The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction = 3.7 × 10−4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

中文翻译：

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PPARA 多态性影响非诺贝特对 2 型糖尿病的心血管益处：来自 ACCORD 脂质的发现

贝特类的心血管益处已被证明是异质的，并且取决于致动脉粥样硬化的血脂异常的存在。我们研究了编码贝特类药物靶点 (PPAR-α) 的 PPARA 基因的遗传变异性是否可用于改善 2 型糖尿病患者的选择，这些患者可能会因将这种治疗添加到他汀类药物而获得心血管益处。我们在 PPARA 基因座 (rs6008845, C/T) 发现了一个常见变异，在 3,065 名自我报告的接受辛伐他汀治疗并随机接受非诺贝特或非诺贝特治疗的白人受试者中，显示出对非诺贝特对主要心血管事件 (MACE) 影响的研究范围内的显着影响。 ACCORD-Lipid 试验中的安慰剂。T/T 纯合子（36% 的参与者）对非诺贝特的反应发生了 51% 的 MACE 降低（风险比 0.49；95% CI 0.34–0。72），而其他基因型没有观察到益处（Pinteraction = 3.7 × 10−4）。rs6008845 与非诺贝特对 MACE 的相互作用在来自 ACCORD 的非裔美国人（N = 585，P = 0.02）和外部队列（ACCORD-BP、ORIGIN 和 TRIUMPH，总 N = 3059，P = 0.005）中得到复制。值得注意的是，即使没有致动脉粥样硬化的血脂异常，rs6008845 T/T 纯合子也能从贝特类中获益。在这些个体中，但不是在其他基因型的携带者中，非诺贝特治疗与 CCL11 的循环水平降低有关 - CCL11 是一种促炎和致动脉粥样硬化趋化因子，也称为嗜酸性粒细胞趋化因子（rs6008845 与非诺贝特相互作用的 P = 0.003）。GTEx 数据集揭示了 rs6008845 对许多组织中 PPARA 表达的调节功能。总之，