Associations of ATP-Sensitive Potassium Channel's Gene Polymorphisms With Type 2 Diabetes and Related Cardiovascular Phenotypes

Type 2 diabetes (T2D) is characterized by increased levels of blood glucose but is increasingly recognized as a heterogeneous disease, especially its multiple discrete cardiovascular phenotypes. Genetic variations play key roles in the heterogeneity of diabetic cardiovascular phenotypes. This study investigates possible associations of ATP-sensitive potassium channel ( ) variants with cardiovascular phenotypes among the Chinese patients with T2D. Six hundred thirty-six patients with T2D and 634 non-diabetic individuals were analyzed in the study. Nine variants were determined by MassARRAY. The ( + , OR = 1.43, 95% CI: 1.13-1.81, = 0.003), ( , OR = 1.42, 95% CI: 1.12-1.78, = 0.004), and ( , OR = 1.45, 95% CI: 1.15-1.83, = 0.002) are associated with increased T2D risk. A follow-up of at least 45.8-months (median) indicates further association between the 3 variants and risks of diabetic-related cardiovascular conditions. The associations are categorized as follows: new-onset/recurrent acute coronary syndrome (ACS) ( + , HR = 1.37, 95% CI: 1.10-1.70, = 0.005; + , HR = 1.59, 95% CI: 1.28-1.99, < 0.001), new-onset stroke ( , HR = 2.58, 95% CI: 1.22-5.43, = 0.013; , HR = 2.30, 95% CI: 1.16-4.55, = 0.017), new-onset of heart failure (HF) ( + , HR = 2.78, 95% CI: 2.07-3.74, < 0.001; + , HR = 1.45, 95% CI: 1.07-1.96, = 0.015), and new-onset atrial fibrillation (AF) ( + , HR = 2.05, 95% CI: 1.25-3.37, = 0.004; , HR = 2.31, 95% CI: 1.40-3.82, = 0.001). In particular, the genotype of (OR = 2.38, 95% CI: 1.11-5.10, = 0.025) and (OR = 1.95, 95% CI: 1.04-3.66, = 0.037) are only associated with the risk of ischemic stroke while its counterpart genotype ( + ) is associated with the risks of HF with preserved ejection fraction (HFpEF) ( , OR = 3.46, 95% CI: 2.31-5.18, < 0.001) and HF with mildly reduced ejection fraction (HFmrEF) ( , OR = 2.74, 95% CI: 1.05-7.15, = 0.039). Furthermore, the 3 variants are associated with increased risks of abnormal serum levels of triglyceride (TIRG) (≥ 1.70 mmol/L), low-density lipoprotein cholesterol (LDL-C) (≥ 1.40 mmol/L), apolipoprotein B (ApoB) (≥ 80 mg/dL), apolipoprotein A-I (ApoA-I) level (< 120 mg/dL), lipoprotein(a) Lp(a) (≥ 300 mg/dL) and high-sensitivity C-reactive protein (HsCRP) (≥ 3.0 mg/L) but exhibited heterogeneity (all < 0.05). The , , and are associated with increased risks of T2D and its related cardiovascular phenotypes (ACS, stroke, HF, and AF), but show heterogeneity. The 3 variants may be promising markers for diabe