In a genome‐wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration‐time curve from time zero to infinity (AUC0–∞) of atorvastatin (P = 1.2 × 10−10), 2‐hydroxy atorvastatin (P = 4.0 × 10−8), and 4‐hydroxy atorvastatin (P = 2.9 × 10−8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0–∞ (P = 3.8 × 10−8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2‐hydroxy atorvastatin lactone AUC0–∞ (P = 3.9 × 10−8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0–∞ was 145% (90% confidence interval: 98‐203%; P = 5.6 × 10−11) larger in individuals with poor function, 24% (9‐41%; P = 0.0053) larger in those with decreased function, and 41% (16‐59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14‐55%; P = 0.022) larger atorvastatin AUC0–∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5‐25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22‐44%; P = 4.8 × 10‐5) smaller atorvastatin AUC0–∞ than noncarriers. = 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P× 10−5) smaller in homozygotes for LPP noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure.

中文翻译：

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阿托伐他汀药代动力学的全基因组关联研究：与 SLCO1B1、UGT1A3 和 LPP 的关联

在 158 名健康志愿者参与的阿托伐他汀药代动力学全基因组关联研究中，SLCO1B1c.521T>C (rs4149056) 变体与血浆浓度-时间曲线下面积从零时间到无穷大 (AUC0–无穷大）阿托伐他汀（磷= 1.2 × 10−10），2-羟基阿托伐他汀（磷= 4.0 × 10−8）和4-羟基阿托伐他汀（磷= 2.9 × 10−8）。内含子LPP变体，rs1975991，与阿托伐他汀内酯 AUC 降低相关0–无穷大（磷= 3.8 × 10−8）。三UGT1A与链接的变体UGT1A3*2与 2-羟基阿托伐他汀内酯 AUC 增加相关0–无穷大（磷= 3.9 × 10−8）。此外，一项包含 243 名参与者的候选基因分析表明，功能增强SLCO1B1变异和活性降低CYP3A4变异体影响阿托伐他汀药代动力学。与功能正常的人相比SLCO1B1基因型、阿托伐他汀 AUC0–无穷大为 145%（90% 置信区间：98‐203%；磷= 5.6 × 10−11) 在功能较差的个体中更大，24% (9‐41%;磷= 0.0053) 功能下降的人更大，41% (16‐59%;磷= 0.016) 功能高度增强的患者较小SLCO1B1基因型。具有中间代谢者的个体CYP3A4基因型（CYP3A4*2或者CYP3A4*22杂合子）占 33%（14‐55%；磷= 0.022) 更大的阿托伐他汀 AUC0–无穷大高于具有正常代谢基因型的人。UGT1A3*2杂合子有 16% (5‐25%;磷= 0.017) 更小并且LPPrs1975991 纯合子有 34% (22‐44%;磷= 4.8 × 10‐5) 较小的阿托伐他汀 AUC0–无穷大比非携带者。 = 0.017) 杂合子较小UGT1A3*2和 34%（22%、44%；磷× 10−5）纯合子中较小LPP非携带者。这些数据表明，遗传变异SLCO1B1,UGT1A3,LPP， 和CYP3A4影响阿托伐他汀药代动力学。这是第一项研究表明LPPrs1975991 可能会减少阿托伐他汀暴露。