23(10):1929–32.Li W, Zhang H, Assaraf YG, Zhao K, Xu X, Xie J, et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resistance Updates [Internet]. 2016;27:14–29. Available from: http://www.sciencedirect.com/science/article/pii/S1368764616300127Fletcher JI, Williams RT, Henderson MJ, Norris MD, Haber M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug Resistance Updates [Internet]. 2016;26:1–9. Available from: http://www.sciencedirect.com/science/article/pii/S1368764616000200Genovese I, Ilari A, Assaraf YG, Fazi F, Colotti G. Not only P-glycoprotein: Amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins. Drug Resistance Updates. 2017;Kim R B, Leake B F, Choo E F, Dresser G K, Kubba S V, Schwarz U I, Taylor A, Xie H G, McKinsey J, Zhou S, Lan L B, Schuetz J D, Schuetz E G WGR. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70(2):189–99.de Kouchkovsky I, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update.’ Blood Cancer J [Internet]. 2016;6(7):e441–e441. Available from: https://doi.org/10.1038/bcj.2016.50Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics. 2003 Aug;13(8):481–94.Ayala EV, Carbajal PM, Coelho EB, Sandoval JS, Granara AS. Geographic distribution of the 3435C>T polymorphism of the MDR1 gene in Peruvian populations. Drug Metab Pers Ther [Internet]. 2019;34(3):20180041. Available from: https://www.degruyter.com/view/journals/dmdi/34/3/article-20180041.xmlLamba J, Strom S, Venkataramanan R, Thummel KE, Lin YS, Liu W, et al. MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin Pharmacol Ther. 2006 Apr;79(4):325–38.Seedhouse CH, Grundy M, White P, Li Y, Fisher J, Yakunina D, et al. Sequential influences of leukemia-specific and genetic factors on p-glycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials. Clin Cancer Res. 2007 Dec;13(23):7059–66.Xiao Q, Zhou Y, Lauschke VM. Ethnogeographic and inter-individual variability of human ABC transporters. Hum Genet. 2020 May;139(5):623–46.van den Heuvel-Eibrink MM, Wiemer EA, de Boevere MJ, van der Holt B, Vossebeld PJ, Pieters R, et al. MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood. 2001 Jun;97(11):3605–11.Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002 Sep;62(17):4955–62.Kim DH, Park JY, Sohn SK, Lee NY, Baek JH, Jeon SB, et al. Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer. 2006 May;118(9):2195–201.Piacentini S, Polimanti R, Porreca F, Martínez-Labarga C, de Stefano GF, Fuciarelli M. GSTT1 and GSTM1 gene polymorphisms in European and African populations. Mol Biol Rep [Internet]. 2011;38(2):1225–30. Available from: https://doi.org/10.1007/s11033-010-0221-0Frova C. Glutathione transferases in the genomics era: New insights and perspectives. Biomol Eng [Internet]. 2006;23(4):149–69. Available from: http://www.sciencedirect.com/science/article/pii/S1389034406000414Xu S, Wang Y, Roe B, Pearson WR. Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion. J Biol Chem. 1998 Feb;273(6):3517–27.Weiss JR, Kopecky KJ, Godwin J, Anderson J, Willman CL, Moysich KB, et al. Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials. Vol. 20, Leukemia. England; 2006. p. 2169–71.Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: a review. Mutat Res. 2000 Oct;463(3):247–83.Coggan M, Whitbread L, Whittington A, Board P. Structure and organization of the human theta-class glutathione S-transferase and D-dopachrome tautomerase gene complex. Biochem J. 1998 Sep;334 ( Pt 3(Pt 3):617–23.Parl FF. Glutathione S-transferase genotypes and cancer risk. Cancer Lett [Internet]. 2005;221(2):123–9. Available from: http://www.sciencedirect.com/science/article/pii/S0304383504004628Sprenger R, Schlagenhaufer R, Kerb R, Bruhn C, Brockmöller J, Roots I, et al. Characterization of the glutathione S-transferase GSTT1 deletion: discrimination of all genotypes by polymerase chain reaction indicates a trimodular genotype–phenotype correlation. Pharmacogenet Genomics [Internet]. 2000;10(6). Available from: https://journals.lww.com/jpharmacogenetics/Fulltext/2000/08000/Characterization_of_the_glutathione_S_transferase.9.aspxRebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997 Sep;6(9):733–43.Palma-Cano LE, Córdova EJ, Orozco L, Martínez-Hernández A, Cid M, Leal-Berumen I, et al. GSTT1 and GSTM1 null variants in Mestizo and Amerindian populations from northwestern Mexico and a literature review. Genet Mol Biol. 2017 Nov 6;40(4):727–35.Ramírez B, Niño-Orrego MJ, Cárdenas D, Ariza KE, Quintero K, Contreras Bravo NC, et al. Copy number variation profiling in pharmacogenetics CYP-450 and GST genes in Colombian population. BMC Med Genomics [Internet]. 2019;12(1):110. Available from: https://doi.org/10.1186/s12920-019-0556-xYunis JJ, Yunis EJ, Yunis E. Genetic relationship of the Guambino, Paez, and Ingano Amerindians of Southwest Colombia using major histocompatibility complex class II haplotypes and blood groups. Hum Immunol. 2001 Sep;62(9):970–8.Usme-Romero S, Alonso M, Hernandez-Cuervo H, Yunis EJ, Yunis JJ. Genetic differences between Chibcha and Non-Chibcha speaking tribes based on mitochondrial DNA (mtDNA) haplogroups from 21 Amerindian tribes from Colombia. Genet Mol Biol. 2013 Mar 5;36(2):149–57.Mehta B, Daniel R, Phillips C, Mcnevin D. Forensically relevant SNaPshot(®) assays for human DNA SNP analysis: a review. Int J Legal Med. 2016 Nov 14;131.Lindblad-Toh K, Winchester E, Daly MJ, Wang DG, Hirschhorn JN, Laviolette JP, et al. Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat Genet. 2000 Apr;24(4):381–6.Stanford University. PHARMGKB [Internet]. 2019. Available from: http://www.pharmgkb.org/Rodrigues JCG, Fernandes MR, Guerreiro JF, da Silva AL da C, Ribeiro-dos-Santos Â, Santos S, et al. Polymorphisms of ADME-related genes and their implications for drug safety and efficacy in Amazonian Amerindians. Sci Rep. 2019 Dec 10;9(1):7201.Gregers J, Gréen H, Christensen IJ, Dalhoff K, Schroeder H, Carlsen N, et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2015 Aug 13;15(4):372–9.Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein*. Clin Pharmacol Ther. 2002 Aug;72(2):209–19.Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BHc. Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males. Pharmacogenomics. 2009 Nov;10(11):1743–51.Yang HC, Chen CW, Lin YT, Chu SK. Genetic ancestry plays a central role in population pharmacogenomics. Commun Biol. 2021 Dec 5;4(1):171.Dessilly G, Panin N, Elens L, Haufroid V, Demoulin JB. Impact of ABCB1 1236C > T-2677G > T-3435C > T polymorphisms on the anti-proliferative activity of imatinib, nilotinib, dasatinib and ponatinib. Sci Rep. 2016 Jul 12;6(1):29559.Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, et al. SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia. 2009 Oct 21;23(10):1929–32.Schroder JK, Kirch C, Seeber S, Schutte J. Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br J Haematol. 1998 Dec;103(4):1096–103.Abraham A, Varatharajan S, Karathedath S, Philip C, Lakshmi KM, Jayavelu AK, et al. RNA expression of genes involved in cytarabine metabolism and transport predicts cytarabine response in acute myeloid leukemia. Pharmacogenomics. 2015 Jul;16(8):877–90.Abraham A, Varatharajan S, Abbas S, Zhang W, Shaji R v, Ahmed R, et al. Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics. 2012 Feb;13(3):269–82.Carpi FM, Vincenzetti S, Ubaldi J, Pucciarelli S, Polzonetti V, Micozzi D, et al. CDA gene polymorphisms and enzyme activity: genotype-phenotype relationship in an Italian-Caucasian population. Pharmacogenomics. 2013 May;14(7):769–81.Hyo Kim L, Sub Cheong H, Koh Y, Ahn KS, Lee C, Kim HL, et al. Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML. J Hum Genet. 2015 Dec;60(12):749–54.Pinto-Merino Á, Labrador J, Zubiaur P, Alcaraz R, Herrero MJ, Montesinos P, et al. Role of Pharmacogenetics in the Treatment of Acute Myeloid Leukemia: Systematic Review and Future Perspectives. Pharmaceutics. 2023 Mar 3;14(3):559.Burmester JK, Sedova M, Shapero MH, Mansfield E. DMETTM Microarray Technology for Pharmacogenomics-Based Personalized Medicine BT - Microarray Methods for Drug Discovery. In: Chittur S v, editor. Totowa, NJ: Humana Press; 2010. p. 99–124. Available from: https://doi.org/10.1007/978-1-60761-663-4_7Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther [Internet]. 2017 Oct 1;102(4):688–700. Available from: https://doi.org/10.1002/cpt.690Schärfe CPI, Tremmel R, Schwab M, Kohlbacher O, Marks DS. Genetic variation in human drug-related genes. Genome Med [Internet]. 2017;9(1):117. Available from: https://doi.org/10.1186/s13073-017-0502-5Hovelson DH, Xue Z, Zawistowski M, Ehm MG, Harris EC, Stocker SL, et al. Characterization of ADME gene variation in 21 populations by exome sequencing. Pharmacogenet Genomics [Internet]. 2017 Mar;27(3):89–100. Available from: https://pubmed.ncbi.nlm.nih.gov/27984508Tafazoli A, Guchelaar HJ, Miltyk W, Kretowski AJ, Swen JJ. Applying Next-Generation Sequencing Platforms for Pharmacogenomic Testing in Clinical Practice. Front Pharmacol. 2021 Aug 25;12.Clinical Pharmacogenetics Implementation Consortium [Internet]. CPIC . 2021 [citado 27 octubre 2023]. Disponible en: https://cpicpgx.org/.Caracterización molecular y farmacológica en una muestra de pacientes con Leucemia Mieloide Aguda y su correlación con la estratificación del riesgo y respuesta al tratamiento. Una aproximación hacia los patrones moleculares de la Leucemia Mieloide Aguda Pediátrica en población colombianaColcienciasBibliotecariosEstudiantesInvestigadoresMaestrosMedios de comunicaciónPersonal de apoyo escolarProveedores de ayuda financiera para estudiantesPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84164/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL52896947.2023.pdf52896947.2023.pdfTesis de Maestría en Genética Humanaapplication/pdf2053139https://repositorio.unal.edu.co/bitstream/unal/84164/2/52896947.2023.pdf3bcdd7791e7f0534ff542c0cd84e90a1MD52THUMBNAIL52896947.2023.pdf.jpg52896947.2023.pdf.jpgGenerated Thumbnailimage/jpeg4458https://repositorio.unal.edu.co/bitstream/unal/84164/3/52896947.2023.pdf.jpg379575923277d05ead59a2ad802d96e8MD53unal/84164oai:repositorio.unal.edu.co:unal/841642023-08-12 23:03:52.62Repositorio Institucional Universidad Nacional de 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