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1
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Jia W, Chan JC, Wong TY, Fisher EB. Diabetes in China: epidemiology, pathophysiology and multi-omics. Nat Metab 2025; 7:16-34. [PMID: 39809974 DOI: 10.1038/s42255-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.
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Affiliation(s)
- Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute for Proactive Healthcare, Shanghai Jiao Tong University, Shanghai, China.
| | - Juliana Cn Chan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences and Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Tien Y Wong
- Tsinghua Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Singapore National Eye Center, SingHealth, Singapore, Singapore
| | - Edwin B Fisher
- Peers for Progress, Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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2
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Li H, Li W, Li D, Yuan L, Xu Y, Su P, Wu L, Zhang Z. Based on systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for diabetes. Front Endocrinol (Lausanne) 2024; 15:1366290. [PMID: 38915894 PMCID: PMC11194396 DOI: 10.3389/fendo.2024.1366290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 05/28/2024] [Indexed: 06/26/2024] Open
Abstract
Purpose Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, as well as to discover new therapeutic targets. Therefore, based on systematic "druggable" genomics, we aim to identify new therapeutic targets for diabetes and analyze its pathophysiological mechanisms to promote its new therapeutic strategies. Material and method We used double sample MR to integrate the identified druggable genomics to evaluate the causal effect of quantitative trait loci (eQTLs) expressed by druggable genes in blood on type 1 and 2 diabetes (T1DM and T2DM). Repeat the study using different data sources on diabetes and its complications to verify the identified genes. Not only that, we also use Bayesian co-localization analysis to evaluate the posterior probabilities of different causal variations, shared causal variations, and co-localization probabilities to examine the possibility of genetic confounding. Finally, using diabetes markers with available genome-wide association studies data, we evaluated the causal relationship between established diabetes markers to explore possible mechanisms. Result Overall, a total of 4,477 unique druggable genes have been gathered. After filtering using methods such as Bonferroni significance (P<1.90e-05), the MR Steiger directionality test, Bayesian co-localization analysis, and validation with different datasets, Finally, 7 potential druggable genes that may affect the results of T1DM and 7 potential druggable genes that may affect the results of T2DM were identified. Reverse MR suggests that C4B may play a bidirectional role in the pathogenesis of T1DM, and none of the other 13 target genes have a reverse causal relationship. And the 7 target genes in T2DM may each affect the biomarkers of T2DM to mediate the pathogenesis of T2DM. Conclusion This study provides genetic evidence supporting the potential therapeutic benefits of targeting seven druggable genes, namely MAP3K13, KCNJ11, REG4, KIF11, CCNE2, PEAK1, and NRBP1, for T2DM treatment. Similarly, targeting seven druggable genes, namely ERBB3, C4B, CD69, PTPN22, IL27, ATP2A1, and LT-β, has The potential therapeutic benefits of T1DM treatment. This will provide new ideas for the treatment of diabetes and also help to determine the priority of drug development for diabetes.
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Affiliation(s)
- Hu Li
- Emergency Department, Binzhou Medical University Hospital, Binzhou, China
| | - Wei Li
- Urology Department, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Dongyang Li
- Internal Medicine-Neurology, Binzhou Medical University Hospital, Binzhou, China
| | - Lijuan Yuan
- Emergency Department, Binzhou Medical University Hospital, Binzhou, China
| | - Yucheng Xu
- Department of Critical Care Medicine, Jinan Central Hospital, Jinan, China
| | - Pengtao Su
- Emergency Department, Binzhou Medical University Hospital, Binzhou, China
| | - Liqiang Wu
- Emergency Department, Binzhou Medical University Hospital, Binzhou, China
| | - Zhiqiang Zhang
- Emergency Department, Binzhou Medical University Hospital, Binzhou, China
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3
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Qu J, Wang Y, Wang Q. Cuproptosis: potential new direction in diabetes research and treatment. Front Endocrinol (Lausanne) 2024; 15:1344729. [PMID: 38904034 PMCID: PMC11188452 DOI: 10.3389/fendo.2024.1344729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 05/22/2024] [Indexed: 06/22/2024] Open
Abstract
Cuproptosis, a recently discovered form of cell death, stems from an overabundance of copper ions infiltrating mitochondria. These ions directly engage lipoylated proteins, prompting their oligomerization and subsequent loss of iron-sulfur clusters. This sequence induces proteotoxic stress, ultimately culminating in cell death. Type 2 diabetes, a chronic metabolic disorder resulting from a complex interplay of genetic and environmental factors, has not yet been fully understood in terms of its etiology and pathogenesis. Intricately, it is linked to various modalities of cell death, including mitochondrial autophagy, apoptosis, pyroptosis, and ferroptosis. Studies have discovered impaired copper metabolism in individuals with Type 2 diabetes, hinting at a unique role for copper homeostasis in the progression of the disease. To this end, the present research aims to delineate the potential correlation between cuproptosis and Type 2 diabetes by exhaustively reviewing the existing literature. By synthesizing relevant research on cuproptosis, the paper intends to lay the groundwork for a thorough exploration of the pathogenesis of Type 2 diabetes and the development of targeted therapeutic interventions. The ultimate objective is to facilitate a deeper understanding of Type 2 diabetes and to identify novel therapeutic strategies associated with cuproptosis.
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Affiliation(s)
| | | | - Qiuyue Wang
- Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, China
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4
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Li J, Ye Q, Jiao H, Wang W, Zhang K, Chen C, Zhang Y, Feng S, Wang X, Chen Y, Gao H, Wei F, Li WD. An early prediction model for type 2 diabetes mellitus based on genetic variants and nongenetic risk factors in a Han Chinese cohort. Front Endocrinol (Lausanne) 2023; 14:1279450. [PMID: 37955008 PMCID: PMC10634500 DOI: 10.3389/fendo.2023.1279450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 09/25/2023] [Indexed: 11/14/2023] Open
Abstract
Aims We aimed to construct a prediction model of type 2 diabetes mellitus (T2DM) in a Han Chinese cohort using a genetic risk score (GRS) and a nongenetic risk score (NGRS). Methods A total of 297 Han Chinese subjects who were free from type 2 diabetes mellitus were selected from the Tianjin Medical University Chronic Disease Cohort for a prospective cohort study. Clinical characteristics were collected at baseline and subsequently tracked for a duration of 9 years. Genome-wide association studies (GWASs) were performed for T2DM-related phenotypes. The GRS was constructed using 13 T2DM-related quantitative trait single nucleotide polymorphisms (SNPs) loci derived from GWASs, and NGRS was calculated from 4 biochemical indicators of independent risk that screened by multifactorial Cox regressions. Results We found that HOMA-IR, uric acid, and low HDL were independent risk factors for T2DM (HR >1; P<0.05), and the NGRS model was created using these three nongenetic risk factors, with an area under the ROC curve (AUC) of 0.678; high fasting glucose (FPG >5 mmol/L) was a key risk factor for T2DM (HR = 7.174, P< 0.001), and its addition to the NGRS model caused a significant improvement in AUC (from 0.678 to 0.764). By adding 13 SNPs associated with T2DM to the GRS prediction model, the AUC increased to 0.892. The final combined prediction model was created by taking the arithmetic sum of the two models, which had an AUC of 0.908, a sensitivity of 0.845, and a specificity of 0.839. Conclusions We constructed a comprehensive prediction model for type 2 diabetes out of a Han Chinese cohort. Along with independent risk factors, GRS is a crucial element to predicting the risk of type 2 diabetes mellitus.
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Affiliation(s)
- Jinjin Li
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Qun Ye
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hongxiao Jiao
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wanyao Wang
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Kai Zhang
- Geriatric Medicine, Tianjin General Hospital of Tianjin Medical University, Tianjin, China
| | - Chen Chen
- Geriatric Medicine, Tianjin General Hospital of Tianjin Medical University, Tianjin, China
| | - Yuan Zhang
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shuzhi Feng
- Geriatric Medicine, Tianjin General Hospital of Tianjin Medical University, Tianjin, China
| | - Ximo Wang
- Tianjin Nankai Hospital, Tianjin, China
| | - Yubao Chen
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Huailin Gao
- Hebei Yiling Hospital, Shijiazhuang, Hebei, China
| | - Fengjiang Wei
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wei-Dong Li
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
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5
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Zhang Y, Han S, Liu C, Zheng Y, Li H, Gao F, Bian Y, Liu X, Liu H, Hu S, Li Y, Chen ZJ, Zhao S, Zhao H. THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass. Nat Commun 2023; 14:1020. [PMID: 36823211 PMCID: PMC9950491 DOI: 10.1038/s41467-023-36680-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in β-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving β-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.
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Affiliation(s)
- Yuqing Zhang
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Shan Han
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Congcong Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Yuanwen Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong, China
| | - Hao Li
- Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, Shandong, China
| | - Fei Gao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, 100101, Beijing, China
| | - Yuehong Bian
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Xin Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Hongbin Liu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Shourui Hu
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Yuxuan Li
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. .,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, 200135, Shanghai, China. .,Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Shandong, 250012, Jinan, China.
| | - Shigang Zhao
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
| | - Han Zhao
- Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. .,Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. .,Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
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6
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Ustianowski P, Malinowski D, Czerewaty M, Safranow K, Tarnowski M, Dziedziejko V, Pawlik A. THADA, SDHAF4, and MACF1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes. Genes (Basel) 2022; 14:genes14010083. [PMID: 36672824 PMCID: PMC9859259 DOI: 10.3390/genes14010083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/13/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnant women leading to various complications. Consequently, factors predisposing its development are being sought. Previous studies have shown that the pathogenesis of GDM is similar to that of type 2 diabetes, and it is therefore thought that the two diseases may have a common genetic basis. The aim of this study was to examine the associations between thyroid adenoma-associated (THADA) rs7578597 T>C, succinate dehydrogenase complex assembly factor 4 (SDHAF4) rs1048886 A>G, and microtubule-actin crosslinking factor 1 (MACF1) rs2296172 A>G gene polymorphisms and the risk of GDM development as well as selected clinical parameters in women with GDM. We also examined the expression of these genes in the placenta of women with and without GDM in association with clinical parameters. This case-control study included 272 pregnant women with GDM and 348 pregnant women with normal glucose tolerance. There were no statistically significant differences in the distribution of the THADA rs7578597 T>C, SDHAF4 rs1048886 A>G, and MACF1 rs2296172 A>G gene polymorphisms between pregnant control women and women with GDM. The associations between clinical parameters such as body mass before pregnancy, body mass at birth, body mass increase during pregnancy, BMI before pregnancy, BMI at birth, BMI increase during pregnancy, glycated hemoglobin (HbA1c), daily insulin requirement, childbirth time, and newborn body mass and APGAR score, and the THADA rs7578597 T>C, SDHAF4 rs1048886 A>G, and MACF1 rs2296172 A>G genotypes were statistically non-significant. We only observed lower values of body mass before pregnancy and body mass at birth in women with the SDHAF4 rs1048886 AG genotype in comparison with AA genotype carriers. There was no statistically significant difference in the expression of THADA, SDHAF4, and MACF1 genes in the placenta between women with GDM and healthy women. There were also no statistically significant correlations between THADA, SDHAF4, and MACF1 gene expression in the placenta and clinical parameters. The results of our study suggest that THADA rs7578597 T>C, SDHAF4 rs1048886 A>G, and MACF1 rs2296172 A>G gene polymorphisms are not significant factors associated with GDM onset. In addition, SDHAF4 rs1048886 A>G may be associated with body mass before pregnancy and body mass at birth in pregnant women.
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Affiliation(s)
| | - Damian Malinowski
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Michał Czerewaty
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Pomeranian Medical University, 70-210 Szczecin, Poland
| | - Violetta Dziedziejko
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
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7
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Moazzam-Jazi M, Najd-Hassan-Bonab L, Masjoudi S, Tohidi M, Hedayati M, Azizi F, Daneshpour MS. Risk of type 2 diabetes and KCNJ11 gene polymorphisms: a nested case-control study and meta-analysis. Sci Rep 2022; 12:20709. [PMID: 36456687 PMCID: PMC9715540 DOI: 10.1038/s41598-022-24931-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022] Open
Abstract
Due to the central role in insulin secretion, the potassium inwardly-rectifying channel subfamily J member 11 (KCNJ11) gene is one of the essential genes for type 2 diabetes (T2D) predisposition. However, the relevance of this gene to T2D development is not consistent among diverse populations. In the current study, we aim to capture the possible association of common KCNJ11 variants across Iranian adults, followed by a meta-analysis. We found that the tested variants of KCNJ11 have not contributed to T2D incidence in Iranian adults, consistent with similar insulin secretion levels among individuals with different genotypes. The integration of our results with 72 eligible published case-control studies (41,372 cases and 47,570 controls) as a meta-analysis demonstrated rs5219 and rs5215 are significantly associated with the increased T2D susceptibility under different genetic models. Nevertheless, the stratified analysis according to ethnicity showed rs5219 is involved in the T2D risk among disparate populations, including American, East Asian, European, and Greater Middle Eastern, but not South Asian. Additionally, the meta-regression analysis demonstrated that the sample size of both case and control groups was significantly associated with the magnitude of pooled genetic effect size. The present study can expand our knowledge about the KCNJ11 common variant's contributions to T2D incidence, which is valuable for designing SNP-based panels for potential clinical applications in precision medicine. It also highlights the importance of similar sample sizes for avoiding high heterogeneity and conducting a more precise meta-analysis.
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Affiliation(s)
- Maryam Moazzam-Jazi
- Cellular, and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Najd-Hassan-Bonab
- Cellular, and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajedeh Masjoudi
- Cellular, and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Tohidi
- Prevention of Metabolic Disorder Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam S Daneshpour
- Cellular, and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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8
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Sá P, Santos D, Chiaia H, Leitão A, Cordeiro JM, Gama LT, Amaral AJ. Lost pigs of Angola: Whole genome sequencing reveals unique regions of selection with emphasis on metabolism and feed efficiency. Front Genet 2022; 13:1003069. [PMID: 36353101 PMCID: PMC9639768 DOI: 10.3389/fgene.2022.1003069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/20/2022] [Indexed: 11/26/2022] Open
Abstract
Angola, in the western coast of Africa, has been through dramatic social events that have led to the near-disappearance of native swine populations, and the recent introduction of European exotic breeds has also contributed to the erosion of this native swine repertoire. In an effort to investigate the genetic basis of native pigs in Angola (ANG) we have generated whole genomes from animals of a remote local pig population in Huambo province, which we have compared with 78 genomes of European and Asian pig breeds as well as European and Asian wild boars that are currently in public domain. Analyses of population structure showed that ANG pigs grouped within the European cluster and were clearly separated from Asian pig breeds. Pairwise FST ranged from 0.14 to 0.26, ANG pigs display lower levels of genetic differentiation towards European breeds. Finally, we have identified candidate regions for selection using a complementary approach based on various methods. All results suggest that selection towards feed efficiency and metabolism has occurred. Moreover, all analysis identified CDKAL1 gene, which is related with insulin and cholesterol metabolism, as a candidate gene overlapping signatures of selection unique to ANG pigs. This study presents the first assessment of the genetic relationship between ANG pigs and other world breeds and uncovers selection signatures that may indicate adaptation features unique to this important genetic resource.
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Affiliation(s)
- Pedro Sá
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
- Laboratório Associado para a Ciência Animal e Veterinária (AL4AnimalS), Avenida da Universidade Técnica, Lisboa, Portugal
| | - Dulce Santos
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
- Laboratório Associado para a Ciência Animal e Veterinária (AL4AnimalS), Avenida da Universidade Técnica, Lisboa, Portugal
| | - Hermenegildo Chiaia
- Faculdade de Medicina Veterinária, Universidade José Eduardo dos Santos, Huambo, Angola
| | - Alexandre Leitão
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
- Laboratório Associado para a Ciência Animal e Veterinária (AL4AnimalS), Avenida da Universidade Técnica, Lisboa, Portugal
| | - José Moras Cordeiro
- Faculdade de Medicina Veterinária, Universidade José Eduardo dos Santos, Huambo, Angola
| | - Luís T. Gama
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
- Laboratório Associado para a Ciência Animal e Veterinária (AL4AnimalS), Avenida da Universidade Técnica, Lisboa, Portugal
| | - Andreia J. Amaral
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa, Portugal
- Laboratório Associado para a Ciência Animal e Veterinária (AL4AnimalS), Avenida da Universidade Técnica, Lisboa, Portugal
- *Correspondence: Andreia J. Amaral,
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9
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Xu J, Jin L, Chen J, Zhang R, Zhang H, Li Y, Peng D, Gu Y, Wheeler MB, Hu C. Common variants in genes involved in islet amyloid polypeptide (IAPP) processing and the degradation pathway are associated with T2DM risk: A Chinese population study. Diabetes Res Clin Pract 2022; 185:109235. [PMID: 35131375 DOI: 10.1016/j.diabres.2022.109235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 11/28/2022]
Abstract
AIM To explore the genetic effects of SLC30A8, IAPP, PCSK1, PCSK2, CPE, PAM and IDE, key genes involved in IAPP processing and degradation pathway on T2DM risk and metabolic traits in Chinese population. METHODS Common variants were genotyped in 10936 Chinese subjects by Asian Screening Array and Multi-Ethnic Global Array. Associations of SNPs with occurrences of T2DM and related traits were evaluated through logistic and multiple linear regression. Genetic risk score (GRS) model was constructed based on 6 T2DM-variants, and its relationship with T2DM and related traits was assessed. RESULTS SLC30A8-rs13266634, PCSK1-rs155980, PCSK2-rs6136035, CPE-rs532192464, PAM-rs7716941, and IDE-rs117929184 were the top SNPs significantly associated with T2DM after adjusting for age, sex, and BMI, associated with blood glucose level, insulin secretion, and insulin sensitivity (all FDR p < 0.05). GRS calculated based on the above SNPs was remarkably correlated with T2DM, blood glucose, and insulin secretion. Furthermore, there was a significant interaction between SLC30A8 and IAPP in patients with T2DM (P = 0.0083). CONCLUSION Our study showed that common variants in genes involved in IAPP processing and the degradation pathway were associated with T2DM in Chinese population. Subjects with high GRS exhibited poorer glucose metabolism and insulin secretion.
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Affiliation(s)
- Jie Xu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Department of Physiology, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S4L5, Canada
| | - Li Jin
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Jie Chen
- Department of Clinical Laboratory, Shanghai Xuhui Central Hospital, Shanghai 200020, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yangyang Li
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Danfeng Peng
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yunjuan Gu
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu 226001, China.
| | - Michael B Wheeler
- Department of Physiology, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S4L5, Canada.
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China.
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10
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Zeng Q, Zou D, Gu S, Han F, Cao S, Wei Y, Guo R. Different Associations Between CDKAL1 Variants and Type 2 Diabetes Mellitus Susceptibility: A Meta-analysis. Front Genet 2022; 12:783078. [PMID: 35069684 PMCID: PMC8766415 DOI: 10.3389/fgene.2021.783078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Background: CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients. Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models. Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103-1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073-1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056-1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265-1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187-1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155-1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167-1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model. Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.
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Affiliation(s)
- Qiaoli Zeng
- Department of Internal Medicine, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Dehua Zou
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau SAR, China
| | - Shanshan Gu
- Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengqiong Han
- Department of Obstetric, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Shilin Cao
- Department of Medical, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Yue Wei
- Department of Ultrasound, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China
| | - Runmin Guo
- Department of Internal Medicine, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, China.,Matenal and Child Research Institute, Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, China.,Department of Endocrinology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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11
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Shen F, Weng S, Tsai M, Su Y, Li S, Chang S, Chen J, Chang Y, Liou C, Lin T, Chuang J, Lin C, Wang P. Mitochondrial haplogroups have a better correlation to insulin requirement than nuclear genetic variants for type 2 diabetes mellitus in Taiwanese individuals. J Diabetes Investig 2022; 13:201-208. [PMID: 34255930 PMCID: PMC8756312 DOI: 10.1111/jdi.13629] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/03/2021] [Accepted: 07/05/2021] [Indexed: 11/30/2022] Open
Abstract
AIMS/INTRODUCTION Identifying diabetes-susceptible genetic variants will help to provide personalized therapy for the management of type 2 diabetes. Previous studies have reported a genetic risk score (GRS), computed by the sum of nuclear DNA (nDNA) risk alleles, that may predict the future requirement for insulin therapy. Although mitochondrial dysfunction has a close association with insulin resistance (IR), there are few studies investigating whether genetic variants of mitochondrial DNA (mtDNA) will affect the clinical characteristics of type 2 diabetes. MATERIALS AND METHODS Mitochondrial haplogroups were determined using mtDNA whole genome next generation sequencing and 13 single nucleotide polymorphisms (SNPs) in nDNA susceptibility loci of 13 genes in 604 Taiwanese subjects with type 2 diabetes. A GRS of nDNA was computed by summation of the number of risk alleles. The correlation between the mtDNA haplogroup and the clinical characteristics of type 2 diabetes was assessed by logistic regression analysis. The results were compared with the GRS subgroups for the risk of insulin requirement. RESULTS Mitochondrial haplogroups modulate the clinical characteristics of type 2 diabetes, in which patients harboring haplogroup D4, compared with those harboring non-D4 haplotypes, were less prone to require insulin treatment, after adjusting for age, gender, and diabetes duration. However, there was no association between insulin requirement and GRS calculated from nuclear genetic variants. CONCLUSIONS Mitochondrial haplogroups, but not nuclear genetic variants, have a better association with the insulin requirement. The results highlight the role of mitochondria in the management of common metabolic diseases.
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Affiliation(s)
- Feng‐Chih Shen
- Division of Endocrinology and MetabolismDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
| | - Shao‐Wen Weng
- Division of Endocrinology and MetabolismDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Meng‐Han Tsai
- Department of NeurologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Yu‐Jih Su
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Division of Rheumatology, Allergy, and ImmunologyDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Sung‐Chou Li
- Genomics & Proteomics Core LaboratoryDepartment of Medical ResearchKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
| | - Shun‐Jen Chang
- Department of Kinesiology, Health and Leisure StudiesNational University of KaohsiungTaiwan
| | - Jung‐Fu Chen
- Division of Endocrinology and MetabolismDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Yen‐Hsiang Chang
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Department of Nuclear MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Chia‐Wei Liou
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Department of NeurologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Tsu‐Kung Lin
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Department of NeurologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Jiin‐Haur Chuang
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Department of SurgeryKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
| | - Ching‐Yi Lin
- Division of Endocrinology and MetabolismDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
| | - Pei‐Wen Wang
- Division of Endocrinology and MetabolismDepartment of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
- Center for Mitochondrial Research and MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- Department of Nuclear MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungTaiwan
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12
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The association between FTO polymorphisms and type 2 diabetes in Asian populations: A meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100958] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
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13
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Shulman ED, Elkon R. Genetic mapping of developmental trajectories for complex traits and diseases. Comput Struct Biotechnol J 2021; 19:3458-3469. [PMID: 34194671 PMCID: PMC8220172 DOI: 10.1016/j.csbj.2021.05.055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/30/2021] [Accepted: 05/30/2021] [Indexed: 11/04/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified numerous common genetic variants associated with complex human traits and diseases. However, the translation of GWAS discoveries into biological and clinical insights is highly challenging. In this study, we present a novel bioinformatics approach for enhancing the functional interpretation of GWAS signals, based on their integration with single-cell (sc)RNA-seq datasets that examine developmental processes. Our approach performs three tasks: (1) Identification of links between cell differentiation trajectories and traits; (2) Elucidation of biological processes and molecular pathways that underlie such trajectory-trait links; and (3) Prioritization of target genes that carry the links between trajectories, pathways and traits. We applied our method to a set of 11 traits of various pathologies, and 12 scRNA-seq datasets of diverse developmental processes, and it readily detected well-established biological connections, including those between the maturation of cortical inhibitory interneurons and schizophrenia, hepatocytes and cholesterol levels, and pancreatic beta-islet cells and type-2 diabetes. For each of these associations, our method pinpointed top candidate genes that are strongly associated with both the kinetics of the differentiation trajectory and the disease's genetic risk. By the identification of trajectory-disease links, molecular pathways that underlie them and prioritizing candidate risk genes, our method improves the understanding of the etiology of complex diseases, and thus holds promise for enhancing rational drug development that is aimed at targeting specific biological processes that mediate the genetic predisposition to diseases.
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Affiliation(s)
- Eldad David Shulman
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ran Elkon
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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14
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Wu Q, Hu Y. Systematic Evaluation of the Mechanisms of Mulberry Leaf (Morus alba Linne) Acting on Diabetes Based on Network Pharmacology and Molecular Docking. Comb Chem High Throughput Screen 2021; 24:668-682. [PMID: 32928080 DOI: 10.2174/1386207323666200914103719] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Diabetes mellitus is one of the most common endocrine metabolic disorder- related diseases. The application of herbal medicine to control glucose levels and improve insulin action might be a useful approach in the treatment of diabetes. Mulberry leaves (ML) have been reported to exert important activities of anti-diabetic. OBJECTIVE In this work, we aimed to explore the multi-targets and multi-pathways regulatory molecular mechanism of Mulberry leaves (ML, Morus alba Linne) acting on diabetes. METHODS Identification of active compounds of Mulberry leaves using Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was carried out. Bioactive components were screened by FAF-Drugs4 website (Free ADME-Tox Filtering Tool). The targets of bioactive components were predicted from SwissTargetPrediction website, and the diabetes related targets were screened from GeneCards database. The common targets of ML and diabetes were used for Gene Ontology (GO) and pathway enrichment analysis. The visualization networks were constructed by Cytoscape 3.7.1 software. The biological networks were constructed to analyze the mechanisms as follows: (1) compound-target network; (2) common target-compound network; (3) common targets protein interaction network; (4) compound-diabetes protein-protein interactions (ppi) network; (5) target-pathway network; and (6) compound-target-pathway network. At last, the prediction results of network pharmacology were verified by molecular docking method. RESULTS 17 active components were obtained by TCMSP database and FAF-Drugs4 website. 51 potential targets (11 common targets and 40 associated indirect targets) were obtained and used to build the PPI network by the String database. Furthermore, the potential targets were used for GO and pathway enrichment analysis. Eight key active compounds (quercetin, Iristectorigenin A, 4- Prenylresveratrol, Moracin H, Moracin C, Isoramanone, Moracin E and Moracin D) and 8 key targets (AKT1, IGF1R, EIF2AK3, PPARG, AGTR1, PPARA, PTPN1 and PIK3R1) were obtained to play major roles in Mulberry leaf acting on diabetes. And the signal pathways involved in the mechanisms mainly include AMPK signaling pathway, PI3K-Akt signaling pathway, mTOR signaling pathway, insulin signaling pathway and insulin resistance. The molecular docking results show that the 8 key active compounds have good affinity with the key target of AKT1, and the 5 key targets (IGF1R, EIF2AK3, PPARG, PPARA and PTPN1) have better affinity than AKT1 with the key compound of quercetin. CONCLUSION Based on network pharmacology and molecular docking, this study provided an important systematic and visualized basis for further understanding of the synergy mechanism of ML acting on diabetes.
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Affiliation(s)
- Qiguo Wu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yeqing Hu
- Department of Pharmacy, Anqing Medical College, Anqing 246052, China
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15
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Leissring MA, González-Casimiro CM, Merino B, Suire CN, Perdomo G. Targeting Insulin-Degrading Enzyme in Insulin Clearance. Int J Mol Sci 2021; 22:ijms22052235. [PMID: 33668109 PMCID: PMC7956289 DOI: 10.3390/ijms22052235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.
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Affiliation(s)
- Malcolm A. Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI MIND), Irvine, CA 92697-4545, USA
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
| | - Carlos M. González-Casimiro
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
| | - Caitlin N. Suire
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306-4300, USA;
| | - Germán Perdomo
- Instituto de Biología y Genética Molecular (University of Valladolid-CSIC), 47003 Valladolid, Spain; (C.M.G.-C.); (B.M.)
- Correspondence: (M.A.L.); (G.P.); Tel.: +1-904-254-3050 (M.A.L.); +34-983-184-805 (G.P.)
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16
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Xu N, Zhang TT, Han WJ, Yin LP, Ma NZ, Shi XY, Sun JJ. Association of CDKAL1 RS10946398 Gene Polymorphism with Susceptibility to Diabetes Mellitus Type 2: A Meta-Analysis. J Diabetes Res 2021; 2021:1254968. [PMID: 34977253 PMCID: PMC8719992 DOI: 10.1155/2021/1254968] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/12/2021] [Accepted: 11/13/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Diabetes is one of the common chronic diseases in which susceptibility is determined by a combination of genetic and environmental factors, and more than 90% of diabetic patients are diabetes mellitus type 2 (T2DM). The existing studies on the association between CDKAL1 rs10946398 gene polymorphism and susceptibility to type 2 diabetes are inconsistent across populations. AIM We aim to explore the association between CDKAL1 rs10946398 gene polymorphism and susceptibility to type 2 diabetes in different populations. METHODS We examined all studies before June 12, 2021, that associated CDKAL1 rs10946398 with T2DM. Heterogeneity was assessed by meta-analysis of allelic inheritance models (A vs. C), dominant inheritance models (AA vs. AC+CC), and recessive inheritance model (AA+AC vs. CC); I 2 was used to assess the heterogeneity (if I 2 < 50%, the fixed-effects model was used; if I 2 ≥ 50%, the random-effects model was used for data consolidation); correlation was judged by a forest map; potential publication bias was tested by the Egger test (p > 0.05 indicates that there is no publication bias). RESULTS Fourteen data totaling 30288 subjects, including 19272 controls and 11016 patients with T2DM, met our inclusion criteria. In the Asian population, the differences were statistically significant (p < 0.01) for dominant genetic model (OR = 0.75, 95%CI = 0.64-0.88, p = 0.0003). But the allelic effect model (OR = 0.87, 95%CI = 0.75-1.02, p = 0.08) and the recessive genetic model (OR = 0.85, 95%CI = 0.66-1.10, p = 0.23) were not statistically significant (p > 0.01). In the non-Asian population, the differences were statistically significant (p < 0.01) for the allelic effect model (OR = 0.83, 95%CI = 0.77-0.88, p < 0.00001), the dominant model (OR = 0.79, 95%CI = 0.72-0.87, p < 0.00001), and the recessive model (OR = 0.78, 95%CI = 0.70-0.87, p < 0.0001). CONCLUSION In this study, CDKAL1 RS10946398 was positively associated with T2DM, but the association was different in Asian populations.
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Affiliation(s)
- Ning Xu
- School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Ting-Ting Zhang
- School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China
| | - Wen-Jia Han
- School of Dentistry, Anhui Medical University, Hefei, Anhui 230032, China
| | - Li-Ping Yin
- Medical Examination Center, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Nan-Zheng Ma
- Anhui Medical University, Affiliated Hospital, Nationalities, Hefei, Anhui 230032, China
| | - Xiu-Yan Shi
- Nanjing Prevention and Treatment Center for Occupational Diseases, Nanjing 23100, China
| | - Jiang-Jie Sun
- Health Management College, Anhui Medical University, Hefei, Anhui 230032, China
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17
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Identification of the potential type 2 diabetes susceptibility genetic elements in South Asian populations. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100771] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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18
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Mashal S, Khanfar M, Al-Khalayfa S, Srour L, Mustafa L, Hakooz NM, Zayed AA, Khader YS, Azab B. SLC30A8 gene polymorphism rs13266634 associated with increased risk for developing type 2 diabetes mellitus in Jordanian population. Gene 2020; 768:145279. [PMID: 33161057 DOI: 10.1016/j.gene.2020.145279] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/08/2020] [Accepted: 10/23/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Several genome-wide association studies (GWAS) have identified the single nucleotide polymorphism (SNP) rs13266634 in the Solute carrier family 30 member 8 (SLC30A8) gene as a risk factor to type 2 diabetes mellitus (T2DM). Nevertheless, other studies reported controversial findings of no significant association between the rs13266634 with T2DM. In this study, we aimed to investigate the association of this SNP with T2DM among Jordanian population in addition to define its corresponding allelic and genotypic frequencies. METHOD This case-control study enrolled 358 T2DM patients and 326 healthy controls who fulfilled the inclusion criteria. Blood samples were collected from all participants and were used for the rs13266634 SNP genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS We demonstrated a significant association between the C/T rs13266634 SNP and T2DM among Jordanian population. A significant difference was found between the cases and controls regarding the allelic (P = 0.003) distribution. Compared to people having T allele, those with C allele had higher risk of T2DM (OR = 1.47 ; 95% CI: 1.14 - 1.89; P = 0.003). Having a CC genotype versus TT genotype was significantly associated with increased risk to T2DM (OR = 2.44; 95% CI: 1.16 - 5.12; P = 0.019) after adjusting for age, gender, and BMI. Under the recessive model, subjects with CC genotype were more likely to have T2DM compared to those with CT or TT genotypes, (OR = 1.64; 95% CI: 1.18 - 2.26; P = 0.003) after adjusting for age, gender and BMI. CONCLUSION The rs13266634 SNP is significantly associated with T2DM susceptibility among Jordanian Population.
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Affiliation(s)
- Safaa Mashal
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Mariam Khanfar
- Department of Medical Laboratory Sciences, Jordan University of Science and Technology, P.O.Box 3030, Irbid 22110, Jordan
| | - Sawsan Al-Khalayfa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Luma Srour
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Lina Mustafa
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Nancy M Hakooz
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Ayman A Zayed
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, School of Medicine, The University of Jordan, Jordan University Hospital, PO Box: 13617, Queen Rania St., Amman 11942, Jordan
| | - Yousef S Khader
- Department of Community Medicine, Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, P.O.Box 3030, Irbid 22110, Jordan
| | - Bilal Azab
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, PO Box: 13617, Queen Rania St., Amman 11942, Jordan; Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, United States.
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Banihashemi P, Aghaei Meybodi HR, Afshari M, Sarhangi N, Hasanzad M. Association analysis of HHEX gene variant with type 2 diabetes risk. Int J Diabetes Dev Ctries 2020. [DOI: 10.1007/s13410-020-00870-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Chen ACH, Lee KF, Yeung WSB, Lee YL. Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes. World J Stem Cells 2020; 12:761-775. [PMID: 32952857 PMCID: PMC7477660 DOI: 10.4252/wjsc.v12.i8.761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/28/2020] [Accepted: 06/14/2020] [Indexed: 02/06/2023] Open
Abstract
The developmental origins of health and diseases (DOHaD) is a concept stating that adverse intrauterine environments contribute to the health risks of offspring. Since the theory emerged more than 30 years ago, many epidemiological and animal studies have confirmed that in utero exposure to environmental insults, including hyperglycemia and chemicals, increased the risk of developing noncommunicable diseases (NCDs). These NCDs include metabolic syndrome, type 2 diabetes, and complications such as diabetic cardiomyopathy. Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development. Embryonic stem cells (ESCs) have also been utilized by researchers to study the DOHaD. ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage; therefore, they are excellent in vitro models for studying early developmental events. More importantly, human ESCs (hESCs) are the best alternative to human embryos for research because of ethical concerns. In this review, we will discuss different maternal conditions associated with DOHaD, focusing on the complications of maternal diabetes. Next, we will review the differentiation protocols developed to generate different cell lineages from hESCs. Additionally, we will review how hESCs are utilized as a model for research into the DOHaD. The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.
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Affiliation(s)
- Andy Chun-Hang Chen
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Kai Fai Lee
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - William Shu Biu Yeung
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China
| | - Yin Lau Lee
- Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong Shenzhen Hospital, Shenzhen 518053, Guangdong Province, China.
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Gupta MK, Vadde R. Divergent evolution and purifying selection of the Type 2 diabetes gene sequences in Drosophila: a phylogenomic study. Genetica 2020; 148:269-282. [PMID: 32804315 DOI: 10.1007/s10709-020-00101-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 08/12/2020] [Indexed: 11/24/2022]
Abstract
The recently developed phylogenomic approach provides a unique way to identify disease risk or protective allele in any organism. While risk alleles evolve mostly under purifying selection, protective alleles are evolving either under balancing or positive selection. Owing to insufficient information, authors employed the phylogenomic approach to detect the nature of selection acting on type 2 diabetes (T2D) genes in Drosophila genus using various models of CODEML utility of PAML. The obtained result revealed that T2D gene sequences are evolving under purifying selection. However, only a few sites in membrane proteins encoded via CG8051, ZnT35C, and kar, are significantly evolving under positive selection under specific scenarios, which might be because of positive or adaptive evolution in response to changing niche, diet or other factors. In the near future, this information will be highly useful in the field of evolutionary medicine and the drug discovery process.
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Affiliation(s)
- Manoj Kumar Gupta
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, 516005, India
| | - Ramakrishna Vadde
- Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, 516005, India.
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22
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Liu X, Liang J, Geng H, Xu W, Teng F, Yang M. Association of the CDKAL1 polymorphism rs10946398 with type 2 diabetes mellitus in adults: A meta-analysis. Medicine (Baltimore) 2020; 99:e21383. [PMID: 32791750 PMCID: PMC7387030 DOI: 10.1097/md.0000000000021383] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Previous studies had reported that the CDKAL1 (cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1) rs10946398 C/A polymorphism associated with type 2 diabetes mellitus (T2DM) in various ethnic groups, however, inconsistent results have been obtained in studies of different populations.We performed a meta-analysis of 13 studies for rs10946398 of CDKAL1 on genetic susceptibility for T2DM.The results showed that CDKAL1 rs10946398 C/A polymorphism associated with T2DM under allelic (odds risk (OR): 1.17, 95% CI: 1.07-1.28, P = .0007), homozygous (OR: 1.39, 95% CI: 1.15-1.69, P = .0008), and dominant models (OR: 1.26, 95% CI: 1.09-1.46, P = .001).We found that rs10946398 C/A polymorphism was associated with T2DM, and this association was significantly in population of western country (Europe and United States) and Asian populations.
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Affiliation(s)
- Xuekui Liu
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
| | - Jun Liang
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
- Department of endocrinology, Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
| | - Houfa Geng
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
- Department of endocrinology, Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
| | - Wei Xu
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
- Department of endocrinology, Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
| | - Fei Teng
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
- Department of endocrinology, Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
| | - Manqing Yang
- Department of Endocrinology, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Central Hospital, Affiliated Hospital of Southeast University
- Department of endocrinology, Xuzhou Institute of Medical Sciences, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
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23
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Soltanian AR, Hosseini B, Mahjub H, Bahreini F, Ghaffari ME. A Bayesian analysis for investigating the association between rs13266634 polymorphism in SLC30A8 gene and type 2 diabetes. J Diabetes Metab Disord 2020; 19:337-342. [PMID: 32550184 DOI: 10.1007/s40200-020-00514-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022]
Abstract
Purpose The purpose of this study was to evaluate the association between rs13266634 polymorphism in SLC30A8 gene and type 2 diabetes in Iranian population, and also to provide a way for adjusting the deviation from the Hardy-Weinberg equilibrium. Methods This was a case-control study, the patients were selected from the East Azerbaijan province, Iran. In this study, 125 patients with type 2 diabetes (cases) and 125 healthy individuals (controls) were studied. Genotype and allele frequencies were determined in both groups, and the deviations from the Hardy-Weinberg equilibrium were assessed using Bayesian analysis. Results A statistically significant association was observed between rs13266634 polymorphism in SLC30A8 gene and type 2 diabetes. In genotype assessing, data analysis showed that, TT genotype play a role in diabetes type 2 risk (P = 0.001). Subjects with TT genotype had a lower risk of diabetes compared to those with CC and CT genotypes. Also, there was no significant relationship between this polymorphism and type 2 diabetes mellitus in the absence of Hardy-Weinberg equilibrium. Conclusion Our findings show that, rs13266634 polymorphism was associated with the type 2 diabetes risk in the population of Eastern Azerbaijan province; however, the low number of TT homozygous genotypes affected the precision of the results. Also, the deviation from HWE affected the results. It is recommended to perform further studies to establish Hardy-Weinberg equilibrium. The inconsistency in the results may be due to the ignorance of this equilibrium.
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Affiliation(s)
- Ali Reza Soltanian
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Health Sciences, School of Public Health and, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Bistoon Hosseini
- Kermanshah Province Electricity Distribution Company, Kermanshah, Iran
| | - Hossein Mahjub
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Health Sciences, School of Public Health and, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Bahreini
- Department of Molecular Medicine and Genetics, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Ebrahim Ghaffari
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
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Fan L, Li H, Wang W. Long non-coding RNA PRRT3-AS1 silencing inhibits prostate cancer cell proliferation and promotes apoptosis and autophagy. Exp Physiol 2020; 105:793-808. [PMID: 32086850 DOI: 10.1113/ep088011] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/20/2020] [Indexed: 12/14/2022]
Abstract
NEW FINDINGS What is the central question of this study? What is the role of lncRNA PRRT3-AS1 in the regulation of peroxisome proliferator-activated receptor γ (PPARγ) gene-mediated mechanistic target of rapamycin (mTOR) signalling pathway in proliferation, apoptosis and autophagy of prostate cancer cells? What is the main finding and its importance? The targeting relation between lncRNA PRRT3-AS1 and PPARγ was verified, and it was demonstrated that silencing of lncRNA PRRT3-AS1 can upregulate apoptosis and autophagy yet downregulate proliferation, migration and invasion of prostate cancer cells through the mTOR signalling pathway. Further work is needed to consolidate the therapeutic value of lncRNA PRRT3-AS1 in clinical trials and treatment of prostate cancer. ABSTRACT Although long non-coding RNAs (lncRNAs) are correlated with multiple cancers, their molecular mechanisms in prostate cancer (PC) remain inadequately understood. This study investigated the effects of lncRNA PRRT3-AS1 on the progression of prostate cancer (PC) with involvement of peroxisome proliferator-activated receptor γ (PPARγ). Microarray analysis was used to identify the differentially expressed genes and lncRNAs associated with PC. RT-qPCR and western blot analysis were employed to test the expression of lncRNA PRRT3-AS1, mammalian target of rapamycin (mTOR) signalling pathway-, apoptosis- and autophagy-related genes. A scratch test, Transwell assay, CCK-8 assay, colony formation assay, flow cytometry and monodansylcadaverine staining were employed to identify the migration, invasion, proliferation activity, cell cycle and apoptosis and autophagy of PC3 cells, respectively. Tumorigenicity assays in nude mice were used to detect the tumorigenic ability. GSE55945 and GSE46602 datasets indicated that lncRNA PRRT3-AS1 was highly expressed in PC. PPARγ was predicted as a target gene of lncRNA PRRT3-AS1. Ectopic overexpression of PPARγ or lncRNA PRRT3-AS1 silencing led to inhibited cell viability, migration and invasion, and accelerated apoptosis. Furthermore, the delivery of si-PRRT3-AS1 or PPARγ vector to PC3 cells resulted in the regression of xenografts in nude mice. Based on the in vitro and in vivo experiments, silencing of lncRNA PRRT3-AS1 was observed to activate the PPARγ gene, which in turn could inhibit PC cell proliferation and promote apoptosis and autophagy by blocking the mTOR signalling pathway.
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Affiliation(s)
- Li Fan
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, 130033, P.R. China
| | - Hai Li
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, 130033, P.R. China
| | - Weihua Wang
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, 130033, P.R. China
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Patron J, Serra-Cayuela A, Han B, Li C, Wishart DS. Assessing the performance of genome-wide association studies for predicting disease risk. PLoS One 2019; 14:e0220215. [PMID: 31805043 PMCID: PMC6894795 DOI: 10.1371/journal.pone.0220215] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 11/01/2019] [Indexed: 12/24/2022] Open
Abstract
To date more than 3700 genome-wide association studies (GWAS) have been published that look at the genetic contributions of single nucleotide polymorphisms (SNPs) to human conditions or human phenotypes. Through these studies many highly significant SNPs have been identified for hundreds of diseases or medical conditions. However, the extent to which GWAS-identified SNPs or combinations of SNP biomarkers can predict disease risk is not well known. One of the most commonly used approaches to assess the performance of predictive biomarkers is to determine the area under the receiver-operator characteristic curve (AUROC). We have developed an R package called G-WIZ to generate ROC curves and calculate the AUROC using summary-level GWAS data. We first tested the performance of G-WIZ by using AUROC values derived from patient-level SNP data, as well as literature-reported AUROC values. We found that G-WIZ predicts the AUROC with <3% error. Next, we used the summary level GWAS data from GWAS Central to determine the ROC curves and AUROC values for 569 different GWA studies spanning 219 different conditions. Using these data we found a small number of GWA studies with SNP-derived risk predictors that have very high AUROCs (>0.75). On the other hand, the average GWA study produces a multi-SNP risk predictor with an AUROC of 0.55. Detailed AUROC comparisons indicate that most SNP-derived risk predictions are not as good as clinically based disease risk predictors. All our calculations (ROC curves, AUROCs, explained heritability) are in a publicly accessible database called GWAS-ROCS (http://gwasrocs.ca). The G-WIZ code is freely available for download at https://github.com/jonaspatronjp/GWIZ-Rscript/.
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Affiliation(s)
- Jonas Patron
- Department of Biological Sciences, University of Alberta, Edmonton, Canada
| | | | - Beomsoo Han
- Department of Biological Sciences, University of Alberta, Edmonton, Canada
| | - Carin Li
- Department of Biological Sciences, University of Alberta, Edmonton, Canada
| | - David Scott Wishart
- Department of Biological Sciences, University of Alberta, Edmonton, Canada
- Department of Computing Science, University of Alberta, Edmonton, Canada
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Contemplating the role of genetic variants of HHEX, CDKAL1, WFS1 and SLC30A8 genes of TYPE-2 diabetes in Asians ethnic groups. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100465] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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27
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Fernández-Díaz CM, Merino B, López-Acosta JF, Cidad P, de la Fuente MA, Lobatón CD, Moreno A, Leissring MA, Perdomo G, Cózar-Castellano I. Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity. Am J Physiol Endocrinol Metab 2019; 317:E805-E819. [PMID: 31479304 PMCID: PMC7132327 DOI: 10.1152/ajpendo.00040.2019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.
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Affiliation(s)
- Cristina M Fernández-Díaz
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - José F López-Acosta
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Pilar Cidad
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Miguel A de la Fuente
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Carmen D Lobatón
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Alfredo Moreno
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Malcolm A Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California
| | - Germán Perdomo
- Departmento de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
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Tian Y, Xu J, Huang T, Cui J, Zhang W, Song W, Chen H, Huang P, Yang S, Wang L, He X, Wang L, Cui W. A Novel Polymorphism (rs35612982) in CDKAL1 Is a Risk Factor of Type 2 Diabetes: A Case-Control Study. Kidney Blood Press Res 2019; 44:1313-1326. [PMID: 31639799 DOI: 10.1159/000503175] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/05/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The interaction of environmental factors and genetic factors may contribute to the risk of type 2 diabetes (T2D). We aimed to investigate whether age, gender, body mass index (BMI) and lifestyle factors have an effect on the association between the CDKAL1 polymorphisms and T2D. METHODS Eight single nucleotide polymorphisms in CDKAL1 were genotyped by Agena MassARRAY in 508 T2D patients and 503 controls. The association between the CDKAL1 polymorphisms and T2D was evaluated using logistic regression model by calculating OR and 95% CIs. RESULTS We found a significant association between CDKAL1 polymorphisms (rs4712523, OR 1.42, p = 9.44 × 10-5; rs4712524, OR 1.38, p = 3.28 × 10-4; rs10946398, OR 1.43, p = 6.21 × 10-5; rs7754840, OR 1.43, p = 6.33 × 10-5; rs35612982, OR 1.34, p = 0.0010; and rs10440833, OR 1.32, p = 0.0018) and T2D risk among the Han population from Northwest China. We also found that genetic variants of CDKAL1 could modify the risk of T2D that might be influenced by age, BMI and the status of smoking and drinking. Besides, rs35612982-CT (p = 0.038) and rs10440833-AT (p = 0.044) genotypes were higher insulin level. CONCLUSION CDKAL1 rs35612982 (C/T) polymorphism, as a new polymorphism, was associated with the increased risk of T2D in the Han Chinese population. Moreover, the contribution of CDKAL1 polymorphisms to T2D risk seems to be associated with age, gender, BMI, smoking and drinking.
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Affiliation(s)
- Yanni Tian
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jing Xu
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Huang
- Department of Nursing, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiaqi Cui
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Zhang
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University Xi'an, Xi'an, China
| | - Wei Song
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Huan Chen
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pan Huang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shujun Yang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lu Wang
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin He
- Department of Endocrinology, Xi'an Aerospace General Hospital, Xi'an, China
| | - Lin Wang
- Department of Endocrinology, Xi'an Gaoxin Hospital, Xi'an, China
| | - Wei Cui
- Department of Endocrinology and Second Department of Geriatrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China,
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Al Ali M, El hajj Chehadeh S, Osman W, Almansoori K, Abdulrahman M, Tay G, Alsafar H. Investigating the association of rs7903146 of TCF7L2 gene, rs5219 of KCNJ11 gene, rs10946398 of CDKAL1 gene, and rs9939609 of FTO gene with type 2 diabetes mellitus in Emirati population. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Deng J, Tan H, Hu J, Su G, Cao Q, Huang X, Zhou C, Wang Y, Kijlstra A, Yang P. Genetic aspects of idiopathic paediatric uveitis and juvenile idiopathic arthritis associated uveitis in Chinese Han. Br J Ophthalmol 2019; 104:443-447. [PMID: 30940621 PMCID: PMC7041504 DOI: 10.1136/bjophthalmol-2018-313200] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 02/11/2019] [Accepted: 03/09/2019] [Indexed: 02/06/2023]
Abstract
Background Idiopathic paediatric uveitis (IPU) and juvenile idiopathic arthritis associated uveitis (JIA-U) are the two most common entities in paediatric uveitis. This study addressed the possible association of IPU and JIA-U with genes that had been shown earlier to be associated with juvenile idiopathic arthritis. Methods We carried out a case-control association study involving 286 IPU, 134 JIA-U patients and 743 healthy individuals. A total of 84 candidate single nucleotide polymorphisms (SNPs) in 60 genes were selected for this study. The MassARRAY platform and iPLEX Gold Genotyping Assay was used to genotype 83 candidate SNPs and the remaining SNP (rs27293) was analysed using the TaqMan SNP Genotyping Assay. Results No evidence was found for an association of the candidate polymorphisms tested with IPU. Six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) showed an association with JIA-U (p<1.0×10−2). Conclusion Our findings showed associations of six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) with JIA-U. No association was detected between the 84 tested SNPs and IPU.
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Affiliation(s)
- Jing Deng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Handan Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Jiayue Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Qingfeng Cao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Xinyue Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Chunjiang Zhou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Yao Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, The Netherlands
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P. R. China
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Gupta MK, Vadde R. Insights into the structure–function relationship of both wild and mutant zinc transporter ZnT8 in human: a computational structural biology approach. J Biomol Struct Dyn 2019; 38:137-151. [DOI: 10.1080/07391102.2019.1567391] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Manoj Kumar Gupta
- Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India
| | - Ramakrishna Vadde
- Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India
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Gupta MK, Sarojamma V, Vadde R. Diabetes and Pancreatic Cancer: A Bidirectional Relationship Perspective. EXPLORING PANCREATIC METABOLISM AND MALIGNANCY 2019:35-51. [DOI: 10.1007/978-981-32-9393-9_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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Huang Q, Du J, Merriman C, Gong Z. Genetic, Functional, and Immunological Study of ZnT8 in Diabetes. Int J Endocrinol 2019; 2019:1524905. [PMID: 30936916 PMCID: PMC6413397 DOI: 10.1155/2019/1524905] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/14/2018] [Accepted: 12/05/2018] [Indexed: 12/11/2022] Open
Abstract
Zinc level in the body is finely regulated to maintain cellular function. Dysregulation of zinc metabolism may induce a variety of diseases, e.g., diabetes. Zinc participates in insulin synthesis, storage, and secretion by functioning as a "cellular second messenger" in the insulin signaling pathway and glucose homeostasis. The highest zinc concentration is in the pancreas islets. Zinc accumulation in cell granules is manipulated by ZnT8, a zinc transporter expressed predominately in pancreatic α and β cells. A common ZnT8 gene (SLC30A8) polymorphism increases the risk of type 2 diabetes mellitus (T2DM), and rare mutations may present protective effects. In type 1 diabetes mellitus (T1DM), autoantibodies show specificity for binding two variants of ZnT8 (R or W at amino acid 325) dictated by a polymorphism in SLC30A8. In this review, we summarize the structure, feature, functions, and polymorphisms of ZnT8 along with its association with diabetes and explore future study directions.
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Affiliation(s)
- Qiong Huang
- Department of Pharmacy, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Jie Du
- Department of Pharmacy, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Chengfeng Merriman
- Department of Physiology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA
| | - Zhicheng Gong
- Department of Pharmacy, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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Witka BZ, Oktaviani DJ, Marcellino M, Barliana MI, Abdulah R. Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors. Diabetes Metab Syndr Obes 2019; 12:2689-2706. [PMID: 31908510 PMCID: PMC6927489 DOI: 10.2147/dmso.s230061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a major cause of mortality worldwide. There are several types of diabetes, with type 2 diabetes mellitus (T2DM) being the most common. Many factors, including environmental and genetic factors, are involved in the etiology of the disease. Numerous studies have reported the role of genetic polymorphisms in the initiation and development of T2DM. While genome-wide association studies have identified around more than 200 susceptibility loci, it remains unclear whether these loci are correlated with the pathophysiology of the disease. The present review aimed to elucidate the potential genetic mechanisms underlying T2DM. We found that some genetic polymorphisms were related to T2DM, either in the form of single-nucleotide polymorphisms or direct amino acid changes in proteins. These polymorphisms are potential predictors for the management of T2DM.
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Affiliation(s)
- Beska Z Witka
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Dede J Oktaviani
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Marcellino Marcellino
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Melisa I Barliana
- Departement of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
- Correspondence: Melisa I Barliana Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor45363, Indonesia Email
| | - Rizky Abdulah
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
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Zhou J, Chen WR, Yang LC, Wang J, Sun JY, Zhang WW, He ZY, Wu SG. KIF11 Functions as an Oncogene and Is Associated with Poor Outcomes from Breast Cancer. Cancer Res Treat 2018; 51:1207-1221. [PMID: 30590004 PMCID: PMC6639218 DOI: 10.4143/crt.2018.460] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022] Open
Abstract
Purpose The study aimed to search and identify genes that were differentially expressed in breast cancer, and their roles in cancer growth and progression. Materials and Methods The Gene Expression Omnibus (Oncomine) and The Cancer Genome Atlas databases (https://cancergenome.nih.gov/) were screened for genes that were expressed differentially in breast cancer and were closely related to a poor prognosis. Gene expressions were verified by quantitative real-time polymerase chain reaction, and genes were knocked down by a lentivirus-based system. Cell growth and motility were evaluated and in vivo nude mice were used to confirm the in vitro roles of genes. Markers of epithelial-to-mesenchymal transition and the associations of KIF11 with the classical cancer signaling pathways were detected by Western blot. Results A series of genes expressed differentially in patients with breast cancer. The prognosis associated with high KIF11 expression was poor, and the expression of KIF11 increased significantly in high stage and malignant tumor cells. Inhibiting KIF11 expression in lentivirus-suppressed cells revealed that KIF11 inhibition significantly reduced cell viability and colony formation, inhibited migration and invasion, but promoted apoptosis. The sizes and weights of KIF11-inhibited tumors in nude mice were significantly lower than in the negative controls. Western blot showed that E-cadherin in breast cancer was significantly upregulated in KIF-inhibited cells and tumor tissues, whereas N-cadherin and vimentin were significantly downregulated. BT549 and MDA231 cells with KIF11 knockdown exhibited decreased ERK, AMPK, AKT, and CREB phosphorylation. Conclusion KIF11 acts as a potential oncogene that regulates the development and progression of breast cancer.
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Affiliation(s)
- Juan Zhou
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Wei-Rong Chen
- Department of Breast Surgery, Zhuhai Maternity and Child Health Hospital, Zhuhai, China
| | - Li-Chao Yang
- Department of Basic Medical Science, Medical College of Xiamen University, Xiamen, China
| | - Jun Wang
- Department of Radiation Oncology, Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jia-Yuan Sun
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Wen-Wen Zhang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Zhen-Yu He
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - San-Gang Wu
- Department of Radiation Oncology, Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University, Xiamen, China
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Yan J, Jiang F, Zhang R, Xu T, Zhou Z, Ren W, Peng D, Liu Y, Hu C, Jia W. Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10. J Mol Cell Biol 2018; 9:376-383. [PMID: 28992123 DOI: 10.1093/jmcb/mjx039] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 08/18/2017] [Indexed: 12/28/2022] Open
Abstract
Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0.09% of cases. Intracellular trafficking of insulin proteins was assessed in INS1-E and HEK293T cells. p.Ala2Thr preproinsulin-GFP was markedly retained in the endoplasmic reticulum (ER) in INS1-E cells. Activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in INS responsible for maturity-onset diabetes of the young 10 (MODY10) in a Chinese population and demonstrated that this mutation affected β cell function by inducing ER stress.
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Affiliation(s)
- Jing Yan
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Feng Jiang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Tongfu Xu
- The Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China
| | - Zhou Zhou
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Ren
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Danfeng Peng
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Liu
- The Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Plengvidhya N, Chanprasert C, Chongjaroen N, Yenchitsomanus PT, Homsanit M, Tangjittipokin W. Impact of KCNQ1, CDKN2A/2B, CDKAL1, HHEX, MTNR1B, SLC30A8, TCF7L2, and UBE2E2 on risk of developing type 2 diabetes in Thai population. BMC MEDICAL GENETICS 2018; 19:93. [PMID: 29871606 PMCID: PMC5989367 DOI: 10.1186/s12881-018-0614-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 05/23/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several type 2 diabetes (T2D) susceptibility loci identified via genome-wide association studies were found to be replicated among various populations. However, the influence of these loci on T2D in Thai population is unknown. The aim of this study was to investigate the influence of eight single nucleotide polymorphisms (SNPs) reported in GWA studies on T2D and related quantitative traits in Thai population. METHODS Eight SNPs in or near the KCNQ1, CDKN2A/2B, SLC30A8, HHEX, CDKAL1, TCF7L2, MTNR1B, and UBE2E2 genes were genotyped. A case-control association study comprising 500 Thai patients with T2D and 500 ethnically-matched control subjects was conducted. Associations between SNPs and T2D were examined by logistic regression analysis. The impact of these SNPs on quantitative traits was examined by linear regression among case and control subjects. RESULTS Five SNPs in KCNQ1 (rs2237892), CDK2A/2B (rs108116610, SLC30A8 (rs13266634), TCF7L2 (rs7903146) and MTNR1B (rs1387153) were found to be marginally associated with risk of developing T2D, with odds ratios ranging from 1.43 to 2.02 (p = 0.047 to 3.0 × 10-4) with adjustments for age, sex, and body mass index. Interestingly, SNP rs13266634 of SLC30A8 gene reached statistical significance after correcting for multiple testing (p = 0.0003) (p < 0.006 after Bonferroni correction). However, no significant association was detected between HHEX (rs1111875), CDKAL1 (rs7756992), or UBE2E2 (rs7612463) and T2D. We also observed association between rs10811661 and both waist circumference and waist-hip ratio (p = 0.007 and p = 0.023, respectively). In addition, rs13266634 in SLC30A8 was associated with glycated hemoglobin (p = 0.018), and rs7903146 in TCF7L2 was associated with high-density lipoprotein cholesterol level (p = 0.023). CONCLUSION Of the eight genes included in our analysis, significant association was observed between KCNQ1, CDKN2A/2B, SLC30A8, TCF7L2, and MTNR1B loci and T2D in our Thai study population. Of these, CDKN2A/2B, SLC30A8, and TCF7L2 genes were also significantly associated with anthropometric, glycemic and lipid characteristics. Larger cohort studies and meta-analyses are needed to further confirm the effect of these variants in Thai population.
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Affiliation(s)
- Nattachet Plengvidhya
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chutima Chanprasert
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Research Division, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nalinee Chongjaroen
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-thai Yenchitsomanus
- Siriraj Center of Research Excellence for Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Mayuree Homsanit
- Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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The Effects of Structured Exercise or Lifestyle Behavior Interventions on Long-Term Physical Activity Level and Health Outcomes in Individuals With Type 2 Diabetes: A Systematic Review, Meta-Analysis, and Meta-Regression. J Phys Act Health 2018; 15:697-707. [PMID: 29741425 DOI: 10.1123/jpah.2017-0589] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Systematically evaluate the effects of structured exercise and behavioral intervention (physical activity [PA] alone/PA + diet) on long-term PA in type 2 diabetes. METHODS Systematic search of 11 databases (inception to March, 2017). Randomized controlled trials investigating structured exercise/behavioral interventions in type 2 diabetes reporting PA outcomes ≥6 months were selected. RESULTS Among 107,797 citations retrieved, 23 randomized controlled trials (including 18 behavioral programs and 5 structured exercise) met inclusion criteria (n = 9640, 43.6% men, age = 60.0 (4.0) y). All structured exercise trials demonstrated increased objective PA outcomes relative to control (pooling was inappropriate; I2 = 92%). Of 18 behavioral interventions, 10 increased PA significantly, with effect sizes ranging from 0.2 to 6.6 (pooling was inappropriate; I2 = 96%). After removing 1 outlier, the remaining 17 studies significantly improved PA (pooled effect size = 0.34), although smaller compared with structured exercise. After removing the outlier, meta-regression also revealed significant direct relationships between total contacts (r = .50, P < .01) and more face-to-face counseling (r = .75, P < .001) and increased PA. However, long-term changes in PA and HbA1c were not related. CONCLUSION Both structured exercise and behavioral interventions increased PA in type 2 diabetes, although effect sizes were larger for supervised exercise. The effectiveness of behavioral programs was improved when delivery included more extensive and face-to-face contact.
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Hu C, Jia W. Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication. Diabetes 2018; 67:3-11. [PMID: 29263166 DOI: 10.2337/dbi17-0013] [Citation(s) in RCA: 254] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/03/2017] [Indexed: 12/15/2022]
Abstract
The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.
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Affiliation(s)
- Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, People's Republic of China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
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Dong F, Zhang BH, Zheng SL, Huang XX, Du XB, Zhu KH, Chen XJ, Wu J, Liu DD, Wen ZH, Zou XQ, Liu YM, Dong SR, Zeng FF, Yang G, Jing CX. Association Between SLC30A8 rs13266634 Polymorphism and Risk of T2DM and IGR in Chinese Population: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2018; 9:564. [PMID: 30319545 PMCID: PMC6167413 DOI: 10.3389/fendo.2018.00564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 09/04/2018] [Indexed: 12/18/2022] Open
Abstract
Introduction: Published data regarding the association between solute carrier family 30, member 8 (SLC30A8) rs13266634 polymorphism and type 2 diabetes mellitus (T2DM) and impaired glucose regulation (IGR) risks in Chinese population are in-consistent. The purpose of this meta-analysis was to evaluate the association between SLC30A8 rs13266634 and T2DM/IGR in a Chinese population. Material and Methods: Three English (PubMed, Embase, and Web of Science) and three Chinese databases (Wanfang, CNKI, and CBMD database) were used for searching articles from January 2005 to January 2018. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated with the random-effect model. Trial sequential analysis was also utilized. Results: Twenty-eight case-control studies with 25,912 cases and 26,975 controls were included for SLC30A8 and T2DM. Pooled risk allele C frequency for rs13266634 was 60.6% (95%CI: 59.2-62.0%) in the T2DM group and 54.8% (95%CI: 53.2-56.4%) in the control group which had estimated OR of 1.23 (95%CI: 1.17-1.28). Individuals who carried major homozygous CC and heterozygous CT genotype were at 1.51 and 1.23 times higher risk of T2DM, respectively, than those carrying minor homozygous TT. The most appropriate genetic analysis model was the co-dominant model based on comparison of OR1, OR2 and OR3. Five articles that involved 4,627 cases and 6,166 controls were included for SLC30A8 and IGR. However, no association was found between SLC30A8 rs13266634 and IGR (C vs. T, OR = 1.13, 95%CI: 0.98-1.30, p = 0.082). TSA revealed that the pooled sample sizes of T2DM exceeded the estimated required information size but not the IGR. Conclusion: The present meta-analysis demonstrated that SLC30A8 rs13266634 was a potential risk factor for T2DM, and more studies should be performed to confirm the association between rs13266634 polymorphism and IGR.
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Affiliation(s)
- Fang Dong
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
- Department of Information and Statistics, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Bao-huan Zhang
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Shao-ling Zheng
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiu-xia Huang
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiu-ben Du
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Ke-hui Zhu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiao-jing Chen
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Jing Wu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Dan-dan Liu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Zi-hao Wen
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiao-qian Zou
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Yu-mei Liu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Shi-rui Dong
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Fang-fang Zeng
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
- *Correspondence: Fang-fang Zeng
| | - Guang Yang
- Department of Pathogenic Biology, School of Medicine, Jinan University, Guangzhou, China
- Guangzhou Key Laboratory of Environmental Exposure and Health, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, China
- Guang Yang
| | - Chun-xia Jing
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
- Guangzhou Key Laboratory of Environmental Exposure and Health, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, China
- Chun-xia Jing
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Kodama S, Fujihara K, Ishiguro H, Horikawa C, Ohara N, Yachi Y, Tanaka S, Shimano H, Kato K, Hanyu O, Sone H. Quantitative Relationship Between Cumulative Risk Alleles Based on Genome-Wide Association Studies and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. J Epidemiol 2017; 28:3-18. [PMID: 29093303 PMCID: PMC5742374 DOI: 10.2188/jea.je20160151] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-ΔRA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-ΔRA was 1.16 (95% confidence interval [CI], 1.13–1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08–1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-ΔRA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.
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Affiliation(s)
- Satoru Kodama
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Niigata University Graduate School of Medical and Dental Sciences
| | - Kazuya Fujihara
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Hajime Ishiguro
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Chika Horikawa
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture
| | - Nobumasa Ohara
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Yoko Yachi
- Department of Administrative Dietetics, Faculty of Health and Nutrition, Yamanashi Gakuin University
| | - Shiro Tanaka
- Department of Clinical Trial, Design & Management, Translational Research Center, Kyoto University Hospital
| | - Hitoshi Shimano
- Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine
| | - Kiminori Kato
- Department of Laboratory Medicine and Clinical Epidemiology for Prevention of Noncommunicable Niigata University Graduate School of Medical and Dental Sciences
| | - Osamu Hanyu
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine
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Nikitin AG, Potapov VY, Brovkina OI, Koksharova EO, Khodyrev DS, Philippov YI, Michurova MS, Shamkhalova MS, Vikulova OK, Smetanina SA, Suplotova LA, Kononenko IV, Kalashnikov VY, Smirnova OM, Mayorov AY, Nosikov VV, Averyanov AV, Shestakova MV. Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population. PeerJ 2017; 5:e3414. [PMID: 28717589 PMCID: PMC5511504 DOI: 10.7717/peerj.3414] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/14/2017] [Indexed: 01/11/2023] Open
Abstract
Background The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. Methods The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-β were used to measure insulin resistance and β-cell secretory function, respectively. Results The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired β-cell function. Conclusion In the Russian population, genes, which affect insulin synthesis and secretion in the β-cells of the pancreas, play a central role in the development of T2DM.
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Affiliation(s)
- Aleksey G Nikitin
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | - Viktor Y Potapov
- Clinic of New Medical Technologies "Archimedes", Moscow, Russian Federation
| | - Olga I Brovkina
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | | | - Dmitry S Khodyrev
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | | | | | | | - Olga K Vikulova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | | | | | - Irina V Kononenko
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | | | - Olga M Smirnova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Alexander Y Mayorov
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Valery V Nosikov
- State Research Institute of Genetics and Selection of Industrial Microorganisms, Moscow, Russian Federation
| | - Alexander V Averyanov
- Federal Research Clinical Center for Specialized Types of Health Care and Medical Technologies of Federal Medical and Biology Agency, Moscow, Russian Federation
| | - Marina V Shestakova
- Endocrinology Research Centre, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Association of the type 2 diabetes mellitus susceptibility gene (IGF2BP2) with schizophrenia in an Egyptian sample. MIDDLE EAST CURRENT PSYCHIATRY 2017. [DOI: 10.1097/01.xme.0000513071.88010.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Yang Y, Liu B, Xia W, Yan J, Liu HY, Hu L, Liu SM. FTO Genotype and Type 2 Diabetes Mellitus: Spatial Analysis and Meta-Analysis of 62 Case-Control Studies from Different Regions. Genes (Basel) 2017; 8:E70. [PMID: 28208657 PMCID: PMC5333059 DOI: 10.3390/genes8020070] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 02/06/2017] [Accepted: 02/07/2017] [Indexed: 02/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a global health problem that results from the interaction of environmental factors with genetic variants. Although a number of studies have suggested that genetic polymorphisms in the fat mass and obesity-associated (FTO) gene are associated with T2DM risk, the results have been inconsistent. To investigate whether FTO polymorphisms associate with T2DM risk and whether this association is region-related, we performed this spatial analysis and meta-analysis. More than 60,000 T2DM patients and 90,000 controls from 62 case-control studies were included in this study. Odds ratios (ORs), 95% confidence intervals (CIs) and Moran's I statistic were used to estimate the association between FTO rs9939609, rs8050136, rs1421085, and rs17817499, and T2DM risk in different regions. rs9939609 (OR = 1.15, 95% CI 1.11-1.19) and rs8050136 (OR = 1.14, 95% CI 1.10-1.18) conferred a predisposition to T2DM. After adjustment for body mass index (BMI), the association remained statistically significant for rs9939609 (OR = 1.11, 95% CI 1.05-1.17) and rs8050136 (OR = 1.08, 95% CI 1.03-1.12). In the subgroup analysis of rs9939609 and rs8050136, similar results were observed in East Asia, while no association was found in North America. In South Asia, an association for rs9939609 was revealed but not for rs8050136. In addition, no relationship was found with rs1421085 or rs17817499 regardless of adjustment for BMI. Moran's I statistic showed that significant positive spatial autocorrelations existed in rs9939609 and rs8050136. Studies on rs9939609 and rs8050136 focused on East Asia and South Asia, whereas studies on rs1421085 and rs17817499 were distributed in North America and North Africa. Our data suggest that the associations between FTO rs9939609, rs8050136 and T2DM are region-related, and the two single-nucleotide polymorphisms contribute to an increased risk of T2DM. Future studies should investigate this issue in more regions.
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Affiliation(s)
- Ying Yang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Donghu Road 169#, Wuhan 430071, China.
| | - Boyang Liu
- Department of Geography, Wilkeson Hall, State University of New York at Buffalo, Buffalo, NY 14261, USA.
| | - Wei Xia
- Department of Clinical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, China.
| | - Jing Yan
- Hubei Meteorological Information and Technology Support Center, Wuhan 430074, China.
| | - Huan-Yu Liu
- Department of Clinical Medicine, Hubei University of Medicine, Hubei 442000, China.
| | - Ling Hu
- Department of Neurology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, China.
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Donghu Road 169#, Wuhan 430071, China.
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Type 2 Diabetes Susceptibility in the Greek-Cypriot Population: Replication of Associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 Polymorphisms. Genes (Basel) 2017; 8:genes8010016. [PMID: 28067832 PMCID: PMC5295011 DOI: 10.3390/genes8010016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/13/2016] [Accepted: 12/30/2016] [Indexed: 01/17/2023] Open
Abstract
Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing a replication case-control study. One thousand and eighteen individuals (528 T2D patients, 490 controls) were genotyped at 21 T2D susceptibility loci, using the allelic discrimination method. Statistically significant associations of T2D with five of the tested single nucleotide polymorphisms (SNPs) (TCF7L2 rs7901695, FTO rs8050136, HHEX rs5015480, SLC30A8 rs13266634 and IGF2BP2 rs4402960) were observed in this study population. Furthermore, 14 of the tested SNPs had odds ratios (ORs) in the same direction as the previously published studies, suggesting that these variants can potentially be used in the Greek-Cypriot population for predictive testing of T2D. In conclusion, our findings expand the genetic assessment of T2D susceptibility loci and reconfirm five of the worldwide established loci in a distinct, relatively small, newly investigated population.
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Chang W. Non-coding RNAs and Berberine: A new mechanism of its anti-diabetic activities. Eur J Pharmacol 2017; 795:8-12. [DOI: 10.1016/j.ejphar.2016.11.055] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 12/20/2022]
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Affiliation(s)
- Weiping Jia
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory for Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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Zhang Y, Chen H, Lu H, Shen Y, Chen R, Fang P, Du X, Bao Y, Wang C, Jia W. Prevalence and risk of diabetes based on family history in the Shanghai High-Risk Diabetic Screen (SHiDS) study. Diabet Med 2016; 33:1705-1711. [PMID: 26511673 DOI: 10.1111/dme.13013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 09/08/2015] [Accepted: 10/26/2015] [Indexed: 12/26/2022]
Abstract
AIMS To evaluate the prevalence and risk of diabetes based on family history in high-risk subjects and also to evaluate insulin sensitivity and insulin secretion in these subjects. METHODS Data were analysed from 9756 participants in the Shanghai High-Risk Diabetic Screen (SHiDS) Project. Family history of diabetes was classified according to parental and sibling diabetes status. The prevalence and odds ratios were calculated for each grouping after adjusting for other risk factors. Insulin resistance and sensitivity were evaluated using oral glucose tolerance test-derived indices that were validated by hyperinsulinaemic-euglycaemic and hyperglycaemic clamps. RESULTS A total of 30.4% of the subjects had a family history of diabetes in a first-degree relative. The proportions of subjects with a father, mother or sibling with diabetes were 7.5, 11.9 and 5.5%, respectively. The prevalence rates of diabetes in subjects with sibling history, maternal history or paternal history of diabetes were 39.3, 38.3 and 36.4%, respectively. Sibling history was a strong risk factor for diabetes (odds ratio 1.53, 95% CI 1.27-1.84; P < 0.05). Insulin secretion was significantly lower in those with a maternal or sibling history of diabetes; however, insulin sensitivity was not significantly different among subjects with a family history of diabetes. CONCLUSIONS Sibling history of diabetes was more strongly associated with diabetes risk than parental history among high-risk subjects. Subjects with a sibling or maternal history of diabetes had significantly lower insulin secretion. Sibling history is an important and independent risk factor for diabetes even among multi-risk populations. Those with a sibling history of diabetes warrant intensive care and follow-up screening.
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Affiliation(s)
- Y Zhang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - H Chen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Centre of Diabetes, Shanghai Diabetes Institute, Shanghai, China
| | - H Lu
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Y Shen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - R Chen
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - P Fang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - X Du
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Y Bao
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - C Wang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - W Jia
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai, China
- The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Centre of Diabetes, Shanghai Diabetes Institute, Shanghai, China
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Khodyrev DS, Nikitin AG, Brovkin AN, Lavrikova EY, Lebedeva NO, Vikulova OK, Shamhalova MS, Shestakova MV, Mayorov MY, Potapov VA, Nosikov VV, Averyanov AV. The analysis of association between type 2 diabetes and polymorphic markers in the CDKAL1 gene and in the HHEX/IDE locus. RUSS J GENET+ 2016. [DOI: 10.1134/s1022795416110065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Quantitative assessment of genetic testing for type 2 diabetes mellitus based on findings of genome-wide association studies. Ann Epidemiol 2016; 26:816-818.e6. [PMID: 27751632 DOI: 10.1016/j.annepidem.2016.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 08/26/2016] [Accepted: 09/16/2016] [Indexed: 12/29/2022]
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