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

Abstract

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 (KATP) 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 KATP variants were determined by MassARRAY. The KATP rs2285676 (AA + GA, OR = 1.43, 95% CI: 1.13-1.81, P = 0.003), rs1799858 (CC, OR = 1.42, 95% CI: 1.12-1.78, P = 0.004), and rs141294036 (CC, OR = 1.45, 95% CI: 1.15-1.83, P = 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) (rs2285676/AA + GA, HR = 1.37, 95% CI: 1.10-1.70, P = 0.005; rs141294036/TT + CT, HR = 1.59, 95% CI: 1.28-1.99, P < 0.001), new-onset stroke (rs1799858/CC, HR = 2.58, 95% CI: 1.22-5.43, P = 0.013; rs141294036/CC, HR = 2.30, 95% CI: 1.16-4.55, P = 0.017), new-onset of heart failure (HF) (rs1799858/TT + CT, HR = 2.78, 95% CI: 2.07-3.74, P < 0.001; rs141294036/TT + CT, HR = 1.45, 95% CI: 1.07-1.96, P = 0.015), and new-onset atrial fibrillation (AF) (rs1799858/TT + CT, HR = 2.05, 95% CI: 1.25-3.37, P = 0.004; rs141294036/CC, HR = 2.31, 95% CI: 1.40-3.82, P = 0.001). In particular, the CC genotype of rs1799858 (OR = 2.38, 95% CI: 1.11-5.10, P = 0.025) and rs141294036 (OR = 1.95, 95% CI: 1.04-3.66, P = 0.037) are only associated with the risk of ischemic stroke while its counterpart genotype (TT + CT) is associated with the risks of HF with preserved ejection fraction (HFpEF) (rs1799858, OR = 3.46, 95% CI: 2.31-5.18, P < 0.001) and HF with mildly reduced ejection fraction (HFmrEF) (rs141294036, OR = 2.74, 95% CI: 1.05-7.15, P = 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 P < 0.05). The KATP rs2285676, rs1799858, and rs141294036 are associated with increased risks of T2D and its related cardiovascular phenotypes (ACS, stroke, HF, and AF), but show heterogeneity. The 3 KATP variants may be promising markers for diabetic cardiovascular events favoring "genotype-phenotype" oriented prevention and treatment strategies.

Keywords: ATP-sensitive potassium channels; cardiovascular phenotype; gene polymorphism; genotype; type 2 diabetes.

FIGURE 1

Association of ATP-sensitive potassium channels (KATP) single nucleotide polymorphisms (SNPs) with Type 2 diabetes (T2D) in the study participants. ^aModel: After adjustment for gender, age, smoking, alcohol consumption, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-sensitivity C-reactive protein (HsCRP), and renin-angiotensin-aldosterone system (RAAS activity) [angiotensin converting enzyme (ACE), renin, angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (ALD)].

FIGURE 2

Association of KATP SNPs with new onset/recurrent ACS in the study participants. ^aModel: After adjustment for gender, age, smoking, alcohol consumption, BMI, white blood cell count (WBC), blood glucose levels [fasting blood sugar (FBS), postprandial blood glucose 2 h (P2hBS) and glycosylated hemoglobin (HbA1C), liver function [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (Alb)], renal function [serum creatinine (Scr), blood urea nitrogen (BUN) and uric acid (UA)], serum sodium and potassium levels, HsCRP, HbA1C, RAAS activity (ACE, renin, Ang I, Ang II, and ALD), dyslipidemia {triglyceride (TRIG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoproteinB (ApoB), high-density lipoprotein cholesterol (HDL-C), apolipoproteinA-I (ApoA-I), and lipoprotein(a) [Lp(a)]}, medical condition [type 2 diabetes (T2D), EH, heart failure (HF) and atrial fibrillation (AF)], NYHA functional classification, and echocardiography index [right ventricular end-diastolic diameter (RVD), right atrial end-diastolic dimension (RAD), left ventricular end-diastolic diameter (LVD), left atrial end-diastolic dimension (LAD), left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF)], and combined medication [antiplatelet drugs, warfarin, statins, renin-angiotensin system inhibitors (RSIs), beta-receptor blockers (BBs), mineralocorticoid receptor antagonist (MRA), calcium-channel blockers (CCBs), diuretics, digoxin, nitrates, and hypoglycemic agents].

FIGURE 3

Association of KATP SNPs with the new-onset of stroke in the study participants. ^aModel (A) After adjustment for gender, age, smoking, alcohol consumption, BMI, WBC, blood glucose levels (FBS, P2hBS and HbA1C), liver function (ALT, AST and Alb), renal function (Scr, BUN and UA), serum sodium and potassium levels, HsCRP, RAAS activity (ACE, renin, Ang I, Ang II, and ALD), dyslipidemia [TRIG, TC, LDL-C, ApoB, HDL-C, ApoA-I and Lp(a)], medical condition [T2D, EH, CAD(ACS), AF, and LCI], NYHA functional classification, and echocardiography index (RVD, RAD, LVD, LAD, and LVEF), and combined medication (antiplatelet drugs, warfarin, statins, RSIs, BBs, MRA, CCBs, diuretics, digoxin, nitrates, and hypoglycemic agents). ^bModel (B) It is the same as Model (A).

FIGURE 4

Association of KATP SNPs with incidence of HF in the study participants. ^aModel (A) After adjustment for gender, age, smoking, alcohol consumption, BMI, WBC, blood glucose levels (FBS, P2hBS, and HbA1C), liver function (ALT, AST, and Alb), renal function (Scr, BUN, and UA), serum sodium and potassium levels, HsCRP, RAAS activity (ACE, renin, Ang I, Ang II, and ALD), dyslipidemia [TRIG, TC, LDL-C, ApoB, HDL-C, ApoA-I, and Lp(a)], medical condition [T2D, HTN, CAD(ACS), and AF], echocardiography index (RVD, RAD, LVD, LAD, and LVEF), and combined medication (antiplatelet drugs, warfarin, statins, RSIs, BBs, MRA, CCBs, diuretics, digoxin, nitrates, and hypoglycemic agents). ^bModel (B) It is the same as Model (A).

FIGURE 5

Association of KATP SNPs with the new-onset of AF in the study participants. ^aModel: After adjustment for gender, age, smoking, alcohol consumption, BMI, WBC, blood glucose levels (FBS, P2hBS and HbA1C), liver function (ALT, AST and Alb), renal function (Scr, BUN, and UA), serum sodium and potassium levels, HsCRP, RAAS activity (ACE, renin, Ang I, Ang II and ALD), dyslipidemia [TRIG, TC, LDL-C, ApoB, HDL-C, ApoA-I and Lp(a)], medical condition [T2D, HTN, CAD(ACS), and HF], echocardiography index (RVD, RAD, LVD, LAD, and LVEF), and combined medication (antiplatelet drugs, warfarin, statins, RSIs, BBs, MRA, CCBs, diuretics, digoxin, nitrates, and hypoglycemic agents).

FIGURE 6

Association of KATP SNPs with abnormal serum levels of blood lipid and HsCRP in the study participants. ^aModel (A) After adjustment for gender, age, smoking, alcohol consumption, BMI, WBC, T2D, SBP, DBP, blood glucose levels (FBS, P2hBS, and HbA1C), liver function (ALT, AST, and Alb), renal function (Scr, BUN, and UA), serum sodium and potassium levels, HsCRP, RAAS activity (ACE, renin, Ang I, Ang II, and ALD), and dyslipidemia [TC, LDL-C, ApoB, HDL-C, ApoA-I, and Lp(a)]. ^bModel (B) Is the same as Model 6a except LDL-C, and including TRIG. ^cModel (C) Is the same as Model 6a except ApoB, and including TRIG. ^dModel (D) Is the same as Model 6a except ApoA-I, and including TRIG. ^eModel (E) Is the same as Model 6a except Lp(a), and including TRIG. ^fModel (F) After adjustment for gender, age, smoking, alcohol consumption, WBC, BMI, T2D, SBP, DBP, blood glucose levels (FBS, P2hBS, and HbA1C), liver function (ALT, AST, and Alb), renal function (Scr, BUN and UA), serum sodium and potassium levels, HsCRP, dyslipidemia (TRIG, TC, LDL-C, HDL-C, ApoA-I, and ApoB) and RAAS activity (ACE, renin, Ang I, Ang II, and ALD).