A Genome‐wide Association Study of Circulating Levels of Atorvastatin and Its Major Metabolites

Abstract

Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome‐wide association study of circulating levels of ATV, 2‐hydroxy (2‐OH) ATV, ATV lactone (ATV L) and 2‐OH ATV L was performed in 590 patients that had been hospitalised with a non‐ST elevation acute coronary syndrome one month earlier and were on high dose ATV (80mg or 40mg daily). The UGT1A locus (lead SNP, rs887829) was strongly associated with both increased 2‐OH ATV/ATV (p=7.25x10^‐16) and 2‐OH ATV L/ATV L (p=3.95x10^‐15) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2‐OH ATV/ATV (p=6.18x10^‐7), and SLCO1B1 rs4149056 with increased ATV (p=2.21x10^‐6) and 2‐OH ATV (p=1.09x10^‐6) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalisation (n=149), all of these associations remained, except for 2‐OH ATV and rs4149056 (p=0.057). Clinically, rs4149056 was associated with increased muscular symptoms (OR 3.97, 95% CI 1.29‐12.27, p=0.016) and ATV intolerance (OR 1.55, 95% CI 1.09‐2.19, p=0.014) in patients (n=870) primarily discharged on high dose ATV. In summary, both novel and recognised genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high dose ATV.