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A pharmacogenomic dissection of a Rosuvastatin-induced rhabdomyolysis case evokes the polygenic nature of adverse drug reactions

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dc.creatorCalderón Ospina, Carlos Alberto
dc.creatorHernández-Sómerson, Mariospa
dc.creatorGarcía, Ana Maríaspa
dc.creatorMejia, Adrianaspa
dc.creatorTamayo-Agudelo, Carollspa
dc.creatorLaissue, Paulspa
dc.creatorFonseca Mendoza, Dora Janeth
dc.date.accessioned2020-05-25T23:58:05Z
dc.date.available2020-05-25T23:58:05Z
dc.date.created2020spa
dc.description.abstractRosuvastatin, is a widely-used statin for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases. Although rosuvastatin is well tolerated, about 3/10.000 patients can suffer severe myopathy. Rhabdomyolysis is a severe medical condition that causes injury to the skeletal muscle, electrolyte imbalances, acute renal failure and extreme creatine kinase (CK) elevation. Little is known regarding the molecular involvement of rosuvastatin-induced rhabdomyolysis (RIR). It has been demonstrated that genomic variants associated with decreased enzymatic activity of proteins are important determinants in plasmatic and skeletal muscle distribution of rosuvastatin and its toxicity. Until now, no interactions of ticagrelor, ezetimibe and rosuvastatin have been described with the consideration of pharmacogenomics predisposition. The present report involves a whole-exome sequencing (WES), in a patient affected by rosuvastatin-induced rhabdomyolysis. A pharmacogenomic dissection was performed by analyzing a comprehensive subset of candidate genes (n=160) potentially related to RIR. The genes were selected according to their implication in drug metabolism or inherited myopathies. Using an innovative approach of bioinformatics analysis, considering rare and common variants, we identified 19 genomic variations potentially related to the pharmacokinetic/pharmacodynamic modifications of rosuvastatin, ezetimibe and ticagrelor. The affected genes are involved in Phase I metabolism (CYP2C19, CYP2E1, CYP1A1, CYP2D6 and CYP2C9), Phase II metabolism (UGT2B15 and UGT2B7), influx transportation (SLCO1B3 and SLCO2B1), efflux transportation (ABCG8, ABCB11, ABCC4 and ABCB1), drug targeting (NPC1L1) and inherited myopathy etiology (OBSCN). We report three rare, potentially pathogenic molecular variants in CYP2C19, NPC1L1 and OBSCN genes. Pharmacogenetic analysis indicated that the patient was a carrier of inactivating alleles in several pharmacogenes involved in drug toxicity. The whole-exome sequencing and bioinformatics analysis presented here represents an innovative way to identify genomic variants contributing with RIR´s origin and evokes the polygenic nature of adverse drug reactions. © 2020 Calderon-Ospina et al.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.2147/PGPM.S228709
dc.identifier.issn11787066
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22797
dc.language.isoengspa
dc.publisherDove Medical Press Ltdspa
dc.relation.citationEndPage70
dc.relation.citationStartPage59
dc.relation.citationTitlePharmacogenomics and Personalized Medicine
dc.relation.citationVolumeVol. 13
dc.relation.ispartofPharmacogenomics and Personalized Medicine, ISSN:11787066, Vol.13,(2020); pp. 59-70spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85081276202&doi=10.2147%2fPGPM.S228709&partnerID=40&md5=a1e89ca7a34173b8dd92e9d66cb1983fspa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordAcetylsalicylic acidspa
dc.subject.keywordAminotransferasespa
dc.subject.keywordAntihyperkalemic agentspa
dc.subject.keywordCarvedilolspa
dc.subject.keywordCreatine kinasespa
dc.subject.keywordCreatininespa
dc.subject.keywordCytochrome p450 2c19spa
dc.subject.keywordEzetimibespa
dc.subject.keywordInsulin detemirspa
dc.subject.keywordLinagliptinspa
dc.subject.keywordLosartanspa
dc.subject.keywordObscurinspa
dc.subject.keywordRosuvastatinspa
dc.subject.keywordTicagrelorspa
dc.subject.keywordAbdominal distensionspa
dc.subject.keywordAbdominal painspa
dc.subject.keywordAbnormal urine compositionspa
dc.subject.keywordAgedspa
dc.subject.keywordArticlespa
dc.subject.keywordCase reportspa
dc.subject.keywordChronic kidney failurespa
dc.subject.keywordClinical articlespa
dc.subject.keywordCongestive cardiomyopathyspa
dc.subject.keywordCoronary artery diseasespa
dc.subject.keywordCyp2c19 genespa
dc.subject.keywordDark urinespa
dc.subject.keywordDehydrationspa
dc.subject.keywordDrug induced diseasespa
dc.subject.keywordDrug metabolismspa
dc.subject.keywordDrug safetyspa
dc.subject.keywordElectromyographyspa
dc.subject.keywordEmergency wardspa
dc.subject.keywordEyelid edemaspa
dc.subject.keywordFemalespa
dc.subject.keywordGenespa
dc.subject.keywordGene frequencyspa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordHeart left ventricle ejection fractionspa
dc.subject.keywordHeart muscle revascularizationspa
dc.subject.keywordHemodialysisspa
dc.subject.keywordHospital admissionspa
dc.subject.keywordHospital dischargespa
dc.subject.keywordHumanspa
dc.subject.keywordHuman tissuespa
dc.subject.keywordHyperkalemiaspa
dc.subject.keywordHyperphosphatemiaspa
dc.subject.keywordHypertensionspa
dc.subject.keywordHypocalcemiaspa
dc.subject.keywordHyponatremiaspa
dc.subject.keywordHypotensionspa
dc.subject.keywordIntervention studyspa
dc.subject.keywordLeukocytosisspa
dc.subject.keywordLimb painspa
dc.subject.keywordMetabolic acidosisspa
dc.subject.keywordMuscle biopsyspa
dc.subject.keywordMyoglobinuriaspa
dc.subject.keywordNon insulin dependent diabetes mellitusspa
dc.subject.keywordNpc1l1 genespa
dc.subject.keywordObscn genespa
dc.subject.keywordPharmacogenomicsspa
dc.subject.keywordPhase 1 clinical trialspa
dc.subject.keywordPhysical examinationspa
dc.subject.keywordPolymerase chain reactionspa
dc.subject.keywordPyelonephritisspa
dc.subject.keywordRhabdomyolysisspa
dc.subject.keywordRosuvastatin induced rhabdomyolysisspa
dc.subject.keywordScoring systemspa
dc.subject.keywordTachycardiaspa
dc.subject.keywordUrea nitrogen blood levelspa
dc.subject.keywordUrinalysisspa
dc.subject.keywordWhole exome sequencingspa
dc.subject.keywordAdverse drug reactionspa
dc.subject.keywordPharmacogenomicsspa
dc.subject.keywordPolymorphismsspa
dc.subject.keywordRhabdomyolysisspa
dc.subject.keywordRosuvastatinspa
dc.subject.keywordWhole-exome sequencingspa
dc.titleA pharmacogenomic dissection of a Rosuvastatin-induced rhabdomyolysis case evokes the polygenic nature of adverse drug reactionsspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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