伴有血清脂蛋白(a)水平升高的冠心病患者中KATP变异体与心肌病和反复心绞痛的关联

Association of KATP Variants With CMD and RAP in CAD Patients With Increased Serum Lipoprotein(a) Levels.

作者信息

Pei Jingxian, Liu Cheng, Yang Zhengxia, Lai Yanxian, Zhang Shenghui, Guan Tianwang, Shen Yan

机构信息

Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.

Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510180, China.

出版信息

J Clin Endocrinol Metab. 2023 Apr 13;108(5):1061-1074. doi: 10.1210/clinem/dgac709.

DOI:10.1210/clinem/dgac709

PMID:36469795

Abstract

CONTEXT

Refractory angina pectoris (RAP) is a specific subtype of coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] and its induced coronary microvascular dysfunction (CMD) play an important role in pathogenesis of RAP, but its metabolism was mostly genetically determined. The adenosine triphosphate (ATP)-sensitive potassium channel (KATP) is involved in lipid metabolism and microvascular homeostasis and becomes a promising target for the management of Lp(a) and its related RAP.

OBJECTIVE

To investigate associations of KATP variants with hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD.

DESIGN, PATIENTS, SETTINGS: A total of 1148 newly diagnosed patients with CAD were prospectively selected and divided into control (Lp(a) < 180 mg/dL) and case (Lp(a) ≥ 180 mg/dL, hyperlipoprotein(a)emia) group.

METHODS

9 KATP variants were genotyped by MassARRAY system. The expression profile of exosome-derived microRNAs (exo-miRs) was identified by next-generation sequencing, and the expression levels of differentially expressed exo-miRs were evaluated by quantitative RT-PCR in verification cohort.

RESULTS

Three KATP variants were associated with increased risk of hyperlipoprotein(a)emia in patients with CAD as follows: rs2285676 (AA + GA genotype, adjusted odds ratio [OR] = 1.44; 95% CI, 1.10-1.88; P = 0.008), rs1799858 (CC genotype, adjusted OR = 1.33; 95% CI, 1.03-1.73; P = 0.030), and rs141294036 (CC genotype, adjusted OR = 1.43; 95% CI, 1.10-1.87; P = 0.008). Only rs141294036 was associated with increased risk of CMD (CC genotype, adjusted OR = 1.62; 95% CI, 1.23-2.13; P = 0.001), and further with increased RAP risk (CC genotype, adjusted hazard ratio = 2.05; 95% CI, 1.22-3.43; P = 0.007) after median follow-up of 50.6 months. Between the 2 genotypes of rs141294036, 152 exo-miRs were significantly differentially expressed, but only 10 exo-miRs (miR-7110-3p, miR-548az-5p, miR-214-3p, let-7i-5p, miR-218-5p, miR-128-3p, miR-378i, miR-625-3p, miR-128-1-5p, and miR-3187-3p) were further confirmed in patients with RAP with hyperlipoprotein(a)emia and CMD.

CONCLUSION

KATP rs141294036 may serve a potential genetic marker for hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD.

摘要

背景

难治性心绞痛（RAP）是冠状动脉疾病（CAD）的一种特殊亚型。脂蛋白（a）[Lp（a）]及其诱导的冠状动脉微血管功能障碍（CMD）在RAP的发病机制中起重要作用，但其代谢大多由基因决定。三磷酸腺苷（ATP）敏感性钾通道（KATP）参与脂质代谢和微血管稳态，成为治疗Lp（a）及其相关RAP的一个有前景的靶点。

目的

研究CAD患者中KATP变异与高脂蛋白（a）血症、CMD和RAP的相关性。

设计、患者、研究地点：前瞻性选取1148例新诊断的CAD患者，分为对照组[Lp（a）<180mg/dL]和病例组[Lp（a）≥180mg/dL，高脂蛋白（a）血症]。

方法

采用MassARRAY系统对9个KATP变异进行基因分型。通过下一代测序鉴定外泌体衍生的微小RNA（exo-miRs）的表达谱，并在验证队列中通过定量逆转录聚合酶链反应评估差异表达的exo-miRs的表达水平。

结果

3个KATP变异与CAD患者高脂蛋白（a）血症风险增加相关，如下：rs2285676（AA+GA基因型，校正比值比[OR]=1.44；95%可信区间[CI]，1.10-1.88；P=0.008），rs1799858（CC基因型，校正OR=1.33；95%CI，1.03-1.73；P=0.030），以及rs141294036（CC基因型，校正OR=1.43；95%CI，1.10-1.87；P=0.008）。仅rs141294036与CMD风险增加相关（CC基因型，校正OR=1.62；95%CI，1.23-2.13；P=0.001），在中位随访50.6个月后，进一步与RAP风险增加相关（CC基因型，校正风险比=2.05；95%CI，1.22-3.43；P=0.007）。在rs141294036的两种基因型之间，152个exo-miRs有显著差异表达，但在伴有高脂蛋白（a）血症和CMD的RAP患者中仅10个exo-miRs（miR-7110-3p、miR-548az-5p、miR-214-3p、let-7i-5p、miR-218-5p、miR-128-3p、miR-378i、miR-625-3p、miR-128-1-5p和miR-3187-3p）得到进一步验证。