Genetic predisposition and bioinformatics analysis of ATP-sensitive potassium channels polymorphisms with the risks of elevated apolipoprotein B serum levels and its related arteriosclerosis cardiovascular disease

Abstract

Serum concentration of apolipoprotein B (Apo B) is causally associated with arteriosclerosis cardiovascular disease (ASCVD) risk. Whether ATP-sensitive potassium channels (KATP) variants predict the risk of increased Apo B concentration (≥ 80 mg/dL) and related ASCVD remain less clear. We recruited 522 subjects with elevated Apo B concentration (≥ 80 mg/dL) and 522 counterpart subjects (< 80 mg/dL) from South China to assess the associations of KATP variants (rs11046182, rs78148713, rs145456027 and rs147265929) with the risks of increased Apo B serum concentration (≥ 80 mg/dL), carotid artery stenosis (CAS) ≥ 50% and new-onset ischemic stroke (IS). Our results showed that only KATP SNP rs11046182 (GG genotype) was associated with increased risk of Apo B ≥ 80 mg/dL (adjusted OR=2.17, P<0.001) and CAS ≥ 50% (adjusted OR=2.63, P=0.011). After median 50.6-months follow-up, subjects carrying GG genotype of rs11046182 were associated with higher risk of new-onset IS (adjusted HR=2.24, P=0.024). Further, the exosome-derived microRNAs (exo-miRs) expression profile was identified by next-generation sequencing. 41 exo-miRs were significantly differentially expressed under cross-talk status between high Apo B level (≥ 80 mg/dL) and KATP rs11046182. Our study demonstrated that KATP variant rs11046182 was associated with higher risks of elevated serum Apo B levels and its related ASCVD, and the possible mechanism was related to specific exo-miRs expression profile of KATP rs11046182.

Keywords: ATP-sensitive potassium channels; apolipoprotein B; arteriosclerosis cardiovascular disease; exosome-derived microRNAs; polymorphism.

Figure 1

Association of KATP rs11046182 with new-onset IS in study subjects^*. *Model 4: After adjustment for gender, age, smoking, drinking, WBC, BMI, liver function (ALT, AST and Alb), renal function (Scr, BUN and UA), HsCRP, HbA1C, HCY, and RAAS activity (ACE, renin, Ang I, Ang II and ALD), dyslipidemia (TRIG, TC, LDL-C, Apo B, HDL-C and Apo AI), medical condition (EH, CAD, T2D and AF), NYHA functional classification, combined medication (antiplatelet drugs, warfarin, statins, RSIs, BBs, MRAs, CCBs, diuretics, digoxin, nitrates, and hypoglycemic agents) and echocardiography index (RVD, RAD, LVD, LAD, and LVEF).

Figure 2

Heatmap of DE exo-miRs between different genotypes of KATP rs11046182 in subjects with elevated Apo B serum levels (≥ 80 mg/dL).

Figure 3

GO analysis of enriched biological processes, cellular component and molecular functions regulated by CTGs of top 10 DE exo-miRs.

Figure 4

KEGG analysis of enrichment pathway regulated by CTGs of top 10 DE exo-miRs.

Figure 5

The cross-talk diagram on miRs-gene and gene-gene from top 10 DE exo-miRs. **Using combined score > 0.9 as threshold cutoff, 10 exo-miRs and 65 CTGs were included in the internet. Red color represents the up-regulated exo-miRs; Green color represents the down-regulated exo-miRs.