Showing papers by "Cheng Hu published in 2015"

Genome-Wide Association Meta-analysis Identifies Novel Variants Associated With Fasting Plasma Glucose in East Asians

Abstract: Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.

Uric Acid Is Independently Associated with Diabetic Kidney Disease: A Cross-Sectional Study in a Chinese Population

Abstract: Background Association between hyperuricaemia and chronic kidney disease has been studied widely, but the influence of uric acid on the kidneys remains controversial We aimed to summarize the association between uric acid and diabetic kidney disease (DKD), and to evaluate the role of uric acid in DKD Methods We enrolled 3,212 type 2 diabetic patients in a cross-sectional study The patients’ basic characteristics (sex, age, BMI, duration of disease, and blood pressure) and chemical parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), microalbuminuria, creatinine, and uric acid) were recorded, and the association between uric acid and DKD was evaluated Results In the 3,212 diabetic patients, the prevalence of diabetic kidney disease was higher in hyperuricaemic patients than in patients with normouricaemia (683% vs 415%) The prevalence of DKD increased with increasing uric acid (p <00001) Logistic analysis identified uric acid as an independent predictor of DKD (p <00001; adjusted OR (95%CI) = 1005 (1004–1007), p <00001) Uric acid was positively correlated with albuminuria and creatinine levels (p<00001) but negatively correlated with eGFR (p<00001) after adjusting for confounding factors Conclusions Hyperuricaemia is a risk factor for DKD Serum uric acid levels within the high-normal range are independently associated with DKD

Circulating Betatrophin Correlates with Triglycerides and Postprandial Glucose among Different Glucose Tolerance Statuses--A Case-Control Study.

Abstract: Purpose Previous researches of betatrophin on glucose and lipids metabolism under insulin-resistant condition have reached controversial conclusions. To further identify the possible impact of betatrophin, we measured the circulating betatrophin levels in newly diagnosed type 2 diabetes (T2DM) patients, and in subjects with both impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) and investigated the relationship between serum betatrophin and other clinical parameters in these patients with different glucose tolerance statuses.

Association between body mass index and diabetic retinopathy in Chinese patients with type 2 diabetes

Abstract: To explore the factors mediating the relationship between body mass index (BMI) and diabetic retinopathy (DR) in Chinese type 2 diabetes patients This is a cross-sectional study Data of 2,533 patients with type 2 diabetes were studied from the Shanghai Diabetes Registry Database DR was assessed using non-mydriatic fundus photography and graded as non-DR, mild–moderate (DR I–II), and sight-threatening (DR III–IV) BMI (kg/m2) was classified as normal weight (185 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30) β cell function was evaluated by fasting C-peptide (FCP) DR was present in 701 (277 %) patients Patients with DR had lower BMI (243 vs 249 kg/m2, P = 0001) and fasting C-peptide (146 vs 186 ng/ml, P < 0001) than those without DR The association between BMI (2 kg/m2 interval) and DR was U-shaped; patients with BMI 28–299 kg/m2 had the lowest DR rate Compared with normal weight, overweight was associated with reduced risk of any DR [odds ratio (OR) 073], DR I–II (OR 076), and DR III–IV (OR 064) after adjustment for sex, age at diabetes diagnosis, and duration of diabetes This negative association attenuated after adjustment for other confounders and became nonsignificant after further adjustment for FCP Patients with different BMI categories had similar DR risk when stratified by FCP tertiles Overweight patients have lower DR prevalence than normal weight individuals, which may be attributable to better β cell function in overweight patients

Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes.

Abstract: Aims/hypothesis Three recent genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms (SNPs) with modest effects on diabetic retinopathy in Mexican-American and white patients with diabetes. This study aimed to evaluate the effects of these variants on diabetic retinopathy in Chinese patients with type 2 diabetes.

Associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults and type 2 diabetes.

Abstract: Background This study aimed to assess the associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults (LADA) and type 2 diabetes. Methods This is a retrospective study. Our diabetes registry included 6975 patients aged 30–75 years old with phenotypic type 2 diabetes who underwent islet autoantibody screening between 2003 and 2012; 384 patients were identified to have LADA. Rates of chronic complications for LADA and type 2 diabetes were compared using a 1 : 2 matched design. Logistic models were fitted to identify the presence of chronic diabetic complications using clinical characteristics including gender, age, duration of diabetes, glycemic control and metabolic syndrome. Results When duration of diabetes is <5 years, the prevalence of diabetic nephropathy (nephropathy; 12.2% versus 21.8%, p = 0.018) and diabetic retinopathy (retinopathy; 8.1% versus 15.9%, p = 0.011) were significantly lower in patients with LADA than in patients with type 2 diabetes; the prevalence of nephropathy and retinopathy were comparable between both groups when duration is ≥5 years. There was no significant difference in the prevalence of macrovascular complications between groups. The areas under the receiver operating characteristic curves based on the nephropathy and retinopathy models were larger for LADA than for type 2 diabetes (0.72 versus 0.61, p = 0.013; 0.76 versus 0.68, p = 0.056). Conclusions Patients with LADA had a lower prevalence of microvascular complications than patients with type 2 diabetes when the duration of diabetes was <5 years. Regression equation fitted by clinical characteristics can better predict the risk of microvascular complications in LADA than in type 2 diabetes. Copyright © 2014 John Wiley & Sons, Ltd.

Circulating irisin levels are associated with lipid and uric acid metabolism in a Chinese population.

Abstract: Summary Irisin is a novel hormone secreted by skeletal muscle after exercise, which may ameliorate insulin resistance. In this study, we aimed to explore the relationship between circulating irisin levels and type 2 diabetes mellitus (T2DM) as well as related metabolic traits in a Chinese population. A total of 203 subjects were recruited. Of these, 68 subjects with normal glucose tolerance (NGT), 63 subjects with impaired glucose regulation (IGR) and 72 subjects with new-onset T2DM. Circulating irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). Detailed clinical investigations and biochemistry measurements were carried out in all of the subjects. Multivariate linear regression analysis was performed to assess the association between irisin levels and related metabolic characteristics. All subjects were classified into normal weight and overweight/obese subgroups according to body mass index (BMI). No significant differences in circulating irisin levels were identified among the three groups (P = 0.9741). After adjusting for covariates, multiple linear regression analysis revealed that serum irisin level was independently and significantly associated with total cholesterol (P = 0.0005), low-density lipoprotein cholesterol (P = 0.0014), fasting fatty acids (P = 0.0402) and uric acid (P = 0.0062). By dividing the serum irisin levels into three tertile groups, the values of total cholesterol, low-density lipoprotein cholesterol, fasting fatty acids and uric acid were all increased significantly with the increase of irisin (P < 0.05). Moreover, serum irisin levels remain closely related to total cholesterol in both normal weight and overweight/obese subgroups. Our study suggests that circulating irisin concentrations are significantly associated with lipid and uric acid metabolism in a Chinese population.

Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans.

Abstract: Context: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. Objective: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. Design: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. Results: Variants in five genes were associated with glycemic traits and in three genes with diabete...

Common variants related to serum uric acid concentrations are associated with glucose metabolism and insulin secretion in a Chinese population.

Abstract: Background Elevated serum uric acid concentration is an independent risk factor and predictor of type 2 diabetes (T2D). Whether the uric acid-associated genes have an impact on T2D remains unclear. We aimed to investigate the effects of the uric acid-associated genes on the risk of T2D as well as glucose metabolism and insulin secretion.

Pharmacogenomics of glinides

Abstract: Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.

C-reactive protein genetic variant is associated with diabetic retinopathy in Chinese patients with type 2 diabetes

Abstract: Diabetic retinopathy (DR) is an important microvascular complication of diabetes with a high concordance rate in patients with diabetes. Inflammation is supposed to participate in the development of DR. This study aimed to investigate whether genetic variants of CRP are associated with DR. A total of 1,018 patients with type 2 diabetes were recruited in this study. Of these patients, 618 were diagnosed with DR, 400 were patients with diabetes for over 10 years but without DR, considered as cases and controls for DR, respectively. Four tagging SNPs (rs2808629, rs3093077, rs1130864 and rs2808634) within CRP region were genotyped for all the participants. Fundus photography was performed for diagnosis and classification for DR. rs2808629 was significantly associated with increased susceptibility to DR (odds ratio 1.296, 95% CI 1.076-1.561, P = 0.006, empirical P = 0.029, for G allele). This association remained significant after adjustment for confounding factors (odds ratio 1.261, 95% CI 1.022-1.555, P = 0.030). In this study, we found CRP rs2808629 was associated with DR in the Chinese patients with type 2 diabetes.

Genetic variants of PLA2G6 are associated with Type 2 diabetes mellitus and triglyceride levels in a Chinese population.

Abstract: Aim To test the association of PLA2G6 variants with Type 2 diabetes and clinical characteristics in large Chinese population-based samples. Methods A total of 6822 people were recruited. In the first stage, 15 single nucleotide polymorphisms within the PLA2G6 region were selected and genotyped in 3700 Chinese Han people. In the second stage, the single nucleotide polymorphisms that showed a significant association were genotyped in an additional 3122 samples for replication. Genotype–phenotype association studies and meta-analyses were performed after combining data from the two stages. Results In the first stage, we detected rs132984 and rs2284060 as significantly associated with Type 2 diabetes with odds ratios of 1.247 (95% CI 1.074–1.449, P = 0.004, empirical P = 0.047) and 1.173 (95% CI 1.059–1.299, P = 0.002, empirical P = 0.029), respectively. In the second stage, a similar effect of rs132984 on Type 2 diabetes was observed (odds ratio 1.280, 95% CI 1.094–1.497, P = 0.002). The meta-analysis showed a significant effect of the two single nucleotide polymorphisms on Type 2 diabetes (odds ratio 1.254, 95% CI 1.104–1.451, P = 4.85 × 10-5 for rs132984; odds ratio 1.120, 95% CI 1.046–1.195, P = 0.003 for rs2284060). Moreover, genotype–phenotype association analysis showed that rs132984 was associated with triglyceride levels (P = 0.022, empirical P = 0.044) and area under the curve for glucose (P = 0.015, empirical P = 0.030). Conclusions Our data imply that common single nucleotide polymorphisms within the PLA2G6 region are associated with Type 2 diabetes and triglyceride levels in the Chinese population.

Association of Toll-like Receptor 4 Gene polymorphisms with susceptibility to type 2 diabetes mellitus in the Chinese population.

Abstract: Background Toll-like receptor 4 (TLR4) plays an important role in innate immunity. Activation of innate immune response and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of type 2 diabetes. In this study, we aimed to investigate the association of TLR4 variants with type 2 diabetes in the Chinese population. Methods Seven tag single nucleotide polymorphisms (SNPs) of TLR4 based on HapMap Chinese data were genotyped in the Shanghai Chinese, including 3404 type 2 diabetes patients and 3401 controls. The controls were extensively phenotyped for the traits related to glucose metabolism and insulin secretion. Results In total participants, we identified that rs10759932 and rs1927911 were associated with type 2 diabetes (odds ratio 1.106, P = 0.009 for rs10759532, odds ratio 1.092, P = 0.013 for rs1927911). rs11536889 showed a trend association with type 2 diabetes (odds ratio 0.957, P = 0.057). This SNP was also associated with 2-h plasma glucose (P = 0.033) and high-density lipoprotein-cholesterol (P = 0.031). In female participants, rs10759932, rs1927911 and rs11536889 were associated with type 2 diabetes (odds ratio 1.176, P = 0.002 for rs10759932, odds ratio 1.136, P = 0.009 for rs1927911, odds ratio 0.882, P = 0.024 for rs11536889). Besides, rs11536889 was significantly associated with 2-h plasma glucose (P = 0.050) and HOMA-B (P = 0.046) with adjusting for age and body mass index in female normal subjects. Conclusions We conclude that genetic variants of TLR4 are associated with type 2 diabetes in the Chinese population, especially in female subjects. 摘要 背景： Toll样受体4（toll-like receptor 4）在固有免疫中发挥重要作用。固有免疫的激活及其后续的慢性低度炎症可能也参与了2型糖尿病的发生。本研究旨在探讨中国人群中TLR4基因多态性与2型糖尿病的相关性。 方法： 研究对象来自中国上海，包括3404例2型糖尿病患者及3401例正常对照者。根据HapMap中国人数据库选取了7个TLR4的标签单核苷酸多态性（single nucleotide polymorphism，SNP），并对其在所有研究对象中进行基因分型。收集对照人群的葡萄糖代谢及胰岛素分泌相关的详细表型用于数量性状分析。 结果： 在总人群中，发现rs10759932和rs1927911均与2型糖尿病显著相关（rs10759932：OR，1.106，P = 0.009；rs1927911：OR，1.092，P = 0.013）。rs11536889与2型糖尿病有相关趋势（OR，0.957，P = 0.057），此位点与2小时血糖（P = 0.033）及高密度脂蛋白（P = 0.031）亦相关。在女性人群中，rs10759932、rs1927911及rs11536889均与2型糖尿病显著相关（rs10759932：OR，1.176，P = 0.002；rs1927911：OR，1.136，P = 0.009；rs11536889：OR，0.882，P = 0.024）。此外，在女性对照人群中，校正年龄及BMI后，rs11536889与2小时血糖（P = 0.050）及HOMA-B（P = 0.046）显著相关。 结论： 在中国人群，尤其是女性人群中，TLR4基因变异与2型糖尿病发生风险相关。

A variant of PSMD6 is associated with the therapeutic efficacy of oral antidiabetic drugs in Chinese type 2 diabetes patients

Abstract: The PSMD6 variant rs831571 has been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). This study aimed to investigate the association of this variant with therapeutic effects of oral antidiabetic drugs in Chinese T2DM patients. 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks, and the therapeutic effects were compared. In the rosiglitazone cohort, rs831571 showed significant associations with fasting plasma glucose (FPG), 2-h glucose and decrement of glycated haemoglobin (HbA1c) levels after 24 weeks of treatment (P = 0.0368, 0.0468 and 0.0247, respectively). The C allele was significantly associated with a better attainment of FPG at 24 and 32 weeks (P = 0.0172 and 0.0257, respectively). Survival analyses showed CC homozygotes were more likely to attain a standard FPG level (P = 0.0654). In the repaglinide cohort, rs831571 was significantly associated with decreased HbA1c levels after 24 weeks of treatment, the homeostatic model assessment of insulin resistance and fasting insulin level after 48 weeks of treatment with repaglinide (P = 0.0096, 0235 and 0.0212, respectively). In conclusion, we observed that the PSMD6 variant rs831571 might be associated with the therapeutic effects of rosiglitazone and repaglinide in Chinese T2DM patients. However, these findings need to be confirmed in the future.

Advancement in genetic variants conferring obesity susceptibility from genome-wide association studies

Abstract: Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies (GWAS) has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene (FTO), but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.

Mutation screening for thalassaemia in the Jino ethnic minority population of Yunnan Province, Southwest China.

Abstract: Objectives This study aimed to detect α- and β-thalassaemia mutations in the Jino ethnic minority population of Yunnan Province, Southwest China. Design A total of 1613 Jino adults were continuously recruited from February 2012 to April 2012. Fasting venous blood samples were obtained to determine haematological variables. Haemoglobin analysis was conducted using high-performance liquid chromatography. Participants with hypochromic microcytic anaemia or positive haemoglobin analysis profiles were confirmed by α- and β-globin genetic testing, including DNA microarray analysis, direct sequencing methods and multiplex gap-PCR assays. Setting Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People9s Hospital. Results We found 363 suspected cases by primary screening of haematological variables and haemoglobin analysis. After further genetic testing, four types of α- and β-thalassaemia mutation were detected in 203 out of 363 individuals. Both α 0 - and α + -thalassaemia mutations, -- SEA and -α 3.7 , were identified. β-Thalassaemia mutations included CD17 (HBB:c.52A>T) and CD26 (HbE or HBB:c.79G>A). In addition, 13 HbE carriers had coexisting α 0 - or α + -thalassaemia deletions. Clinical haematological variables indicated that, in this study, carriers of all thalassaemic genotypes had more severe hypochromic microcytic anaemia than non-thalassaemic individuals. Conclusions Our results provide information on the Jino ethnic minority that may be useful for further genetic counselling, prenatal screening and clinical diagnosis of thalassaemia in this region.

Effects of active and passive smoking on the development of cardiovascular disease as assessed by a carotid intima-media thickness examination in patients with type 2 diabetes mellitus

Abstract: Carotid intima-media thickness has been widely used as a surrogate end-point for cardiovascular disease, myocardial infarction, and stroke. This study aimed to assess the effects of active and passive smoking exposure on the development of cardiovascular disease in patients with type 2 diabetes mellitus. Seven hundred twenty-two patients with type 2 diabetes mellitus were recruited for the study. A standardized questionnaire on smoking status, pack-years of smoking, and the number of years of smoking cessation was provided to the patients, and their responses were collected for analysis. The carotid intima-media thickness, carotid plaque, and the internal diameter of the common carotid artery were determined by high-resolution B-mode ultrasonography. Compared to non-smokers, passive female smokers had a higher risk of cardiovascular disease (odds ratio = 3.50, 95% confidence interval: 1.29-9.49, P = 0.009); they also had a significantly larger common carotid artery (P = 0.041) and risk of carotid plaque (odds ratio = 2.20, 95% confidence interval: 1.1980-4.0505, P = 0.01). Both active and passive male smokers had a significantly greater carotid intima-media thickness than non-smokers (P = 0.003 and P = 0.005, respectively). Male active smokers had a significantly higher risk of carotid plaque (odds ratio = 2.88, 95% confidence interval: 1.4788-5.6094, P = 0.001). In conclusion, cumulative active and passive smoking exposures are significant risk factors for carotid atherosclerosis in patients with type 2 diabetes mellitus. Our results highlight the importance of endorsing a smoke-free environment for patients with type 2 diabetes mellitus.