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

• Published in: The journal of clinical endocrinology and metabolism Vol. 108; no. 5; pp. 1061 - 1074
• Main Authors: Pei, Jingxian, Liu, Cheng, Yang, Zhengxia, Lai, Yanxian, Zhang, Shenghui, Guan, Tianwang, Shen, Yan
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.05.2023
• Subjects: Adenosine triphosphate; Angina; Angina Pectoris; Antilipemic agents; ATP; Cardiovascular disease; Coronary Artery Disease; Exosomes - metabolism; Gene expression; Genetic markers; Genotype & phenotype; Genotypes; Heart diseases; Homeostasis; Humans; Ivabradine; Lipid metabolism; Lipoprotein A; Lipoprotein(a) - genetics; Metabolism; MicroRNAs - metabolism; Microvasculature; miRNA; Muscle proteins; Next-generation sequencing; Type 2 diabetes; China; exosome-derived microRNAs; coronary microvascular dysfunction; polymorphisms; refractory angina pectoris; lipoprotein(a); ATP-sensitive potassium channels
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgac709

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.