载脂蛋白 A-I 水平降低的心力衰竭患者中 KATP 变异与心力衰竭风险的临床和遗传分析。
Clinical and Genetic Analysis of KATP Variants With Heart Failure Risk in Patients With Decreased Serum ApoA-I Levels.
机构信息
Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou 510180, China.
Department of Cardiology, the second affiliated hospital of Guangzhou Medical University, Guangzhou 510260, China.
出版信息
J Clin Endocrinol Metab. 2021 Jul 13;106(8):2264-2278. doi: 10.1210/clinem/dgab336.
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.
背景
载脂蛋白 A-I（ApoA-I）血清浓度降低与心力衰竭（HF）风险有关。三磷酸腺苷敏感性钾通道（KATP）作为与血管反应性和代谢相关的门控通道与缺血保护相关，成为 HF 管理的新潜在靶点。KATP 基因序列高度多态性，遗传异质性高。
目的
本研究旨在确定 KATP 变异是否可预测 ApoA-I 浓度降低的风险及其相关 HF。
方法
共纳入 634 例患者，包括 317 例 ApoA-I 浓度降低（＜120mg/dL）患者和 317 例对照参与者（≥120mg/dL）。采用 MassARRAY 平台检测 5 种 KATP 变异。通过下一代测序鉴定外泌体衍生 microRNAs（exo-miRs）表达谱，并在 240 例 ApoA-I 浓度降低的验证队列中采用实时定量聚合酶链反应验证前 10 个差异表达（DE）的 exo-miRs。
结果
KATP rs141294036 与较低的 ApoA-I 水平（校正比值比[OR]＝1.95，P＝.002）和 HF 发生率（校正 OR＝2.38，P＝.009）升高相关，尤其是射血分数保留性心力衰竭（HFpEF；校正 OR＝2.13，P＝.015）。中位随访 48.6 个月后，rs141294036 携带 CC 基因型的参与者 HF 再住院风险升高（校正危险比[HR]＝1.91，P＝.005）。在 ApoA-I 水平降低的参与者中，不同 rs141294036 基因型之间有 36 个 exo-miRs 差异表达，但只有 5 个 exo-miRs（miR-31-5p、miR-126-5p、miR-106a-5p、miR-378i 和 miR-181c-5p）得到进一步验证。
结论
KATP rs141294036 与 5 种确认的 exo-miRs 及其相关代谢途径中具有较低 ApoA-I 水平、HF 发生率（尤其是 HFpEF）和 HF 再住院风险升高相关。
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