Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Real role of growth factor receptor-binding protein 10: Linking lipid metabolism to diabetes cardiovascular complications.

Cardiovascular complications of patients with type 2 diabetes mellitus (T2DM) threaten the health and life of numerous individuals. Recently, growth factor receptor-binding protein 10 (GRB10) was found to play a pivotal role in vascular complications of T2DM, which participates in the regulation of lipid metabolism of T2DM patients. The genetic variation of GRB10 rs1800504 is closely related to the risk of coronary heart disease in patients with T2DM. The development of GRB10 as a key mediator in the association of lipid metabolism with cardiovascular complications in T2DM is detailed in and may provide new potential concerns for the study of cardiovascular complications in T2DM patients.

Association of visit-to-visit HbA1c variability with cardiovascular diseases in type 2 diabetes within or outside the target range of HbA1c.

Background: Although a growing attention has been recently paid to the role of HbA1c variability in the risk of diabetic complications, the impact of HbA1c variability on cardiovascular diseases (CVD) in type 2 diabetes is still debated. The aim of the study is to investigate the association of HbA1c variability with CVD in individuals within or outside the target range of HbA1c. Methods: Using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), we enrolled 855 patients with type 2 diabetes in China. The primary outcomes included major macrovascular events and major microvascular events. Visit-to-visit HbA1c variability was expressed as the coefficient of variation (CV) of five measurements of HbA1c taken 3-24 months after treatment. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR). Results: Among 855 patients in the intensive glucose treatment group, 563 and 292 patients were assigned to the group of "within the target range of HbA1c" (WTH) (updated mean HbA1c ≤ 7.0%) and "outside the target range of HbA1c" (OTH) (updated mean HbA1c > 7.0%), respectively. HbA1c variability was positively associated with the risk of major microvascular events in all patients and both the subgroups during a median follow-up period of 4.8 years. Particularly, the risk related to HbA1c variability was higher in patients in WTH group for the new or worsening nephropathy [aHR: 3.35; 95% confidence interval (CI): 1.05-10.74; P = 0.042]. Conclusions: This retrospective cohort study confirmed the positive correlation between HbA1c variability and major microvascular events, especially in subjects in WTH or OTH.

A novel DNA damage repair-related signature for predicting prognositc and treatment response in non-small lung cancer.

DNA damage repair (DDR) is essential for maintaining genome integrity and modulating cancer risk, progression, and therapeutic response. DDR defects are common among non-small lung cancer (NSCLC), resulting in new challenge and promise for NSCLC treatment. Thus, a thorough understanding of the molecular characteristics of DDR in NSCLC is helpful for NSCLC treatment and management. Here, we systematically analyzed the relationship between DDR alterations and NSCLC prognosis, and successfully established and validated a six-DDR gene prognostic model via LASSO Cox regression analysis based on the expression of prognostic related DDR genes, CDC25C, NEIL3, H2AFX, NBN, XRCC5, RAD1. According to this model, NSCLC patients were classified into high-risk subtype and low-risk subtype, each of which has significant differences between the two subtypes in clinical features, molecular features, immune cell components, gene mutations, DDR pathway activation status and clinical outcomes. The high-risk patients was characterized with worse prognosis, lower proportion and number of DDR mutations, unique immune profile and responsive to immunetherapy. And the low-risk patients tend to have superior survival, while being less responsive to immunotherapy and more sensitive to treatment with DNA-damaging chemotherapy drugs. Overall, this molecular classification based on DDR expression profile enables hierarchical management of patients and personalized clinical treatment, and provides potential therapeutic targets for NSCLC.

TRIB3 promoter 33 bp VNTR is associated with the risk of cerebrovascular disease in type 2 diabetic patients.

Previous studies have demonstrated that TRIB3 is closely related to insulin resistance, metabolic disorders and vascular diseases. Recently, it was reported that a 33 bp variable number of tandem repeats (VNTR) located in the TRIB3 promoter could considerably alter its transcriptional activity. Nonetheless, whether the shift of TRIB3 transcriptional activity has the effect of inducing diabetic vascular complications is still unclear. Therefore, in our study, we aimed to explore the relationship between the TRIB3 33bp VNTR and diabetic vascular complications. The TRIB3 33bp VNTR polymorphisms were determined by PCR and Sanger sequencing, a total of 798 eligible Chinese patients with type 2 diabetes (T2DM) were included in our study and then evaluated with clinical data. After adjusting for age, gender, BMI, smoking history, drinking history and duration of diabetes, we found that the high number of 33 bp tandem repeats (repeats>8) was significantly associated with an increase in the risk of cerebrovascular diseases compared with the low number of 33 bp tandem repeats (repeats≤6) in patients with T2DM(OR 2.66, 95% CI 1.29-5.47, p = 0.008). The intermediate number of 33bp tandem repeats (6 < repeat≤8) was markedly associated with a decreased risk of diabetic retinopathy compared with the low number of tandem repeats (OR 0.65, 95% CI 0.46-0.91, p = 0.012). Adjusting for gender, age and BMI, there was a significant difference in DBP levels among patients with the number of different 33 bp tandem repeats (Low vs. Intermediate vs. High, 81.6 ± 12.8 vs. 79.8 ± 12.4 vs. 78.7 ± 12.6 mmHg; p = 0.045). Subgroup analysis found that TRIB3 VNTR was significantly correlated with the difference in systolic blood pressure (SBP) in T2DM patients taking ACEI/ARB drugs (Low vs. Intermediate vs. High, 146.27 ± 18.23 vs. 140.01 ± 19.91 vs. 140.77 ± 18.64 mmHg; p = 0.018). Our results indicated that TRIB3 promoter 33bp VNTR is related to vascular diseases in T2DM patients, and may serve as a new biomarker for individualized prevention and therapy of T2DM.

Therapeutic efficacy of tacrolimus in vernal keratoconjunctivitis: a meta-analysis of randomised controlled trials.

BACKGROUND AND OBJECTIVE: Tacrolimus has been widely used in recent years for treating allergic conjunctivitis, but there is currently no available meta-analysis regarding its therapeutic efficacy. This study systematically evaluated the effectiveness of tacrolimus in the treatment of allergic conjunctivitis. METHODS: Data obtained from literature searches of the PubMed, Cochrane Library, Embase, CNKI, and Wanfang databases were retrieved by combining medical subject words and free words. Literature was selected on the basis of established inclusion and exclusion criteria, and the extracted data were evaluated for risk of bias using RevMan 5.3 for meta-analysis. RESULTS: A total of 177 articles were retrieved, of which 5 articles were eventually selected, all of which involved tacrolimus treatment for vernal keratoconjunctivitis. A total of 203 samples were analysed. Results of the meta-analysis showed that the tacrolimus treatment group had significantly lower ocular objective sign scores (SMD -1.39, 95% CI -2.50 to -0.27; p<0.05) and had a significantly lower subjective symptom evaluation score (SMD -0.92, 95% CI -1.59 to -0.24; p<0.05) than the control group. CONCLUSION: Current evidence shows that tacrolimus is effective in treating vernal keratoconjunctivitis.

Single-Cell RNA Sequencing Analysis of the Heterogeneity in Gene Regulatory Networks in Colorectal Cancer.

Colorectal cancer (CRC) manifests as gastrointestinal tumors with high intratumoral heterogeneity. Recent studies have demonstrated that CRC may consist of tumor cells with different consensus molecular subtypes (CMS). The advancements in single-cell RNA sequencing have facilitated the development of gene regulatory networks to decode key regulators for specific cell types. Herein, we comprehensively analyzed the CMS of CRC patients by using single-cell RNA-sequencing data. CMS for all malignant cells were assigned using CMScaller. Gene set variation analysis showed pathway activity differences consistent with those reported in previous studies. Cell-cell communication analysis confirmed that CMS1 was more closely related to immune cells, and that monocytes and macrophages play dominant roles in the CRC tumor microenvironment. On the basis of the constructed gene regulation networks (GRNs) for each subtype, we identified that the critical transcription factor ERG is universally activated and upregulated in all CMS in comparison with normal cells, and that it performed diverse roles by regulating the expression of different downstream genes. In summary, molecular subtyping of single-cell RNA-sequencing data for colorectal cancer could elucidate the heterogeneity in gene regulatory networks and identify critical regulators of CRC.

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus.

Diabetic vascular complications are one of the main causes of death and disability. Previous studies have reported that genetic variation is associated with diabetic vascular complications. In this study, we aimed to investigate the association between GRB10 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) vascular complications. Eight single nucleotide polymorphisms (SNPs) in the GRB10 gene were genotyped by MassARRAY system and 934 patients with type 2 diabetes mellitus (T2DM) were included for investigation. We found that GRB10 rs1800504 CC+CT genotypes were significantly associated with increased risk of coronary heart disease (CHD) compared with TT genotype (OR = 2.24; 95%CI: 1.36-3.70, p = 0.002). Consistently, levels of cholesterol (CHOL) (CC+CT vs. TT, 4.44 ± 1.25 vs. 4.10 ± 1.00 mmol/L; p = 0.009) and low density lipoprotein cholesterin (LDL-CH) (CC+CT vs. TT, 2.81 ± 1.07 vs. 2.53 ± 0.82 mmol/L; p = 0.01) in T2DM patients with TT genotype were significant lower than those of CC+CT genotypes. We further validated in MIHA cell that the total cholesterol (TC) level in GRB10-Mut was significantly reduced compared with GRB10-WT; p = 0.0005. Likewise, the reversed palmitic acid (PA) induced lipid droplet formation in GRB10-Mut was more effective than in GRB10-WT. These results suggest that rs1800504 of GRB10 variant may be associated with the blood lipids and then may also related to the risk of CHD in patients with T2DM.

Tribbles pseudokinase 3 (TRIB3) contributes to the progression of hepatocellular carcinoma by activating the mitogen-activated protein kinase pathway.

BACKGROUND: Tribble pseudokinase 3 (TRIB3) plays a key role in regulating the malignancy of many tumors. This study examined its function in cancer cells and explored the potential mechanisms of action. METHODS: The expression of TRIB3 was examined in hepatocellular carcinomas (HCCs) using The Cancer Genome Atlas (TCGA) database. A TRIB3 lentivirus with a flag label was constructed and transfected into Huh7 and Hep3B human hepatoma cell lines to generate cells that stably overexpress TRIB3. A small interfering RNA (siRNA) was designed to knockdown TRIB3 mRNA in HepG2 and Huh7. Cell viability and cell colony formation assays were conducted. Flow cytometry was performed to assess the cell cycle in cells overexpressing TRIB3. Western blotting were performed to examine the expression of (Mitogen-activated protein kinase, MAPKK) (MEK), phosphorylated-MEK (p-MEK), extracellular signal-regulated kinase (ERK), and p-MEK in cells with TRIB3 knockdown. The correlation between TRIB3 and SMARCD3 was assessed using co-immunoprecipitation assays and immunofluorescence. RESULTS: TRIB3 was significantly overexpressed in advanced grade HCC tissues and was closely correlated with poor prognosis. TRIB3 overexpression promoted the cell growth and cell cycle but had little effect on migration capabilities in Huh7 and Hep3B cells. Conversely, knockdown of TRIB3 had slow down the cell growth in Huh7 and HepG2 cells detected by CCK8 and colony formation assay. The expression of MEK and ERK at both the protein and mRNA levels were downregulated when TRIB3 was knocked down. The protein expression of p-ERK and p-MEK were also downregulated upon TRIB3 silencing. SMARCD3 is a transcript factor that is belongs to the SWI/SNF complex and has been shown to regulate many genes. Indeed, co-immunoprecipitation assays demonstrated that TRIB3 interacts with SMARCD3 in the nucleus, suggesting that it may regulate TRIB3 in HCCs. CONCLUSIONS: This study demonstrated that TRIB3 promotes the malignancy of HCC cells and its expression may be a potential diagnostic biomarker for HCC progression.

Lnc-GAN1 expression is associated with good survival and suppresses tumor progression by sponging mir-26a-5p to activate PTEN signaling in non-small cell lung cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) play vital roles in the development and progression of non-small-cell lung cancer (NSCLC); however, the role of most lncRNAs in NSCLC remains unknown. This study explored the clinical significance, biological function and underlying mechanism of lnc-GAN1 in NSCLC. METHODS: With a custom lncRNA microarray we found that lnc-GAN1 is markedly downregulated in NSCLC tissues. Then lnc-GAN1 expression level was measured using qRT-PCR in NSCLC tissues and cell lines. Survival was assessed using the Kaplan-Meier method. The biological functions of lnc-GAN1 in lung cancer cells were evaluated in vitro and in vivo. RNA fluorescence in situ hybridization and subcellular localization assays revealed the subcellular distribution of lnc-GAN1 in cells. Bioinformatic analysis was adopted to predict miRNAs and signaling pathways regulated by lnc-GAN1. RNA immunoprecipitation and Dual-luciferase reporter assays were used to assess the interaction between lnc-GAN1 and miR-26a-5p in lung cancer cells. RESULTS: lnc-GAN1 is downregulated in HCC tissues and associated with larger tumor size and poor overall survival and disease-free survival; its ectopic expression suppresses cell proliferation, colony formation, and cell cycle progression and induces apoptosis in NSCLC cells; it also inhibits tumor growth in the NSCLC xenograft model. We further proved that lnc-GAN1 is localized in cytoplasm and transcribed independently from its parental gene GAN. Mechanistically, lnc-GAN1 acts as a sponge for miR-26a-5p by two seed sequences, and the two non-coding RNAs have a negative relationship in NSCLC tissues; we further prove that PTEN is a direct target of miR-26a-5p and lnc-GAN1 inhibits cell cycle signaling pathway by activating PTEN, whose expression level correlated negatively with miR-26a-5p level but positively with lnc-GAN1 level in NSCLC samples. CONCLUSIONS: Lnc-GAN1 is downregulated and associated with poor survival of NSCLC patients, and mechanistically acts as a tumor suppressor via sponging and inhibiting miR-26a-5p to upregulate PTEN. This study provides a potential prognostic biomarker and treatment target for NSCLC.

Fas-Associated Factor 1 Promotes Hepatic Insulin Resistance via JNK Signaling Pathway.

Fas-associated factor 1 (FAF1), a member of the Fas death-inducing signaling complex, is reported to interact potentially with diverse proteins and function in diverse cellular possesses. It remains unclear, however, whether FAF1 is involved in hepatic metabolic disorder and insulin resistance. This study is aimed at elucidating the role and the molecular mechanism of FAF1 in hepatic insulin resistance. Rats treated with high-fat diets are used as hepatic insulin resistance animal models. Quantitative real-time PCR, immunohistochemistry, and immunofluorescence assay are utilized to detect the FAF1 expression. The expression of relevant proteins is detected by Western blotting. We determine ROS production, lipid accumulation, and glucose uptake by using flow cytometry. Immunoprecipitation is employed to investigate protein-protein interaction. We find that increased expression of FAF1 occurred in the livers of insulin-resistant rats. Using gain-of-function and loss-of-function approaches, we observe dramatic exacerbation of insulin resistance, upregulated gluconeogenesis genes, downregulated glucose transport genes, and enhanced ROS production by FAF1 overexpression, whereas downregulation of FAF1 leads to a completely opposite phenotype. Mechanistically, FAF1 interacts directly with c-Jun N-terminal kinase (JNK) and activates its phosphorylation, thereby blocking the downstream insulin signaling pathway and leading to insulin resistance. Our data indicate that FAF1 is a potent regulator in hepatic metabolic disorder and insulin resistance.

TRIB3 rs6037475 is a potential biomarker for predicting felodipine drug response in Chinese patients with hypertension.

BACKGROUND: Our previous studies have found that single nucleotide polymorphisms (SNPs) of tribbles homolog 3 (TRIB3) are related to the hypotensive effects of calcium-channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors. In this study, we aimed at exploring and validating the effect of TRIB3 polymorphism on antihypertensive drugs responses. METHODS: A total of 830 hypertensive patients, who were administered with open-labeled hydrochlorothiazide (12.5 mg once daily) and randomly assigned to off-labeled felodipine (5 mg) or a matched placebo combination treatment (1:1), were selected from the Felodipine Event Reduction (FEVER) study. A strategy of screening 259 samples and validating the remaining 531 samples was implemented. Four functional SNPs were selected (rs2295490, rs11470129, rs4815567 and rs6037475 in TRIB3). A mixed linear model was performed to analyze the effects of TRIB3 SNPs on antihypertensive drugs responses. RESULTS: We found that TRIB3 rs6037475 CC genotype was associated with a reduction of diastolic blood pressure (DBP) (P=6.3×10-3) in the felodipine treatment group of screening set, and was also associated with a reduction of systolic blood pressure (SBP) (P=0.021), DBP (P=6.0×10-3) and mean arterial pressure (MAP) (P=0.021) in the felodipine treatment group of the validation set. As for the reductions influenced by the rs2295490, rs11470129 and rs4815567 genetic variations, however, the adjusted P-value did not reach statistical significance. Combined screening and validation set analysis found that patients with TRIB3 rs6037475 CC genotype had a significant higher mean SBP, DBP and MAP than those with TT genotype in the felodipine treatment group (CC vs. TT -10.2±0.74 vs. -17.8±0.21, P=7.8×10-3; -4.6±0.50 vs. -10.2±0.23, P=3.0×10-4; -6.5±0.54 vs. -12.7±0.14, P=3.0×10-4, respectively). CONCLUSIONS: These results suggest that TRIB3 rs6037475 genetic variation can be useful as a bio-marker for predicting felodipine drug response in Chinese patients with hypertension.

miR-3188 (rs7247237-C>T) Single-Nucleotide Polymorphism Is Associated With the Incidence of Vascular Complications in Chinese Patients With Type 2 Diabetes.

miR-3188, one of the earliest discovered microRNAs, is involved in regulating the mTOR-p-PI3K/AKT pathway, thus affecting the progression of diabetic complications. In this study, we observed that the miR-3188 (rs7247237-C>T) polymorphism not only affected the production of nitric oxide (NO) production in endothelial cells, but also significantly associated with the incidence of vascular complications in Chinese patients with type 2 diabetes. Mechanistic analyses indicate that miR-3188 (rs7247237-T) polymorphism inhibited its own expression and upregulated the expression of gstm1 and trib3, which impairs NO production in human endothelial cells through inactivating AKT/eNOS signal transduction pathway. In addition, our clinical retrospective study indicated that, compared with patients with the CC genotype (n = 351), patients with rs7247237 TT + CT genotypes (n = 580) exhibited an increased risk of major vascular events during intensive glucose control treatment (hazard ratio = 1.560; 95% CI: 1.055-2.307, P = 0.025). Simultaneously, the risk of major vascular events was marginally decreased in patients with the CC genotype during intensive glucose control treatment compared with standard treatment (hazard ratio = 0.666; 95% CI: 0.433-1.016, P = 0.053). Our findings indicate that the miR-3188 (rs7247237-C>T) polymorphism is associated with the incidence of vascular complications in Chinese patients with type 2 diabetes, likely due to its remarkable effect on miR-3188 expression.

Polytropic Influence of TRIB3 rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension.

Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, ß-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, ß-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.

Prognostic impact of visit-to-visit glycemic variability on the risks of major adverse cardiovascular outcomes and hypoglycemia in patients with different glycemic control and type 2 diabetes.

PURPOSE: The prognostic impact of visit-to-visit glycemic variability on clinical outcomes in patients with different glycemic control and type 2 diabetes remains obscure. We investigated glucose variability and clinical outcomes for patients in the groups of Good glycemic control (GC), Insufficient glycemic control (IC), and Poor glycemic control (PC) in a prospective cohort study. METHODS: By using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 930 patients were enrolled from 61 centers in China and grouped into GC, IC, and PC according to their glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG). Visit-to-visit glycemic variability was defined using the coefficient of variation (CV) of five measurements of HbA1c and FPG taken 3-24 months after treatment. Multivariable Cox proportional hazards models were employed to estimate adjusted hazard ratio (aHR). RESULTS: Among 930 patients in the intensive glucose control, 82, 538, and 310 patients were assigned to GC, IC, and PC, respectively. During the median of 4.8 years of follow-up, 322 patients were observed hypoglycemia and 244 patients experienced major adverse cardiovascular events (MACE). The CV of HbA1c and FPG was significantly lower for GC (6.0 ± 3.8, 11.2 ± 6.2) than IC (8.3 ± 5.6, 17.9 ± 10.6) and PC (9.5 ± 6.3, 19.3 ± 10.8). High glycemic variability was associated with a greater risk of MACE (aHR: 2.21; 95% confidence interval (CI): 1.61-3.03; p < 0.001) and hypoglycemia (aHR: 1.36; 95% CI: 1.04-1.79; p = 0.025) than low glycemic variability in total patients. The consistent trend was also found in subgroups of GC, IC, and PC. CONCLUSIONS: This prospective cohort study showed that glycemic variability was significantly lower for GC than IC and PC. Furthermore, glycemic variability was associated with the risk of MACE and hypoglycemia in total patients and subgroups of different glycemic control.

Cause-specific risk of major adverse cardiovascular outcomes and hypoglycemic in patients with type 2 diabetes: a multicenter prospective cohort study.

PURPOSE: Glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) was identified to account for the risk of cardiovascular diseases in type 2 diabetic patients, but no study evaluated the risk based on both HbA1c and FPG levels. We described the risk of major adverse cardiovascular events (MACE) and hypoglycemic in type 2 diabetic patients according to both HbA1c and FPG levels. METHODS: With the usage of databases of Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 1815 patients from 61 centers in China was identified and grouped according to the criterion value of HbA1c and FPG: Good glycemic control (HbA1c < 6.5%, FPG < 6.1 mmol/L); Insufficient glycemic control (HbA1c < 6.5%, FPG ≥ 6.1 mmol/L or HbA1c ≥ 6.5%, FPG < 6.1 mmol/L); Poor glycemic control (HbA1c ≥ 6.5%, FPG ≥ 6.1 mmol/L). Time-varying multivariable Cox proportional hazards models were employed. RESULTS: Average age was 64.8 ± 5.8 years, with a median of 4.8 years of follow-up. Overall, the incidence rates of MACE were 20.6 per 1000-person-years in Good glycemic control compared with 45.9 per 1000-person-years in Insufficient glycemic control (adjusted hazard ratio (aHR): 1.99; 95% CI 1.11-3.56; p = 0.02) and 54.7 per 1000-person-years in Poor glycemic control (aHR: 2.46; 95% CI 1.38-4.40; p = 0.002), respectively. The risk of hypoglycemic was highest in Insufficient glycemic control; 67.3 per 1000-person-years compared with 46.3 per 1000-person-years in Good glycemic control (aHR: 1.62; 95% CI 1.03-2.56; p = 0.04). Apart from this, we also observed that both MACE (aHR:1.41; 95% CI 1.13-1.77; p = 0.003) and hypoglycemic episodes (aHR: 1.82; 95% CI 1.48-2.24; p < 0.001) were sufficiently more frequent in the insulin-exposed group than the non-exposed group. In a post-hoc analysis, the risk of MACE (aHR:1.43; 95% CI 1.09-1.86; p = 0.01) and hypoglycemic (aHR: 1.99; 95% CI 1.46-2.69; p < 0.001) were more pronounced in Insufficient glycemic control with insulin exposure. CONCLUSIONS: We observed a significant association of cause-specific risk of MACE and hypoglycemic with Insufficient glycemic control, particularly with insulin exposure.

MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion.

PURPOSE: Diabetes mellitus is a major chronic disease and causes over one million deaths. KCNJ11 genetic polymorphisms influence the response of first-line oral antidiabetic agent sulfonylureas. Hsa-miR-4532 correlates with diabetic nephropathy and has a high abundance in urine. MIR4532 rs60452575 G>A variant changes the mature sequence of hsa-miR-4532. We studied whether the genetic polymorphisms of MIR4532 rs60452575 would influence KCNJ11 expression and sulfonylurea-stimulated insulin secretion or not. METHODS: To estimate the influence that rs60452575 G>A variant has on the interaction of hsa-miR-4532 and KCNJ11, we constructed a pmirGLO vector containing 3' UTR of KCNJ11 and co-transfected it with wild-type and mutant hsa-miR-4532 mimics into HEK293 cells; and we overexpressed wild-type and mutant hsa-miR-4532 mimics into HEK293 cells and MIN6 cells to access its effects on KCNJ11 expression and response of sulfonylureas. RESULTS: MIR4532 rs60452575 G>A variant appeared to disrupt the repression of KCNJ11 expression in both cell lines, and reduce the sulfonylurea-stimulated insulin secretion by breaking the binding of the hsa-miR-4532 to 3' UTR of KCNJ11 in MIN6 cells. CONCLUSIONS: Our study indicates that MIR4532 rs60452575 variant influences KCNJ11 expression and sulfonylurea response. It might be a potential predictive factor of sulfonylureas therapy.

Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives.

Drug-induced diabetes is widely reported in clinical conditions, and it is becoming a global issue because of its potential to increase the risk of severe cardiovascular complications. However, which drug mechanisms exert their diabetogenic effects and why the effects present significant inter-individual differences remain largely unknown. Pharmacogenomics, which is the study of how genomic variation influences drug responses, provides an explanation for individual differences in drug-induced diabetes. We highlight that pharmacogenomics can be involved in regulating the expression of genes in signaling pathways related to the pharmacokinetics or pharmacodynamics of drugs or the pathogenesis of diabetes, contributing to the differences in drug-induced glucose impairment. The pharmacogenomics studies of the major diabetogenic drugs are reviewed, including calcineurin inhibitors, antipsychotics, hormones, and antihypertensive drugs. We intend to elucidate the genetic basis of drug-induced diabetes and pave the way for the precise use of these drugs in the clinic.

GT-WGS: an efficient and economic tool for large-scale WGS analyses based on the AWS cloud service.

BACKGROUND: Whole-genome sequencing (WGS) plays an increasingly important role in clinical practice and public health. Due to the big data size, WGS data analysis is usually compute-intensive and IO-intensive. Currently it usually takes 30 to 40 h to finish a 50× WGS analysis task, which is far from the ideal speed required by the industry. Furthermore, the high-end infrastructure required by WGS computing is costly in terms of time and money. In this paper, we aim to improve the time efficiency of WGS analysis and minimize the cost by elastic cloud computing. RESULTS: We developed a distributed system, GT-WGS, for large-scale WGS analyses utilizing the Amazon Web Services (AWS). Our system won the first prize on the Wind and Cloud challenge held by Genomics and Cloud Technology Alliance conference (GCTA) committee. The system makes full use of the dynamic pricing mechanism of AWS. We evaluate the performance of GT-WGS with a 55× WGS dataset (400GB fastq) provided by the GCTA 2017 competition. In the best case, it only took 18.4 min to finish the analysis and the AWS cost of the whole process is only 16.5 US dollars. The accuracy of GT-WGS is 99.9% consistent with that of the Genome Analysis Toolkit (GATK) best practice. We also evaluated the performance of GT-WGS performance on a real-world dataset provided by the XiangYa hospital, which consists of 5× whole-genome dataset with 500 samples, and on average GT-WGS managed to finish one 5× WGS analysis task in 2.4 min at a cost of $3.6. CONCLUSIONS: WGS is already playing an important role in guiding therapeutic intervention. However, its application is limited by the time cost and computing cost. GT-WGS excelled as an efficient and affordable WGS analyses tool to address this problem. The demo video and supplementary materials of GT-WGS can be accessed at https://github.com/Genetalks/wgs_analysis_demo .

Intensive Glucose Control Reduces the Risk Effect of TRIB3, SMARCD3, and ATF6 Genetic Variation on Diabetic Vascular Complications.

Type 2 diabetes mellitus is a complex disease. Our previous study revealed that TRIB3 genetic variations were strongly associated with diabetic vascular complications, although TRIB3 regulation pathways remain poorly understood. We used two extreme treatment groups from a 2 × 2 factorial randomized controlled trial to identify a positive association, which was further validated in patients receiving cross treatment to test the effect of genetic polymorphisms among the different treatment groups. A gene-centric score (GS)-weighted model including the three associated genetic variations TRIB3 rs2295490, ATF6 rs12086247, and SMARCD3 rs58125572 was used. The results of the GS model indicated a 46% reduction in the risk of primary vascular complications in patients bearing more than two risk alleles [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.38-0.76, p < 0.001], following intensive glucose control treatment when compared with patients who received standard glucose control treatment. Furthermore, these patients benefited from active blood pressure-lowering treatment (HR 0.39, 95% CI 0.24-0.64, p < 0.001). However, no significant difference was observed between the two interventions in patients with fewer than two risk alleles (HR 1.09, 95% CI 0.86-1.39, p = 0.47). These results indicate that genetic variants in these three genes may be useful biomarkers for individualized drug therapy in diabetic patients.