AUTHOR=Liu Cheng , Lai Yanxian , Guan Tianwang , Zhan Junfang , Pei Jingxian , Wu Daihong , Ying Songsong , Shen Yan 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.816847

DOI=10.3389/fcvm.2022.816847

ISSN=2297-055X

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