BACKGROUND AND AIMS The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study, we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance. METHODS AND RESULTS A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside, Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance [general statin intolerance (GSI): ORGSI 2.42; 95% confidence interval (CI): 1.29-4.31, P = 0.003; statin-related myopathy: ORSRM 2.51; 95% CI: 1.28-4.53, P = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85; 95% CI: 1.03-6.65, P = 0.02]. In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99; 95% CI: 1.01-3.95, P = 0.048; ORGRS 1.76; 95% CI: 1.16-2.69, P = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared with Val174Ala (GSI: HRVal174Ala 2.49; 95% CI: 1.09-5.68, P = 0.03; HRGRS 2.44; 95% CI: 1.46-4.08, P < 0.001). Finally, sequence kernel association testing confirmed that rare variants in SLCO1B1 are associated with the risk of intolerance (P = 0.02). CONCLUSION We provide evidence that a GRS based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early-onset statin intolerance.

中文翻译：

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使用 SLCO1B1 中错义变异的基因风险评分与早期发病的他汀类药物不耐受相关。

背景和目的 他汀类药物治疗的疗效因治疗不耐受而受到阻碍，导致停药。编码肝脏转运蛋白 OATB1B1 的 SLCO1B1 变异体影响他汀类药物的药代动力学，导致药物及其代谢物的血浆浓度改变。目前的药物遗传学指南要求对 SLCO1B1 基因进行测序，这比基因分型更昂贵且更难获得。在这项研究中，我们的目标是针对 SLCO1B1 的常见变异开发一种简单的、临床上可实施的功能基因风险评分 (GRS)，以识别存在他汀类药物不耐受风险的患者。方法和结果 GRS 是根据 SLCO1B1 的四种常见变体开发的。在英国苏格兰泰赛德的他汀类药物使用者中，那些患有高风险 GRS 的人，他汀类药物不耐受的三种表型的几率有所增加 [一般他汀类药物不耐受 (GSI)：ORGSI 2.42；ORGSI 2.42；95%置信区间（CI）：1.29-4.31，P=0.003；他汀类药物相关肌病：ORSRM 2.51；95% CI：1.28-4.53，P = 0.004；他汀类药物相关的疑似横纹肌溶解症：ORSRSR 2.85；95% CI：1.03-6.65，P = 0.02]。相比之下，单独使用 Val174Ala 基因型或推荐的 OATP1B1 功能表型产生的结果较弱且不太可靠。对 PREDICTION-ADR 联盟中他汀类药物诱发的肌病判定病例结果进行的荟萃分析证实了这些发现（ORVal174Ala 1.99；95% CI：1.01-3.95，P = 0.048；ORGRS 1.76；95% CI：1.16-2.69， P = 0.008）。对于需要高剂量他汀类药物治疗的患者，与 Val174Ala 相比，高风险 GRS 与三种表型中他汀类药物不耐受发作时间的相关性更一致（GSI：HRVal174Ala 2.49；95% CI：1.09-5.68，P = 0.03） ；HRGRS 2.44；95% CI：1.46-4.08，P < 0.001）。最后，序列核关联测试证实 SLCO1B1 中的罕见变异与不耐受风险相关（P = 0.02）。结论 我们提供的证据表明，基于四种常见 SLCO1B1 变体的 GRS 提供了一种易于实施的遗传工具，在估计风险和预测早发他汀类药物不耐受方面比当前推荐的做法更可靠。