Clinical and Genetic Analysis of KATP Variants With Heart Failure Risk in Patients With Decreased Serum ApoA-I Levels

• Published in: The journal of clinical endocrinology and metabolism Vol. 106; no. 8; pp. 2264 - 2278
• Main Authors: Liu, Cheng, Lai, Yanxian, Pei, Jingxian, Huang, Huiling, Zhan, Junfang, Ying, Songsong, Shen, Yan
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.08.2021
• Subjects: Adenosine; Adenosine triphosphate; Apolipoprotein A; Apolipoprotein A-I; Apolipoproteins; Cardiac patients; Channel gating; Congestive heart failure; Genetic analysis; Genetic aspects; Genetic polymorphisms; Genotypes; Heart failure; Ischemia; Metabolic pathways; miRNA; Muscle proteins; Next-generation sequencing; Potassium channels; Risk factors; Type 2 diabetes; China; heart failure; exosome-derived microRNAs; apolipoprotein A-I; genetic polymorphism; ATP-sensitive potassium channels
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgab336

Abstract Context Lower serum concentration of apolipoprotein A-I (ApoA-I) is causally associated with heart failure (HF) risk. Adenosine triphosphate–sensitive potassium channels (KATP), as gating channels coupling vascular reactivity and metabolism with ischemic protection, become a new potential target of management for HF. The KATP gene sequence is highly polymorphic and has a high degree of genetic heterogeneity. Objective This work aimed to determine whether KATP variants predict the risks of decreased ApoA-I concentration and its related HF. Methods A total of 634 individuals, including 317 patients with decreased ApoA-I concentration (< 120 mg/dL) and 317 counterpart participants (≥ 120 mg/dL), were retrospectively selected. Five KATP variants were genotyped through the MassARRAY platform. Exosome-derived microRNAs (exo-miRs) expression profiles were identified by next-generation sequencing, and the top 10 differentially expressed (DE) exo-miRs were verified using quantitative polymerase chain reaction in a validation cohort of 240 individuals with decreased ApoA-I concentration. Results KATP rs141294036 was related to an increased risk of lower ApoA-I levels (adjusted odds ratio [OR] = 1.95, P = .002) and HF incidence (adjusted OR = 2.38, P = .009), especially heart failure with preserved ejection fraction (HFpEF; adjusted OR = 2.13, P = .015). After a median 48.6-month follow-up, participants carrying the CC genotype of rs141294036 were associated with an elevated HF rehospitalization risk (adjusted hazard ratio = 1.91, P = .005). Thirty-six exo-miRs were significantly DE between different genotypes of rs141294036 in participants with lower ApoA-I levels, but only 5 exo-miRs (miR-31-5p, miR-126-5p, miR-106a-5p, miR-378i, and miR-181c-5p) were further confirmed. Conclusion KATP rs141294036 was associated with increased risks of lower ApoA-I levels, HF incidence (especially HFpEF), and HF rehospitalization in those with the 5 confirmed exo-miRs and its related metabolic pathways.