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

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.