Pharmacogenetics in statin use

Abstract

The SLCO1B1 c.521T>C (rs4149056) genetic polymorphism is implicated in decreased SLCO1B1 function which leads to reduced uptake of simvastatin by the liver and higher simvastatin concentrations in the blood. The resulting elevated plasma simvastatin concentrations may increase the risk of simvastatin-induced myopathy (SIM). The aim of the research was to investigate the pharmacogenetic implications of simvastatin. The objectives were to: (i) identify presence of the SLCO1B1 c.521T>C genetic polymorphism in a cohort of cardiac patients on simvastatin and (ii) explore the correlation between genotype results and myopathy risk. Patients on simvastatin were recruited by convenience sampling from the Cardiac Catheterisation Suite at Mater Dei Hospital after ethics approval. A peripheral blood sample was obtained from each patient and genomic DNA was extracted using the QIAamp® DNA Blood Mini kit. Real-time polymerase chain reaction SLCO1B1 c.521T>C rs4149056 genotyping was performed with the Sacace® Biotechnology kits and Rotor-Gene™ 6000/Q. Patients were classified into 3 genotypes (phenotypes): 1. TT (normal SLCO1B1 function), 2. TC (intermediate SLCO1B1 function) or 3. CC (low SLCO1B1 function). TC and CC patients were communicated to the consultant cardiologists with the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommendations for SLCO1B1 and SIM. The patients were followed up 6 months post-recruitment for documented and self-reported muscle symptoms. The 148 patients recruited (all Caucasian, 90 male, mean age 65 years) were genotyped as TT (83.1%, n=123), TC (14.9%, n=22) and CC (2%, n=3). Fifteen of the 25 TC and CC patients were prescribed simvastatin 40mg daily. At follow-up, 15 patients (12 TT, 2 TC, 1 CC) self-reported muscle symptoms; stiffness (n=6; 5 TT, 1 TC), cramps (n=4; all TT), pain (n=4; 3 TT, 1 CC) and weakness (n=1; TC). According to the CPIC guidelines, patients genotyped as TC (15%) have mild myopathy risk and CC patients (2%) have high myopathy risk. Fifteen of the 25 TC and CC patients were prescribed simvastatin 40mg and the CPIC guidelines recommend a lower simvastatin dose (20mg/day) or consideration of another statin (rosuvastatin) in these patients. One of the 3 CC patients had documented myalgia at follow-up. The observed findings from this study are exploratory and warrant further investigation.