Table1_Polygenic risk score predicts all-cause death in East Asian patients with prior coronary artery disease.docx

IntroductionCoronary artery disease (CAD) is a highly heritable and multifactorial disease. Numerous genome-wide association studies (GWAS) facilitated the construction of polygenic risk scores (PRS) for predicting future incidence of CAD, however, exclusively in European populations. Furthermore, identifying CAD patients with elevated risks of all-cause death presents a critical challenge in secondary prevention, which will contribute largely to reducing the burden for public healthcare.MethodsWe recruited a cohort of 1,776 Chinese CAD patients and performed medical follow-up for up to 11 years. A pruning and thresholding method was used to calculate PRS of CAD and its 14 risk factors. Their correlations with all-cause death were computed via Cox regression.Results and discussionWe found that the PRS for CAD and its seven risk factors, namely myocardial infarction, ischemic stroke, angina, heart failure, low-density lipoprotein cholesterol, total cholesterol and C-reaction protein, were significantly associated with death (P ≤ 0.05), whereas the PRS of body mass index displayed moderate association (P < 0.1). Elastic-net Cox regression with 5-fold cross-validation was used to integrate these nine PRS models into a meta score, metaPRS, which performed well in stratifying patients at different risks for death (P < 0.0001). Combining metaPRS with clinical risk factors further increased the discerning power and a 4% increase in sensitivity. The metaPRS generated from the genetic susceptibility to CAD and its risk factors can well stratify CAD patients by their risks of death. Integrating metaPRS and clinical risk factors may contribute to identifying patients at higher risk of poor prognosis.</p

Data_Sheet_1_Tryptophan was metabolized into beneficial metabolites against coronary heart disease or prevented from producing harmful metabolites by the in vitro drug screening model based on Clostridium sporogenes.xlsx

In our previous study of 2,130 Chinese patients with coronary heart disease (CHD), we found that tryptophan (TRP) metabolites contributed to elevated risks of death. Many TRP-derived metabolites require the participation of intestinal bacteria to produce, and they play an important role in the pathogenesis of metabolic diseases such as CHD. So it is necessary to metabolize TRP into beneficial metabolites against CHD or prevent the production of harmful metabolites through external intervention. Indole-3-butyric acid (IBA) may be a key point of gut microbiota that causes TRP metabolism disorder and affects major adverse cardiovascular events in CHD. Therefore, this study aimed to develop a method based on in vitro culture bacteria to evaluate the effects of IBA on specific microbial metabolites quickly. We detected the concentrations of TRP and its metabolites in 11 bacterial strains isolated from feces using liquid chromatography–mass spectrometry, and selected Clostridium sporogenes as the model strain. Then, IBA was used in our model to explore its effect on TRP metabolism. Results demonstrated that the optimal culture conditions of C. sporogenes were as follows: initial pH, 6.8; culture temperature, 37°C; and inoculum amount, 2%. Furthermore, we found that IBA increases the production of TRP and 5-HIAA by intervening TRP metabolism, and inhibits the production of KYNA. This new bacteria-specific in vitro model provides a flexible, reproducible, and cost-effective tool for identifying harmful agents that can decrease the levels of beneficial TRP metabolites. It will be helpful for researchers when developing innovative strategies for studying gut microbiota.</p

Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2

Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including <i>Polygonum multiflorum</i> and <i>Rhubarb</i>. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ∼50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 μM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CL_int, decreased by 18.5%–35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo

Table_4_High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.DOCX

<p>The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.</p

Table_1_High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.DOCX

<p>The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.</p

Table_2_High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.DOCX

<p>The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.</p

Table_3_High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.DOCX

<p>The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.</p

Table_4_High Plasma Exposure of Statins Associated With Increased Risk of Contrast-Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease.DOCX

<p>The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609–3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 ± 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 ± 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441–3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI.</p

CHD_serum_102samples.tar.gz

CHD_serum_102samples.tar.g

CHD_urine_102samples.tar.gz

CHD_urine_102samples.tar.g