From the Montreal Heart Institute, Montreal, Canada (B.J.A., M.-P.D., M.R.B., A.B.d.O.M., V.L., A.-E.K., D.R., É.R., J.-C.T.); Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada (B.J.A., M.-P.D., M.R.B., A.B.d.O.M., É.R., J.-C.T.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Montreal, Canada (M.-P.D., J.-C.T.); Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (S.G.-O., P.M., P.P., Y.B.) and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; Cardiology Department, AP-HP, Bichat Hospital, Paris, France (D.M.-Z.); and INSERM U698, University Paris 7, Paris, France (D.M.-Z.).
Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):457-62. doi: 10.1161/ATVBAHA.113.302730. Epub 2013 Dec 12.
Studies have shown that high-density lipoprotein (HDL)-raising compounds induce regression of aortic valve stenosis (AVS) in animal models. However, whether patients with AVS have an impaired HDL metabolism is unknown.
A total of 1435 single nucleotide polymorphisms in genes associated with HDL cholesterol levels (in or around GALNT2, LPL, ABCA1, APOA5, SCARB1, LIPC, CETP, LCAT, LIPG, APOC4, and PLTP) were genotyped in 382 patients with echocardiography-confirmed AVS (aortic jet velocity ≥2.5 m/s) and 401 controls. After control for multiple testing, none of the genetic variants showed a positive association with case/control status (adjusted P≥0.05 for all single nucleotide polymorphisms tested). In a subsample of this cohort, HDL cholesterol levels, apolipoprotein AI levels, lecithin-cholesterol acyltransferase activity, pre-β-HDL, HDL size, and 4 parameters of cholesterol efflux capacity were measured in apolipoprotein B-depleted serum samples from 86 patients with and 86 patients without AVS. Cholesterol efflux capacity was measured using J774 macrophages with and without stimulation of ATP-binding cassette A-1 expression by cAMP, and HepG2 hepatocytes for scavenger receptor class B type 1-mediated efflux. None of these parameters were different between cases and controls. However, compared with patients without coronary artery disease, sera from patients with coronary artery disease had lower HDL cholesterol levels, scavenger receptor class B type 1-mediated efflux, and HDL size (P≤0.003), independently of the presence or absence of AVS.
Results of the present study suggest that, based on HDL genetics and HDL functionality, HDL metabolism does not seem to predict the risk of AVS. Because of our limited sample size, additional studies are needed to confirm these findings.
研究表明，高密度脂蛋白（HDL）升高化合物可诱导动物模型主动脉瓣狭窄（AVS）的消退。然而，患有 AVS 的患者是否存在 HDL 代谢受损尚不清楚。
对 382 名经超声心动图证实的 AVS 患者（主动脉射流速度≥2.5 m/s）和 401 名对照者进行了与 HDL 胆固醇水平相关的基因中的 1435 个单核苷酸多态性（GALNT2、LPL、ABCA1、APOA5、SCARB1、LIPC、CETP、LCAT、LIPG、APOC4 和 PLTP 内或周围）的基因分型。经多重检验校正后，没有一个遗传变异与病例/对照状态呈正相关（所有检测的单核苷酸多态性调整后的 P 值均≥0.05）。在该队列的一个亚组中，在 86 例有和 86 例无 AVS 的患者的载脂蛋白 B 耗尽血清样本中测量了 HDL 胆固醇水平、载脂蛋白 AI 水平、卵磷脂-胆固醇酰基转移酶活性、前-β-HDL、HDL 大小和胆固醇流出能力的 4 个参数。使用载脂蛋白 B 耗尽的 J774 巨噬细胞和用 cAMP 刺激的 ABCA1 表达的 J774 巨噬细胞以及 HepG2 肝细胞测量胆固醇流出能力，用于清道夫受体 B 型 1 介导的流出。病例和对照者之间这些参数均无差异。然而，与无冠状动脉疾病的患者相比，有冠状动脉疾病的患者的血清 HDL 胆固醇水平、清道夫受体 B 型 1 介导的流出和 HDL 大小较低（P≤0.003），独立于 AVS 的存在与否。
本研究结果表明，根据 HDL 遗传学和 HDL 功能，HDL 代谢似乎不能预测 AVS 的风险。由于我们的样本量有限，需要进一步的研究来证实这些发现。
