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 (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.

Clinical and Genetic Analysis of KATP Variants With Heart Failure Risk in Patients With Decreased Serum ApoA-I Levels.

CONTEXT: Lower serum concentration of apolipoprotein A-I (ApoA-I) is causally associated with heart failure (HF) risk. Adenosine triphosphate-sensitive potassium channels (KATP), as gating channels coupling vascular reactivity and metabolism with ischemic protection, become a new potential target of management for HF. The KATP gene sequence is highly polymorphic and has a high degree of genetic heterogeneity. OBJECTIVE: This work aimed to determine whether KATP variants predict the risks of decreased ApoA-I concentration and its related HF. METHODS: A total of 634 individuals, including 317 patients with decreased ApoA-I concentration (< 120 mg/dL) and 317 counterpart participants (≥ 120 mg/dL), were retrospectively selected. Five KATP variants were genotyped through the MassARRAY platform. Exosome-derived microRNAs (exo-miRs) expression profiles were identified by next-generation sequencing, and the top 10 differentially expressed (DE) exo-miRs were verified using quantitative polymerase chain reaction in a validation cohort of 240 individuals with decreased ApoA-I concentration. RESULTS: KATP rs141294036 was related to an increased risk of lower ApoA-I levels (adjusted odds ratio [OR] = 1.95, P = .002) and HF incidence (adjusted OR = 2.38, P = .009), especially heart failure with preserved ejection fraction (HFpEF; adjusted OR = 2.13, P = .015). After a median 48.6-month follow-up, participants carrying the CC genotype of rs141294036 were associated with an elevated HF rehospitalization risk (adjusted hazard ratio = 1.91, P = .005). Thirty-six exo-miRs were significantly DE between different genotypes of rs141294036 in participants with lower ApoA-I levels, but only 5 exo-miRs (miR-31-5p, miR-126-5p, miR-106a-5p, miR-378i, and miR-181c-5p) were further confirmed. CONCLUSION: KATP rs141294036 was associated with increased risks of lower ApoA-I levels, HF incidence (especially HFpEF), and HF rehospitalization in those with the 5 confirmed exo-miRs and its related metabolic pathways.

Plasma exosome-derived microRNAs expression profiling and bioinformatics analysis under cross-talk between increased low-density lipoprotein cholesterol level and ATP-sensitive potassium channels variant rs1799858.

BACKGROUND: Exosome-derived microRNAs (exo-miRs) as messengers play important roles, in the cross-talk between genetic [ATP-sensitive potassium channels (KATP) genetic variant rs1799858] and environmental [elevated serum low-density lipoprotein cholesterol (LDL-C) level] factors, but the plasma exo-miRs expression profile and its role in biological processes from genotype to phenotype remain unclear. METHODS: A total of 14 subjects with increased LDL-C serum levels (≥ 1.8 mmol/L) were enrolled in the study. The KATP rs1799858 was genotyped by the Sequenom MassARRAY system. The plasma exo-miRs expression profile was identified by next-generation sequencing. RESULTS: 64 exo-miRs were significantly differentially expressed (DE), among which 44 exo-miRs were up-regulated and 20 exo-miRs were down-regulated in those subjects carrying T-allele (TT + CT) of rs1799858 compared to those carrying CC genotype. The top 20 up-regulated DE-exo-miRs were miR-378 family, miR-320 family, miR-208 family, miR-483-5p, miR-22-3p, miR-490-3p, miR-6515-5p, miR-31-5p, miR-210-3p, miR-17-3p, miR-6807-5p, miR-497-5p, miR-33a-5p, miR-3611 and miR-126-5p. The top 20 down-regulated DE-exo-miRs were let-7 family, miR-221/222 family, miR-619-5p, miR-6780a-5p, miR-641, miR-200a-5p, miR-581, miR-605-3p, miR-548ar-3p, miR-135a-3p, miR-451b, miR-509-3-5p, miR-4664-3p and miR-224-5p. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were subsequently implemented to identify the top 10 DE-exo-miRs related specific target genes and signaling pathways. Only 5 DE-exo-miRs were validated by qRT-PCR as follows: miR-31-5p, miR-378d, miR-619-5p, miR-320a-3p and let-7a-5p (all P < 0.05). CONCLUSION: These results firstly indicated the plasma exo-miRs expression profile bridging the link between genotype (KATP rs1799858) and phenotype (higher LDL-C serum level), these 5 DE-exo-miRs may be potential target intermediates for molecular intervention points.

A cross-sectional study: Comparing the attitude and knowledge of medical and non-medical students toward 2019 novel coronavirus.

BACKGROUND AND OBJECTIVES: Since December 2019, the rapid epidemic spread of COVID-19 in China has aroused the attention of the government and the public. The purpose of this study is to investigate the attitude and knowledge among medical students and non-medical students toward SARS-CoV-2 infection. METHODS: A web-based survey was disseminated to the students from medical colleges and comprehensive universities via the survey website (www.wjx.cn) and via WeChat. Participation in the study was voluntary with the instruction to click on the website or scan the QR code to complete the anonymous electronic questionnaire from February 5 to 7, 2020. RESULTS: The questionnaire was completed by 588 students from 20 colleges and universities in China. Of the respondents, 66.0% were medical students and 34.0% were non-medical students. 99.6 % of the students held an optimistic attitude toward the COVID-19 epidemic situation. The majority of participants had a good level of knowledge of common symptoms, transmission, and prevention of the disease. In a comparison between non-medical students with medical students, the medical students had a deeper understanding of COVID-19. In this study, we also found that female students had a better understanding of transmission and prevention than male students did. CONCLUSIONS: The majority of students who participated in the questionnaire had a positive attitude and a good perception about COVID-19.

Effect of CYP2C19 Gene Polymorphisms on Proton Pump Inhibitor, Amoxicillin, and Levofloxacin Triple Therapy for Eradication of Helicobacter Pylori.

BACKGROUND The effects of PPI are variable owing to the CYP2C19 polymorphisms. However, whether the polymorphisms could affect the Hp eradication efficacy of triple therapy is still not clear. The present study aimed to assess the effects of CYP2C19 gene polymorphisms on proton pump inhibitor (PPI), amoxicillin, and levofloxacin triple therapy for Helicobacter pylori (Hp) eradication. MATERIAL AND METHODS We randomly assigned 160 Hp-positive patients with chronic gastritis to 2 groups to receive either 20 mg bid omeprazole (OAL group, n=80) or 10 mg bid rabeprazole (RAL group, n=80), combined with 1000 mg bid amoxicillin and 500 mg qd levofloxacin. The 2 groups were treated for 10 days. The CYP2C19 genotypes included wild-type, M1 mutant gene (*2, the mutation of exon 5), and M2 mutant gene (*3, the mutation of exon 4) identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFIP). According to CYP2C19 genotype combinations, the patients were divided into extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) subgroups. The eradication efficacy of Hp was evaluated by 14C-UBT at 28 days after treatment. RESULTS The trial was completed by 155 patients. Hp eradication rates in OAL and RAL groups were 78.2% and 88.3%, respectively, on per-protocol (PP) analysis, indicating no significant difference (P>0.05). Regarding CYP2C19 genotypes, eradication rates of 60.7%, 84.2%, and 100% were obtained for EM, IM, and PM subgroups, respectively, of the OAL group. EM group eradication rates were significantly lower than IM and PM group values (P<0.05). In the RAL group, no such difference was observed (P>0.05). Hp eradication rates were significantly lower in the EM subgroup of the OAL group compared with that of the RAL group. CONCLUSIONS Hp eradication rates were higher in the RAL group than in OAL-treated patients. Interestingly, omeprazole-based therapy was significantly affected by the CYP2C19 genotype, unlike the rabeprazole-based therapy.

Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors.

1. The role of angiotensin-converting enzyme (ACE) 2 is likely to balance the status of the renin-angiotensin system (RAS) by degrading angiotensin (Ang) II and generating Ang-(1-7). Earlier demonstrations that ACE2 is insensitive to ACE inhibitors prompted us to evaluate the effect of ACE inhibitors on ACE2 expression. 2. Liver fibrosis was induced in rats with 40% CCl(4) (2.5 mL/kg, s.c., twice per week). Half the rats were further treated with perindopril (2 mg/kg, p.o., daily). After 2 and 4 weeks treatment, ACE2 immunoreactivity was assessed by immunohistochemical staining, ACE2 protein expression was determined by western blot and mRNA expression of ACE2 and the Ang-(1-7) receptor Mas was determined by reverse transcription-polymerase chain reaction (RT-PCR). 3. As an in vitro study, hepatic stellate cells (HSC) were treated with AngII (0.1-10 micromol/L) alone or in combination with the synthesized peptide ACEI (Sigma-Aldrich). Western blot and RT-PCR were used to evaluate ACE2 expression and Mas mRNA levels. Furthermore, after treatment of HSC with the Mas antagonist A779 (1 micromol/L), the protein expression of connective tissue growth factor (CTGF) was detected to evaluate the interaction between AngII, ACEI and the ACE2-Mas axis. 4. Expression of both ACE2 mRNA and protein and Mas mRNA was markedly upregulated in both CCl(4)-injured rat liver and AngII-treated HSC. Further significant upregulation was observed following additional administration of ACEI. In addition, ACEI treatment of HSC inhibited AngII-induced overexpression of connective tissue growth factor and this effect was ameliorated by blockade of the Mas receptor with A779. 5. The findings of the present study suggest that ACE inhibitors are able to upregulate ACE2 under conditions of liver injury both in vivo and in vitro, which may indicate potential benefits of ACE inhibitors in the therapeutic treatment of liver fibrosis.

[Effect of angiotensin1-7 on alpha-smooth muscle actin protein expression in rat hepatic stellate cells].

OBJECTIVE: To investigate the effect of angiotensin II and angiotensin1-7 on alpha-smooth muscle actin (alpha-SMA)-induced Ca(2+)-independent pathways mediated by Rho kinase2 in hepatic stellate cells (HSCs). METHODS: HSC-T6 cells were treated with 10 micromol/L of AngII, Ang1-7, AngII +Ang1-7, and Ang1-7+A779. RT-PCR was used to detect the expression of Rho kinase2 (Rock2) in Ca(2+)-independent pathways, and alpha-SMA protein expression was detected by Western blotting. RESULTS: The mRNA expression of Rock2 increased significantly in the cells after AngII treatment (P<0.01), but decreased following Ang1-7 treatment. Ang1-7 treatment significantly reduced alpha-SMA level in AngII-induced cells (P<0.01). CONCLUSION: Ang1-7 can inhibit AngII-induced activation of Rock2 and reduce alpha-SMA expression in HSCs.