Renming Hu

A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans

Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein–coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10−9) and RASGRP1 (rs7403531: P = 3.9 × 10−9), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA1c and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.

Investigation of Type 2 Diabetes Risk Alleles Support CDKN2A/B, CDKAL1, and TCF7L2 As Susceptibility Genes in a Han Chinese Cohort

Background Recent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort. Methodology/Principal Findings Selected type 2 diabetes–associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P≤0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12–1.43) P = 1.8*10−4; CDKAL1 rs10946398, OR: 1.23 (1.09–1.39); P = 7.1*10−4, and TCF7L2 rs7903146, OR: 1.61 (1.19–2.18) P = 2.3 * 10−3. Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002), postprandial plasma glucose (P = 0.002), and fasting C-peptide levels (P = 0.006) in the diabetic patients, and with BMI in controls (P = 0.033). Conclusions/Significance We have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities.

Metabolic effects of bariatric surgery in type 2 diabetic patients with body mass index < 35 kg/m2

Aim: The aim of this meta‐analysis is to assess the metabolic effects of bariatric surgery in type 2 diabetes mellitus (T2DM) patients with body mass index (BMI) < 35 kg/m2.

Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes.

ObjectiveWe aimed to investigate whether elevated serum uric acid concentrations are associated with higher risk of metabolic syndrome (MetS) and carotid atherosclerosis in patients with type 2 diabetes.MethodsWe conducted a population-based cross-sectional survey in Shanghai, with a total of 395 men and 631 women age 41 to 92 years. The carotid artery intima-media thickness (IMT) and carotid atherosclerotic plaques (PLQ) were measured by B-mode ultrasound. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans.ResultsUric acid levels were negatively associated with duration of diabetes, fasting plasma glucose, glycohemoglobin, eGFR, HDL-cholesterol (all P < 0.001) and positively with BMI, CRP, waist circumference, triglycerides, systolic blood pressure, ACR, HOMA-IR and IMT (all P < 0.05). In the highest quartile of uric acid levels, the risks were substantially higher for MetS [odds ratio 3.97, (95% confidence interval 2.58-6.13)] (P < 0.001 for trend) and PLQ [odds ratio 2.71 (95% confidence interval 1.62-4.47)] (p = 0.013 for trend) compared with that in the lowest quartile of uric acid levels after multiple adjustment. These associations remained significant after further adjustment for potential confounders.ConclusionsSerum uric acid level is associated with MetS and is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

Aims/hypothesisMost genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.MethodsWe performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.ResultsWe identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.Conclusions/interpretationOur study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly among Chinese adults, and limited data are available on T2DM management and the status of glycemic control in China. We assessed the efficacy of oral antidiabetes drugs (OADs), glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin for treatment of T2DM across multiple regions in China.MethodsThis was a multicenter, cross-sectional survey of outpatients conducted in 606 hospitals across China. Data from all the patients were collected between April and June, 2011.ResultsA total of 238,639 patients were included in the survey. Eligible patients were treated with either OADs alone (n=157,212 [65.88%]), OADs plus insulin (n=80,973 [33.93%]), or OADs plus GLP-1 receptor agonists (n=454 [0.19%]). The OAD monotherapy, OAD + insulin, and OAD + GLP-1 receptor agonist groups had mean glycosylated hemoglobin (HbA1c) levels (±SD) of 7.67% (±1.58%), 8.21% (±1.91%), and 7.80% (±1.76%), respectively. Among those three groups, 34.63%, 26.21%, and 36.12% met the goal of HbA1c <7.0%, respectively. Mean HbA1c and achievement of A1c <7.0% was related to the duration of T2DM.ConclusionsLess than one third of the patients had achieved the goal of HbA1c <7.0%. Glycemic control decreased and insulin use increased with the duration of diabetes.

Berberine inhibits the expression of TNFα, MCP-1, and IL-6 in AcLDL-stimulated macrophages through PPARγ pathway

Macrophages are the main source of cytokines in atherosclerotic plaques. Modified low-density lipoproteins may stimulate macrophages to produce large quantities of proinflammatory cytokines that promote atherosclerosis. Berberine is the main component of the traditional Chinese medicine umbellatine, which has a widespread effect and was used to treat many diseases clinically. Our previous study found that berberine could increase adipophilin expression in macrophages, which is a target gene of PPARγ. PPARγ agonist could decrease proinflammatory cytokines in macrophage. In this study, we investigated the effects and the mechanism of action of berberine on the expression and secretion of TNFα, MCP-1, and IL-6 in vitro to identify new pharmacological actions of berberine. The results of RT-PCR and ELISA shows that berberine may inhibit the expression and secretion of the tumor necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6) in macrophages stimulated by acetylated low-density lipoprotein (AcLDL), whereas the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor GW9662 could attenuate this effect of berberine. This study demonstrates that berberine may inhibit the expression and production of TNF-α, MCP-1, and IL-6 in AcLDL-stimulated macrophages. This effect might be partially mediated through PPARγ activity.

High prevalence of chronic kidney disease in population-based patients diagnosed with type 2 diabetes in downtown Shanghai

OBJECTIVE This study aimed to evaluate the prevalence of chronic kidney disease (CKD) and the risk factors associated with CKD among Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai and to assess the relationship between CKD and diabetic retinopathy (DR). METHODS We investigated 1039 Chinese patients diagnosed with type 2 diabetes aged over 30 by randomized cluster sampling in downtown Shanghai, and 1009 patients in this study were analyzed based on data integrity. Body measurements including height, weight, waist circumference and hip circumference, resting blood pressure, fasting blood measures, and urinary albumin-to-creatinine ratio (ACR), as well as the digitally stored fundus images, were investigated. Glomerular filtration rate (GFR) was estimated using the Cockcroft-Gault equation. The prevalence of CKD was calculated, and the risk factors associated with CKD were evaluated using stepwise logistic regression. The relationship between CKD and DR was evaluated using Spearman correlation and the chi-square test. RESULTS The following were the results found in this study: (a) The prevalence rate of CKD (Stages 1-5) was 63.9% in Chinese patients diagnosed with type 2 diabetes, 8.8% in those with CKD Stage 1, 22.3% in those with CKD Stage 2, and 32.8% in those with CKD Stages 3-5 (GFR<60 ml/min/1.73 m(2)). The prevalence of CKD increased with age. (b) CKD patients were older and had higher duration of diabetes, systolic blood pressure, urea nitrogen, uric acid, creatinine, and ACR of the first urine than those without CKD. (c) Male patients had a higher percentage of CKD Stages 3-5, and female patients had a higher percentage of CKD Stages 1-2. (d) CKD was significantly associated with duration of diabetes, older age, systolic blood pressure, and serum urea nitrogen based on logistic regression analysis. (e) Of the patients without CKD, 15.6% had DR, and of those with CKD, 27.6% had DR. The decrease in GFR was significantly correlated with DR after controlling for sex, age, and albuminuria staging. CONCLUSION The high prevalence of CKD observed in Chinese patients diagnosed with type 2 diabetes aged over 30 in downtown Shanghai was similar to that in Western patients, and the cause of CKD is likely to be any of the following: type 2 diabetes, IgA nephropathy, hypertension, or any combination of these. The screening program for GFR in type 2 diabetic patients should be performed even on those with normoalbuminuria. The decrease in GFR might predict the occurrence of DR among patients diagnosed with type 2 diabetes.

Osteocalcin, glucose metabolism, lipid profile and chronic low-grade inflammation in middle-aged and elderly Chinese.

Diabet. Med. 30, 309–317 (2013)

Analysis of Gene Expression Profiling in Meningioma: Deregulated Signaling Pathways Associated with Meningioma and EGFL6 Overexpression in Benign Meningioma Tissue and Serum

Molecular mechanisms underlying the pathogenesis of meningioma are not fully elucidated. In this study, we established differential gene expression profiles between meningiomas and brain arachnoidal tissue by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis demonstrated that PI3K/Akt and TGFβ signaling pathways were up-regulated in fibroblastic meningioma, and focal adhesion and ECM-receptor interaction pathways were activated in anaplastic meningioma. EGFL6 was one of the most up-regulated genes in fibroblastic meningioma by microarray analysis. Quantitative real-time PCR demonstrated that benign meningiomas had significantly higher levels of EGFL6 mRNA than brain arachnoidal tissue and atypical and anaplastic meningiomas (P<0.001). EGFL6 gene was also highly expressed in ovarian cancer, but expressed lowly in other investigated tumors. ELISA analysis showed that patients with benign meningiomas and ovarian cancers had the highest serum levels of EGFL6 (mean concentration: 672 pg/ml for benign meningiomas, and 616 pg/ml for ovarian cancers). Healthy people and patients with other tumors, however, had low levels of serum EGFL6. In conclusion, we proposed that activation of PI3K/Akt and integrin-mediated signaling pathways was involved in the pathogenesis of benign and anaplastic meningiomas, respectively. We also presented evidence that EGFL6 was overexpressed in benign meningioma tissues and serum.