A pharmacogenomic dissection of a Rosuvastatin-induced rhabdomyolysis case evokes the polygenic nature of adverse drug reactions
| Autor: | Calderon-Ospina, Carlos Alberto, Hernández-Sómerson, Mario, García, Ana María, Mejia, Adriana, Tamayo-Agudelo, Caroll, Laissue, Paul, Fonseca Mendoza, Dora Janeth |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Ticagrelor
Scoring system Chronic kidney failure Leukocytosis Aminotransferase Case Report Coronary artery disease Gene Rhabdomyolysis Dark urine Tachycardia whole-exome sequencing Drug safety Hospital discharge Heart muscle revascularization Npc1l1 gene Abdominal distension Dehydration Obscn gene Pyelonephritis Intervention study Metabolic acidosis Cytochrome p450 2c19 Myoglobinuria Urea nitrogen blood level Polymerase chain reaction Hyperphosphatemia Eyelid edema Creatinine Hemodialysis Whole-exome sequencing Hypertension Insulin detemir Obscurin Female Muscle biopsy Hypotension Antihyperkalemic agent Abnormal urine composition Human Hyponatremia Abdominal pain Heart left ventricle ejection fraction Limb pain Clinical article adverse drug reaction Adverse drug reaction Emergency ward Linagliptin Urinalysis Losartan Article Rosuvastatin Physical examination Acetylsalicylic acid Case report Creatine kinase Human tissue Aged Drug induced disease pharmacogenomics Drug metabolism Hypocalcemia Electromyography Rosuvastatin induced rhabdomyolysis Whole exome sequencing nutritional and metabolic diseases Phase 1 clinical trial Ezetimibe Hospital admission Gene frequency Congestive cardiomyopathy Cyp2c19 gene rhabdomyolysis Genetic association Hyperkalemia Carvedilol Genetic variability Non insulin dependent diabetes mellitus polymorphisms Pharmacogenomics Polymorphisms rosuvastatin |
| Zdroj: | Repositorio EdocUR-U. Rosario Universidad del Rosario instacron:Universidad del Rosario Pharmacogenomics and Personalized Medicine |
| Popis: | Rosuvastatin, 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. |
| Databáze: | OpenAIRE |
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