RESUMEN
BACKGROUND: Statins are the most prescribed lipid-lowering drugs worldwide. The associated adverse events, especially muscle symptoms, have been frequently reported despite their perceived safety. Three pharmacogenes, the solute carrier organic anion transporter family member 1B1 (SLCO1B1), ATP-binding cassette subfamily G member 2 (ABCG2), and cytochrome P450 2C9 (CYP2C9) are suggested as safety biomarkers for statins. The Clinical Pharmacogenomic Implementation Consortium (CPIC) issued clinical guidelines for statin use based on these three genes. OBJECTIVES: The present study aimed to examine variants in these pharmacogenes to predict the safety of statin use among the Emirati population. METHODS: Analyzing 242 whole exome sequencing data at the three genes enabled the determination of the frequencies of the single nucleotide polymorphisms (SNPs), annotating the haplotypes and the predicted functions of their proteins. RESULTS: In our cohort, 29.8% and 5.4% had SLCO1B1 decreased and poor function, respectively. The high frequency warns of the possibility of significant side effects of some statins and the importance of pharmacogenomic testing. We found a low frequency (6%) of the ABCG2:rs2231142 variant, which indicates the low probability of Emirati patients being recommended against higher rosuvastatin doses compared with other populations with higher frequencies of this variant. In contrast, we found high frequencies of the functionally impaired CYP2C9 alleles, which makes fluvastatin a less favorable choice. CONCLUSION: Among the sparse studies available, the present one demonstrates all SLCO1B1 and CYP2C9 function-impairing alleles among Emiratis. We highlighted how population-specific pharmacogenomic data can predict safer choices of statins, especially in understudied populations.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Citocromo P-450 CYP2C9 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Transportador 1 de Anión Orgánico Específico del Hígado , Variantes Farmacogenómicas , Fenotipo , Polimorfismo de Nucleótido Simple , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Emiratos Árabes Unidos , Femenino , Persona de Mediana Edad , Masculino , Citocromo P-450 CYP2C9/genética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Proteínas de Neoplasias/genética , Anciano , Adulto , Secuenciación del Exoma , Pruebas de Farmacogenómica , Medición de Riesgo , Factores de Riesgo , Seguridad del Paciente , Frecuencia de los GenesRESUMEN
BACKGROUND: Pharmacogenomic (PGx) testing has proved its utility and cost-effectiveness for some commonly prescribed cardiovascular disease (CVD) medications. In addition, PGx-guided dosing guidelines are now available for multiple CVD drugs, including clopidogrel, warfarin, and statins. The United Arab Emirates (UAE) population is diverse and multiethnic, with over 150 nationalities residing in the country. PGx-testing is not part of the standard of care in most global healthcare settings, including the UAE healthcare system. The first pharmacogenomic implementation clinical study in CVD has been approved recently, but multiple considerations needed evaluation before commencing. The current report appraises the PGx-clinical implementation procedure and the potential benefits of pursuing PGx-implementation initiatives in the UAE with global implications. METHODS: Patients prescribed one or more of the following drugs: clopidogrel, atorvastatin, rosuvastatin, and warfarin, were recruited. Genotyping selected genetic variants at genes interacting with the study drugs was performed by real-time PCR. RESULTS: For the current pilot study, 160 patients were recruited. The genotypes and inferred haplotypes, diplotypes, and predicted phenotypes revealed that 11.9% of the participants were poor CYP2C19 metabolizers, 35% intermediate metabolizers, 28.1% normal metabolizers, and 25% rapid or ultrarapid metabolizers. Notably, 46.9% of our cohort should receive a recommendation to avoid using clopidogrel or consider an alternative medication. Regarding warfarin, only 20% of the participants exhibited reference alleles at VKORC1-1639G > A, CYP2C9*2, and CYP2C9*3, leaving 80% with alternative genotypes at any of the two genes that can be integrated into the warfarin dosing algorithms and can be used whenever the patient receives a warfarin prescription. For statins, 31.5% of patients carried at least one allele at the genotyped SLCO1B1 variant (rs4149056), increasing their risk of developing myopathy. 96% of our cohort received at least one PGx-generated clinical recommendation for the studied drugs. CONCLUSION: The current pilot analysis verified the feasibility of PGx-testing and the unforeseen high frequencies of patients currently treated with suboptimal drug regimens, which may potentially benefit from PGx testing.