Showing papers by "Rong Zhang published in 2013"

Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.

Abstract: Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

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

Abstract: 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.

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

Abstract: Aims/hypothesis Most 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.

Low-grade albuminuria is associated with early but not late carotid atherosclerotic lesions in community-based patients with type 2 diabetes

Abstract: Low-grade albuminuria is associated with cardiovascular risk factors and mortality. Our aim was to investigate the association between low-grade albuminuria and carotid atherosclerotic lesions in community-based patients with type 2 diabetes. A cross-sectional study was performed in 475 community-based patients with type 2 diabetes (190 males and 285 females) with normal urinary albumin-to-creatinine ratios (UACR) (< 3.5 mg/mmol) from Shanghai, China. The subjects were stratified into tertiles based on UACR levels (the lowest tertile was UACR ≤ 1.19 mg/mmol, and the highest tertile was UACR ≥ 2 mg/mmol). Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on ultrasonography. The urinary albumin excretion rate was determined as the mean of the values obtained from three separate early morning urine samples. Compared with the subjects with UACR in the lowest tertile, the subjects with UACR in the middle and highest tertiles had greater CIMT values (0.88 ± 0.35 mm, 0.99 ± 0.43 mm and 1.04 ± 0.35 mm, respectively; all p < 0.05) and a higher prevalence of carotid atherosclerotic plaques (25.3%, 39.0% and 46.2%, respectively; all p < 0.05) after adjusting for sex and age. Fully adjusted multiple linear regression and logistic regression analyses revealed that UACR tertiles were significantly associated with elevated CIMT (p = 0.007) and that, compared with the subjects in the first tertile of UACR, those in the second and third tertiles had 1.878- and 2.028-fold risk of carotid plaques, respectively. However, there was no statistical association between UACR tertile and the prevalence of carotid stenosis. Higher UACR within the normal range was independently associated with early but not late carotid atherosclerotic lesions in community-based patients with type 2 diabetes. Low-grade albuminuria contributes to the risk of carotid atherosclerosis and may be used as an early marker for the detection of atherosclerosis in patients with type 2 diabetes.

Genetic variants of LPIN1 indicate an association with Type 2 diabetes mellitus in a Chinese population

Abstract: Diabet Med 30, 118–122 (2013) Abstract Aims Metabolic disorders are independent risk factors for the development of Type 2 diabetes The aim of the study is to test the association of LPIN1 variants with Type 2 diabetes and clinical characteristics in large samples of the Chinese population Methods In the first stage, 15 single nucleotide polymorphisms within the LPIN1 region were selected and genotyped in 3700 Chinese Han participants In the second stage, the single nucleotide polymorphisms showing significant association or trends towards association were genotyped in an additional 3122 samples for replication Meta-analyses and genotype–phenotype association studies were performed after combining the data from the two stages Results In the first stage, we detected that rs16857876 was significantly associated with Type 2 diabetes with an odds ratio of 0806 (95% CI 0677–0958, P = 0015), while rs11695610 showed a trend with Type 2 diabetes (odds ratio 0846, 95% CI 0709–1009, P = 0062) In the second stage, a similar effect of rs11695610 on Type 2 diabetes was observed (odds ratio 0849, 95% CI 0700–1030, P = 0096) The meta-analyses combining the information from the two stages showed a significant effect of rs11695610 on Type 2 diabetes with an odds ratio of 0847 (95% CI 0744–0965, P = 0012) Finally, the phenotype–genotype association analyses showed that rs11695610 was associated with 2-h plasma glucose (P = 0040) and triglyceride levels (P = 0034) Conclusions Our data implied that common single nucleotide polymorphisms within the LPIN1 region were associated with Type 2 diabetes and metabolic traits in the Chinese population

Association of Genetic Variants of BMP4 with Type 2 Diabetes Mellitus and Clinical Traits in a Chinese Han Population

Abstract: BMP4 is one of the transforming growth factor-β superfamily, which can participate in adipogenesis. Gene encoding BMP4 is acknowledged as a convincing candidate that may contribute to both glucose and lipid metabolism. In this paper, we aimed to test the impacts of BMP4 variants on type 2 diabetes in a large sample of Chinese population. We genotyped 10 tagging single nucleotide polymorphisms within the BMP4 region in 6822 participants and acquired detailed clinical investigations and biochemistry measurements. We found that BMP4 rs8014363 showed nominal association towards type 2 diabetes, with the T allele conferring a high risk of type 2 diabetes (OR = 1.108, 95%CI 0.999–1.229, P = 0.051 for allele; OR = 1.110, 95%CI 1.000–1.231, P = 0.050 for genotype), but it was no longer statistically significant after adjusting for multiple testing (empirical P = 0.3689 for allele based on 10,000 permutations). Moreover, we observed a significant association of rs8014363 with triglyceride level and a trend towards association with high-density lipoprotein cholesterol after adjusting for age, gender, and BMI (P = 0.035 and 0.068, resp.). Our data suggested that the genetic variants of BMP4 may not play a dominant role in glucose metabolism in Chinese Han population, but a minor effect cannot be ignored.

Association between KCNQ1 genetic variants and QT interval in a Chinese population.

Abstract: Aim There is a close link between electrocardiographic ventricular repolarization QT parameters and Type 2 diabetes. The aim of the present study was to assess the effects of QT-related and diabetes-related variants in KCNQ1 on QT interval in a Chinese population. Methods We recruited 2415 patients with Type 2 diabetes and 1163 subjects with normal glucose regulation in the present study. QT interval was obtained and the heart rate-corrected QT interval (QTc) was calculated using Bazett's formula. Four single nucleotide polymorphisms in KCNQ1 were selected (rs12296050, rs12576239, rs2237892 and rs2237895) and genotyped. Results In participants with normal glucose regulation, the minor allele T of rs12296050 was associated with a 3.46-ms QTc prolongation under an additive model (P = 0.0109, empirical P = 0.0498). In patients with Type 2 diabetes, we did not find any association for the single nucleotide polymorphisms. Conclusions Our findings indicate that KCNQ1 is associated with QT interval in a Chinese population with normal glucose regulation.

Serum Proteome Changes in Healthy Subjects with Different Genotypes of NOS1AP in the Chinese Population

Abstract: Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of NOS1AP for type 2 diabetes susceptibility in the Chinese population. In this study, we analyzed the total serum profiling among three genotypes of rs12742393 to discover potential crosstalk under the variant and the disease through proteomic analyses for the first time. We used OFFGEL peptide fractionation, LC-MS/MS analysis, and label-free quantification to profile the fasting human serum samples of the genotypes in rs12742393 (n = 4, for CC, AC, and AA, resp.). Four proteins were identified, including apoA4, alpha1-ACT, HABP2, and keratin 10, with blood levels changed significantly between CC and AA homozygotes of rs12742393. Compared with AA group, the levels of apoA4 increased (P = 0.000265), whereas the concentration of alpha1-ACT, HABP2, and keratin 10 decreased in CC group (P = 0.011116, 0.021175, and 0.015661, resp.). Then we selected additional fasting serum samples for ELISA and western blot validation. However, no significant differences were identified by neither ELISA nor western blot (P > 0.05). The protein profiling changes between the genotypes of rs12742393 indicated that this SNP might play a role in the development of type 2 diabetes.