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

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 RTPCR 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, miR378i, 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. [ABSTRACT FROM AUTHOR]

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