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.

The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia

“…The ABCC8 gene variants identified in this study in the 285 probands (including three rare variants detected in this study) are presented in Table 2 . Some common variants of this gene are reported in the literature to be associated with T2DM, but these results are ethnospecific [ 37 ]. No potentially pathogenic variants were identified here in adjacent regions of splice sites of this gene.…”

Diabetes Is the Strongest Predictor of Limited Exercise Capacity in Chronic Heart Failure and Preserved Ejection Fraction (HFpEF)

“…Impaired energy metabolism and muscle fiber-type switches ( 17 , 18 ) found in T2DM, similar to what is seen in CHF, have been previously shown. Accordingly, it can be assumed that T2DM may further reduce the aerobic capacity of patients with HF as a potential mechanism for the known limited exercise tolerance, as has been previously suggested ( 16 , 19 , 20 ). However, the evidence regarding the direct relationship between 6-MWT and phenotypic type of HF, reduced EF (HFrEF), and preserved (HFpEF), remains lacking.…”

“…Type 2 diabetes mellitus (T2DM) is one of the most frequently seen risk factors and comorbidities in patients with congestive heart failure (CHF) ( 11 , 12 ), and it adversely affects outcomes in these patients ( 13 , 14 ). The impact of T2DM on different phenotypic presentations of HF, especially in patients with HF and preserved ejection fraction (HFpEF), remains unclear ( 15 , 16 ). Impaired energy metabolism and muscle fiber-type switches ( 17 , 18 ) found in T2DM, similar to what is seen in CHF, have been previously shown.…”

Association of KCNJ11 and ABCC8 single-nucleotide polymorphisms with type 2 diabetes mellitus in a Kinh Vietnamese population

“…[11,12] Among SNPs in KCNJ11, rs5219, and rs2285676 were chosen for this study as they have been shown to be consistently associated with T2DM in several ethnicities. [13][14][15][16] Further, rs1799859 and rs757110 located in ABCC8 were also selected, for two main reasons. First, these SNPs have been reported to be associated with T2DM and are predicted to affect sulfonylurea treatment.…”

“…First, these SNPs have been reported to be associated with T2DM and are predicted to affect sulfonylurea treatment. [14,[16][17][18] Second, the close location of these 4 SNPs on chromosome arm 11p15 provides useful information for linkage disequilibrium analysis. Therefore, this study sought to elucidate the potential associations of 4 SNPs (rs5219, rs2285676, rs1799859, and rs757110) with T2DM in a Kinh Vietnamese population.…”