Distribution of polymorphisms of genes of statins metabolism and transport in the liver in patients with coronary artery disease ethnic Uzbeks with simvastatin intolerance

Background. It is well-known that in majority of cases treatment with statins can be safe and well tolerated, but in some patients observed statin-induced adverse liver or muscle symptoms - the main reasons for statin discontinuation. Asian ethnicity - is one of the predisposing factors for statin-associated adverse effects. Objective. To study possible effects of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) genetic polymorphism on simvastatin tolerance and safety in ethnic Uzbek patients with Coronary Artery Disease (CAD). Material and methods. The prospective case-control research included 100 patients with CAD. Group "case" were 50 patients who demonstrated statin-induced adverse liver effects (transaminase level increases 3 times and more - in 37 cases) or statin-induced elevations in serum CK (of >3*UNL - in 4 cases) at treatment with simvastatin with the dose of 20 mg/day for 3 months of treatment and 13 with myopathy, associated with increased levels of total creatine phosphokinase (CPK) 3 times or more. In 4 patients with adverse effects on the liver, along with an increase in the enzymes, while there was an increase of CPK levels. Control group contained 50 patient with CAD treated with simvastatin with the dose of 20-40 mg/day for one year without side effects. The both groups of patients were similar in gender, age, original index of kidney function and serum CK level. The comparison group consisted of healthy ethnic Uzbeks (n = 41) of comparable age and sex, with the absence of a family history of coronary artery disease. The research was performed by means of PCR-RFLP method. Results. As a whole, all genotypes (except for CYP2C9 * 2 in patients) were in Hardy-Weinberg equilibrium. Among patients with simvastatin intolerance, compared to the control group, the following genotypes were observed more frequently with high level of confidence: CYP3A5 *3/*3, compared to genotype variants *1/*3 and *1/*1 (OR 9.33; 95% CI 3,37-25,9; P = 0.0001) and BCRP CA (patients with BCRP CC genotype were not observed among those examined) (OR 3.22; 95% CI 1,258,30, P = 0.024). Conclusions. Genotypes CYP3A5 *3/*3 (6986A>G) and BCRP CA (ABCG2, 421C>A) are accompanied with the increase of statin-induced adverse effects in ethnic Uzbek patients with Coronary artery disease.