RESUMO
INTRODUCTION: The aim was to study the pharmacogenetic determinants of switching simvastatin-intolerant ethnic Uzbek patients with coronary artery disease (CAD) to rosuvastatin treatment. MATERIAL AND METHODS: The study included 50 patients with CAD, who demonstrated statin-induced adverse liver symptoms, accompanied by an elevation in transaminase level (3-fold or more in 37 cases) or statin-induced adverse muscle symptoms, accompanied by elevations in serum (CK > 3 times above the upper limit of normal (ULN)) in simvastatin treatment with a dose of 10-20 mg/day. The control group consisted of 50 patients without side effects. Patients were genotyped for polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes CYP3A5(6986A>G), CYP2C9(430C>T), CYP2C9(1075A>C), and hepatic influx and efflux transporters SLCO1B1(521T>C) and BCRP(ABCG2, 421C>A) by means of the PCR-RFLP method. RESULTS: When the 50 patients of the case group were switched to the starting rosuvastatin dose of 5 mg, intolerance symptoms were not observed in 29 (58%) versus 21 with adverse symptoms. In this case-control study, the groups differed significantly only in the prevalence of the *3/*3 genotype CYP3A5 (OR = 5.25; 95% CI: 1.6-17.8; p = 0.014). CONCLUSIONS: In a considerable proportion of ethnic Uzbek patients with CAD and simvastatin intolerance symptoms, serious side effects when switching to a starting dose of rosuvastatin were not observed, and it should be noted that in most cases (72.4%) this phenomenon was observed among the carriers of *3/*3 genotype of the CYP3A5 (6986A> G) gene.
RESUMO
INTRODUCTION: The objective is to study the influence of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) gene polymorphisms on the development of simvastatin intolerance in ethnic Uzbek patients with coronary artery disease (CAD). MATERIAL AND METHODS: The case group contained 50 patients with clinical simvastatin-induced intolerance symptoms; the control group contained 50 patients without side-effects. Genotyping was performed by means of the PCR-RFLP method. RESULTS: Among 37 patients with simvastatin-induced liver symptoms the *3/*3 genotype of the CYP3A5 gene (p = 0.0001) and variant genotype of the CA BCRP gene were observed more frequently than in the control group (p = 0.0001). However, when the 13 patients who had statin-associated muscle symptoms (SAMS) were compared with the control group (n = 50), it was found that in the case group the 3*/3* genotype of the CYP3A5 gene (OR = 8.6; 95% CI: 2.1-34.1; p = 0.003) and C allele carriers of the gene polymorphism SLCO1B1 (OR = 3.54; 95% CI: 1.35-9.27; Χ2 = 5.7; p = 0.017) were predominant. CONCLUSIONS: The *3/*3 genotype of the CYP3A5 (6986A>G) gene and CA genotype of the BCRP (ABCG2, 421C>A) gene were associated with simvastatin-induced liver symptoms in ethnic Uzbek CAD patients, whereas in patients with simvastatin-associated muscle symptoms (SAMS), the combination of *3/*3 genotype of CYP3A5 (6986A> G) and carriage of the C allele of the SLCO1B1 gene polymorphism was predominant.
