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 who had been hospitalized with a non‐ST elevation acute coronary syndrome 1 month earlier and were on high‐dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2‐OH ATV/ATV (P  = 7.25 × 10⁻¹⁶) and 2‐OH ATV L/ATV L (P  = 3.95 × 10⁻¹⁵) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C , was nominally associated with increased 2‐OH ATV/ATV (P  = 6.18 × 10⁻⁷), and SLCO1B1 rs4149056 with increased ATV (P  = 2.21 × 10⁻⁶) and 2‐OH ATV (P  = 1.09 × 10⁻⁶) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (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 (odds ratio (OR) 3.97; 95% confidence interval (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 recognized 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.

中文翻译：

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阿托伐他汀及其主要代谢物循环水平的全基因组关联研究。

阿托伐他汀 (ATV) 经常被开具处方，通常耐受性良好，但会导致肌毒性，尤其是在较高剂量时。对 590 名因非 ST 段抬高住院的患者进行了 ATV、2-羟基 (2-OH) ATV、ATV 内酯 (ATV L) 和 2-OH ATV L 循环水平的全基因组关联研究1 个月前发生急性冠状动脉综合征，并服用高剂量 ATV（每天 80 毫克或 40 毫克）。UGT1A基因座（前导单核苷酸多态性，rs887829）与 2-OH ATV/ATV ( P  = 7.25 × 10 ^-16 ) 和 2-OH ATV L/ATV L ( P  = 3.95 × 10 ^-15 )的增加密切相关代谢率。此外，rs45446698，标记CYP3A7*1C，名义上与增加的 2-OH ATV/ATV ( P  = 6.18 × 10 ^-7 ) 相关，而SLCO1B1 rs4149056 与增加的 ATV ( P  = 2.21 × 10 ^-6 ) 和 2-OH ATV ( P  = 1.09 × 10 ^-6 ) 水平。在住院后 12 个月也测量了 ATV 和代谢物水平的这些患者中（n  = 149），所有这些关联仍然存在，除了 2-OH ATV 和 rs4149056（P  = 0.057）。临床上，rs4149056 与肌肉症状增加相关（优势比 (OR) 3.97；95% 置信区间 (CI) 1.29-12.27；P = 0.016) 和 ATV 不耐受 (OR 1.55; 95% CI 1.09–2.19; P  = 0.014) 患者 ( n  = 870) 主要在高剂量 ATV 出院。总之，新的和公认的遗传关联都与 ATV 及其主要代谢物的循环水平有关。需要进一步研究以确定基因分型 rs4149056 在高剂量 ATV 患者中的临床效用。