Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

中文翻译：

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腺苷酸环化酶 9 在 Dalcetrapib 药物基因组学反应中的作用

在 dal-OUTCOMES 试验的中性结果之后，一项全基因组研究确定了16 号染色体上的9 型腺苷酸环化酶 ( ADCY9 ) 基因中的 rs1967309 变异仅在服用 dalcetrapib 的受试者中与未来发生心血管事件的风险相关。 CETP（胆固醇酯转移蛋白）调节剂。使用dalcetrapib 治疗时，次要A 等位基因(AA) 的纯合子可免于复发性心血管事件，而主要G 等位基因(GG) 的纯合子风险增加。在这里，我们介绍了关于 ADCY9 中的rs1967309对 dalcetrapib 试验中的临床观察和生物标志物的影响以及小鼠ADCY9的影响的当前知识状态基因失活对心血管生理。最后，我们展示了 dalcetrapib 和ADCY9之间相互作用的当前模型动脉壁巨噬细胞中的基因变异，基于 CETP 在复杂脂质从内质网膜转移到脂滴中的细胞内作用。简而言之，该概念是 dalcetrapib 将抑制 CETP 介导的胆固醇酯转移，导致胆固醇酯合成和内质网中游离胆固醇积累的逐渐抑制。降低 ADCY9 活性，自相矛盾地导致更高的环 AMP 水平，进而增加细胞胆固醇流出，可以为 rs1967309 AA 患者提供心血管保护。正在进行的 dal-GenE 试验招募了 6145 名具有保护性 AA 基因型的患者，并将为 dalcetrapib 是否对该人群具有保护作用提供明确的答案。