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Zeng Q, Liu J, Liu X, Liu N, Wu W, Watson RG, Zou D, Wei Y, Guo R. Association between genetic polymorphisms and gestational diabetes mellitus susceptibility in a Chinese population. Front Endocrinol (Lausanne) 2024; 15:1397423. [PMID: 39659616 PMCID: PMC11628248 DOI: 10.3389/fendo.2024.1397423] [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: 03/07/2024] [Accepted: 11/13/2024] [Indexed: 12/12/2024] Open
Abstract
Background Although the association between HHEX, IGF2BP2, and FTO polymorphisms and the risk of GDM has been investigated in several studies, the findings have been inconsistent across different populations. The study aimed to investigate the association between genetic polymorphisms and GDM risk in a Chinese population. Methods 502 control volunteers and 500 GDM patients were enrolled. IGF2BP2 rs11705701 and rs4402960, FTO rs9939609, and HHEX rs1111875 and rs5015480 were all genotyped using the SNPscan™ genotyping assay. The independent sample t-test, logistic regression, and chi-square test were used to assess the variations in genotype and allele and their relationships with the risk of GDM. The blood glucose level, gestational week of delivery, and newborn weight were compared using a one-way ANOVA. Results After adjusting for confounding factors, the results show that the rs1111875 heterozygous (OR=1.370; 95% CI: 1.040-1.805; P = 0.025) and overdominant (OR=1.373; 95% CI: 1.049-1.796; P = 0. 021) models are significantly associated with an increased risk of GDM, especially for the age ≥ 30 years group: heterozygote (OR=1.646; 95% CI: 1.118-2.423; P=0.012) and overdominant (OR=1.553; 95% CI: 1.064-2.266; P = 0.022) models. In the age ≥ 30 years, the rs5015480 overdominant model (OR=1.595; 95% CI: 1.034-2.459; P = 0.035) and the rs9939609 heterozygote model (OR=1.609; 95% CI: 1.016-2.550; P=0.043), allele (OR=1. 504; 95% CI: 1.006-2.248; P = 0.047), dominant model (OR=1.604; 95% CI: 1.026-2.505; P = 0.038), and overdominant model (OR=1.593; 95% CI: 1.007-2.520; P = 0.047) were associated with a significantly increased risk of GDM; Additionally, people with the TC genotype of rs1111875 had a substantially higher 1-hour blood glucose level than TT genotype (P < 0.05). The results of the meta-analysis showed that the A allele of rs11705701 was associated with an increased risk of diabetes mellitus (P < 0.05). Conclusion The study indicates that the TC genotype of rs1111875 is linked to a higher risk of GDM, particularly in women aged 30 years or older. Additionally, rs5015480 and rs9939609 were significantly associated with GDM in the same age group. These SNPs may therefore be more closely linked to GDM in older mothers.
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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, Guangdong, China
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, China
- Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Jia Liu
- Department of Internal Medicine, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, China
- Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Xin Liu
- Department of Internal Medicine, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, China
- Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Na Liu
- Department of Pediatrics, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Weibiao Wu
- Medical Genetics Laboratory, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Ray Gyan Watson
- Department of Internal Medicine, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, China
- Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
| | - Dehua Zou
- School of Pharmacy, Macau University of Science and Technology, Macao, Macao SAR, China
- Guangdong Engineering Research Center of Chinese Medicine and Disease Susceptibility, Jinan University, Guangzhou, Guangdong, China
| | - Yue Wei
- Department of Ultrasound, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, 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, Guangdong, China
- Key Laboratory of Research in Maternal and Child Medicine and Birth Defects, Guangdong Medical University, Foshan, Guangdong, China
- Matenal and Child Research Institute, Shunde Women and Children’s Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan), Guangdong Medical University, Foshan, Guangdong, China
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Nadia SN, Hasib M, Hasan I, Saba AA, Sayem M, Ebihara A, Hasan AM, Nabi AN. Genetic analyses of truncated variant rs200185429 in ZNT8 encoding SLC30A8 gene with respect to prediabetes and type 2 diabetes in Bangladeshi population. ENDOCRINE AND METABOLIC SCIENCE 2024; 16:100189. [DOI: 10.1016/j.endmts.2024.100189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
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Guo J, Zhang C, Zhao H, Yan Y, Liu Z. The key mediator of diabetic kidney disease: Potassium channel dysfunction. Genes Dis 2024; 11:101119. [PMID: 38523672 PMCID: PMC10958065 DOI: 10.1016/j.gendis.2023.101119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 06/11/2022] [Accepted: 06/04/2023] [Indexed: 03/26/2024] Open
Abstract
Diabetic kidney disease is a leading cause of end-stage renal disease, making it a global public health concern. The molecular mechanisms underlying diabetic kidney disease have not been elucidated due to its complex pathogenesis. Thus, exploring these mechanisms from new perspectives is the current focus of research concerning diabetic kidney disease. Ion channels are important proteins that maintain the physiological functions of cells and organs. Among ion channels, potassium channels stand out, because they are the most common and important channels on eukaryotic cell surfaces and function as the basis for cell excitability. Certain potassium channel abnormalities have been found to be closely related to diabetic kidney disease progression and genetic susceptibility, such as KATP, KCa, Kir, and KV. In this review, we summarized the roles of different types of potassium channels in the occurrence and development of diabetic kidney disease to discuss whether the development of DKD is due to potassium channel dysfunction and present new ideas for the treatment of DKD.
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Affiliation(s)
- Jia Guo
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Chaojie Zhang
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Hui Zhao
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Yufan Yan
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
| | - Zhangsuo Liu
- Nephrology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan 450052, China
- Research Center for Kidney Disease, Zhengzhou, Henan 450052, China
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Yang Z, Wang YE, Kirschke CP, Stephensen CB, Newman JW, Keim NL, Cai Y, Huang L. Effects of a genetic variant rs13266634 in the zinc transporter 8 gene (SLC30A8) on insulin and lipid levels before and after a high-fat mixed macronutrient tolerance test in U.S. adults. J Trace Elem Med Biol 2023; 77:127142. [PMID: 36827808 DOI: 10.1016/j.jtemb.2023.127142] [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: 10/25/2022] [Revised: 02/02/2023] [Accepted: 02/17/2023] [Indexed: 02/21/2023]
Abstract
BACKGROUND The common C-allele of rs13266634 (c.973C>T or p.Arg325Trp) in SLC30A8 (ZNT8) is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variant with insulin and glucose metabolism, the effects of this variant on insulin and lipid responses after a lipid challenge in humans remain elusive. The goal of this study was to determine whether the C-allele had an impact on an individual's risk to metabolic syndromes in U.S. adults. METHOD We studied the genotypes of rs13266634 in 349 individuals aged between 18 and 65 y with BMI ranging from 18.5 to 45 kg/m2. The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a high-fat mixed macronutrient tolerance test (MMTT). RESULTS We found that the effects of variants rs13266634 on glucose and lipid metabolism were sex-dimorphic, greater impact on males than on females. Insulin incremental area under the curve (AUC) after MMTT was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting non-esterified fatty acid (NEFA) concentrations. On the other hand, the TT genotype was associated with a slower triglyceride removal from the circulation in men after MMTT. The reduced triglyceride removal was also observed in subjects with BMI ≥ 30 carrying either the heterozygous or homozygous T-allele. Nevertheless, the SNP had little effect on fasting or postprandial blood glucose and cholesterol concentrations. CONCLUSION We conclude that the CC genotype negatively affects insulin response after MMTT while the T-allele may negatively influence lipolysis during fasting and postprandial blood triglyceride removal in men and obese subjects, a novel finding in this study.
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Affiliation(s)
- Zhongyue Yang
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA
| | - Yining E Wang
- USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA
| | - Catherine P Kirschke
- USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA
| | - Charles B Stephensen
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA; USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA
| | - John W Newman
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA; USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA
| | - Nancy L Keim
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA; USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA
| | - Yimeng Cai
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA; Department of Pathology and Laboratory Medicine, University of California at Davis, 2805 50th Street, Sacramento, CA 95817, USA
| | - Liping Huang
- Graduate Group of Nutritional Biology, Department of Nutrition, University of California at Davis, One Shields Ave., Davis, CA 95616, USA; USDA/ARS/Western Human Nutrition Research Center, 430 West Health Sciences Drive, Davis, CA 95616, USA.
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Evidence that the pituitary gland connects type 2 diabetes mellitus and schizophrenia based on large-scale trans-ethnic genetic analyses. J Transl Med 2022; 20:501. [PMID: 36329495 PMCID: PMC9632150 DOI: 10.1186/s12967-022-03704-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/05/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Previous studies on European (EUR) samples have obtained inconsistent results regarding the genetic correlation between type 2 diabetes mellitus (T2DM) and Schizophrenia (SCZ). A large-scale trans-ethnic genetic analysis may provide additional evidence with enhanced power. OBJECTIVE We aimed to explore the genetic basis for both T2DM and SCZ based on large-scale genetic analyses of genome-wide association study (GWAS) data from both East Asian (EAS) and EUR subjects. METHODS A range of complementary approaches were employed to cross-validate the genetic correlation between T2DM and SCZ at the whole genome, autosomes (linkage disequilibrium score regression, LDSC), loci (Heritability Estimation from Summary Statistics, HESS), and causal variants (MiXeR and Mendelian randomization, MR) levels. Then, genome-wide and transcriptome-wide cross-trait/ethnic meta-analyses were performed separately to explore the effective shared organs, cells and molecular pathways. RESULTS A weak genome-wide negative genetic correlation between SCZ and T2DM was found for the EUR (rg = - 0.098, P = 0.009) and EAS (rg =- 0.053 and P = 0.032) populations, which showed no significant difference between the EUR and EAS populations (P = 0.22). After Bonferroni correction, the rg remained significant only in the EUR population. Similar results were obtained from analyses at the levels of autosomes, loci and causal variants. 25 independent variants were firstly identified as being responsible for both SCZ and T2DM. The variants associated with the two disorders were significantly correlated to the gene expression profiles in the brain (P = 1.1E-9) and pituitary gland (P = 1.9E-6). Then, 61 protein-coding and non-coding genes were identified as effective genes in the pituitary gland (P < 9.23E-6) and were enriched in metabolic pathways related to glutathione mediated arsenate detoxification and to D-myo-inositol-trisphosphate. CONCLUSION Here, we show that a negative genetic correlation exists between SCZ and T2DM at the whole genome, autosome, locus and causal variant levels. We identify pituitary gland as a common effective organ for both diseases, in which non-protein-coding effective genes, such as lncRNAs, may be responsible for the negative genetic correlation. This highlights the importance of molecular metabolism and neuroendocrine modulation in the pituitary gland, which may be responsible for the initiation of T2DM in SCZ patients.
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Zhao K, Nie L, Chin GMJ, Ye X, Sun P. Association between fat mass and obesity-related variant and osteoarthritis risk: Integrated meta-analysis with bioinformatics. Front Med (Lausanne) 2022; 9:1024750. [PMID: 36213660 PMCID: PMC9537627 DOI: 10.3389/fmed.2022.1024750] [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: 08/22/2022] [Accepted: 09/02/2022] [Indexed: 11/29/2022] Open
Abstract
Objective The association of fat mass and obesity-related (FTO) gene with osteoarthritis (OA) risk has been investigated in multiple genome-wide association studies but showed inconsistent results. Our study aimed to assess FTO expression in different OA sequencing datasets and to meta-analyze whether FTO polymorphism was associated with the risk of osteoarthritis. Method Gene expression profiles were obtained from ArrayExpress, Gene Expression Omnibus (GEO), and BioProject databases. Three electronic databases including PubMed and EMBASE were systematically retrieved to identify articles exploring the association between FTO polymorphisms and OA risk published before September 2022. Summary odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated to perform the result. Stata software was utilized to conduct analyses on predetermined ethnicity and gender subgroups and sensitivity. Results FTO gene was differentially expressed in the datasets from the UK. This systematic review and meta-analysis encompasses eight studies that revealed a significant association between FTO polymorphisms and OA risk [OR 1.07, 95% CI (1.03, 1.11), P < 0.001] in the overall population. In subgroup analysis, a marked association was observed in European Caucasian [OR 1.08, 95% CI (1.04–1.12), P < 0.001] and North American Caucasian with the Asian subgroups [OR 0.98, 95% CI (0.83–1. 6), P = 0.83] as an exception. Among the studies, four of them demonstrated attenuation in their OA risk after body mass index (BMI) adjustment in Caucasian populations. Conclusion FTO significant differential expression was associated with the increased risk of OA in Caucasian populations. Nevertheless, the causality between FTO polymorphisms and OA risk remains largely elusive. Hence, further studies with larger sample size are necessary to validate whether FTO gene polymorphism contributes to OA susceptibility.
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Affiliation(s)
- Kun Zhao
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Liuyan Nie
- Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Grace Min Jun Chin
- Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, China
| | - Xiangming Ye
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Peng Sun
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation and Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Peng Sun,
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Paz-Pacheco E, Nevado JB, Cutiongco-de la Paz EMC, Jasul GV, Aman AYCL, Ribaya ELA, Francisco MDG, Guanzon MLVV, Uyking-Naranjo ML, Añonuevo-Cruz MCS, Maningat MPDD, Jaring CV, Nacpil-Dominguez PD, Pala-Mohamad AB, Canto AU, Quisumbing JPM, Lat AMM, Bernardo DCC, Mansibang NMM, Calpito KJAC, Ribaya VSD, Ferrer JPY, Biwang JH, Melegrito JB, Deguit CDT, Panerio CEG. Variants of SLC2A10 may be Linked to Poor Response to Metformin. J Endocr Soc 2022; 6:bvac092. [PMID: 35854978 PMCID: PMC9278830 DOI: 10.1210/jendso/bvac092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Indexed: 12/05/2022] Open
Abstract
Purpose A study among Filipinos revealed that only 15% of patients with diabetes achieved glycemic control, and poor response to metformin could be one of the possible reasons. Recent studies demonstrate how genetic variations influence response to metformin. Hence, the present study aimed to determine genetic variants associated with poor response to metformin. Methods Using a candidate variant approach, 195 adult Filipino participants with newly diagnosed type 2 diabetes mellitus (T2DM) were enrolled in a case-control study. Genomic DNA from blood samples were collected. Allelic and genotypic associations of variants with poor response to metformin were determined using exact statistical methods. Results Several polymorphisms were nominally associated with poor response to metformin (Puncorr < 0.05). The most notable is the association of multiple variants in the SLC2A10 gene—rs2425911, rs3092412, and rs2425904—with common additive genetic mode of inheritance. Other variants that have possible associations with poor drug response include rs340874 (PROX-AS1), rs815815 (CALM2), rs1333049 (CDKN2B-AS1), rs2010963 (VEGFA), rs1535435 and rs9494266 (AHI1), rs11128347 (PDZRN3), rs1805081 (NPC1), and rs13266634 (SLC30A8). Conclusion In Filipinos, a trend for the association for several variants was noted, with further observation that several mechanisms may be involved. The results may serve as pilot data for further validation of candidate variants for T2DM pharmacotherapy.
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Affiliation(s)
- Elizabeth Paz-Pacheco
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Jose B Nevado
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | | | - Gabriel V Jasul
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | | | - Elizabeth Laurize A Ribaya
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Mark David G Francisco
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Ma Luz Vicenta V Guanzon
- Corazon Locsin Montelibano Memorial Regional Hospital, Bacolod City, Negros Occidental, Philippines
| | | | - Ma Cecille S Añonuevo-Cruz
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Maria Patricia Deanna D Maningat
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Cristina V Jaring
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Paulette D Nacpil-Dominguez
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Aniza B Pala-Mohamad
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Abigail U Canto
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - John Paul M Quisumbing
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Annabelle Marie M Lat
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Diane Carla C Bernardo
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | - Noemie Marie M Mansibang
- Division of Endocrinology, Diabetes and Metabolism, Philippine General Hospital, University of the Philippines Manila, Philippines
| | | | - Vincent Sean D Ribaya
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Julius Patrick Y Ferrer
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Jessica H Biwang
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Jodelyn B Melegrito
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Christian Deo T Deguit
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
| | - Carlos Emmanuel G Panerio
- Institutes of Human Genetics, National Institutes of Health, University of the Philippines Manila, Philippines
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Alfaifi M. Contribution of genetic variant identified in HHEX gene in the overweight Saudi patients confirmed with type 2 diabetes mellitus. Saudi J Biol Sci 2022; 29:804-808. [PMID: 35197747 PMCID: PMC8847961 DOI: 10.1016/j.sjbs.2021.10.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/13/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022] Open
Abstract
Background The rs7932837 polymorphism in the Hematopoietically expressed homeobox (HHEX) gene was discovered through genome-wide association studies and is a promising candidate for type 2 diabetes mellitus (T2DM), which is one of the risk factors for obesity and other complications. T2DM has been identified as a heterogeneous and multifactorial disease characterized by insulin resistance and secretion. Aim The aim of this study was to investigate the rs7932837 polymorphism in the HHEX gene in overweight patients diagnosed with T2DM in the Saudi Population. Methods In this case-control study, one hundred T2DM cases and 100 controls were selected based on inclusion and exclusion criteria. Genotyping was performed with polymerase chair reaction-restriction fragment length polymorphism analysis and statistical analysis was performed between T2DM cases and controls for clinical characteristics, genotype and allele frequencies and multiple logistic regression analysis. Results In this study, T2DM cases were compared with healthy control subjects. Clinical characteristic analysis revealed the statistical analysis between age, weight, BMI, FBG, HDL-c, TC, TG and family history (p < 0.05). HWE analysis was in the accordance (p < 0.05). The rs7932837 polymorphism in the recessive model showed the positive association (AA + AG vs AA: 2.22 [1.25–3.96] & p = 0.006) and none of the genotypes or alleles were in the statistical association. Multiple logistic regression analysis revealed positive association with age, BMI and FBG (p < 0.05). Conclusion This study concludes as rs7932837 polymorphism in the HHEX gene showed positive association with recessive model and future studies recommend to carry out with large number of sample size with additional polymorphisms in HHEX gene.
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Amin USM, Parvez N, Rahman TA, Hasan MR, Das KC, Jahan S, Hasanat MA, Seraj ZI, Salimullah M. CDKAL1 gene rs7756992 A/G and rs7754840 G/C polymorphisms are associated with gestational diabetes mellitus in a sample of Bangladeshi population: implication for future T2DM prophylaxis. Diabetol Metab Syndr 2022; 14:18. [PMID: 35090536 PMCID: PMC8796445 DOI: 10.1186/s13098-021-00782-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/30/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Association of single nucleotide polymorphisms (SNP) rs7756992 A/G and rs7754840 G/C of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene with the susceptibility of gestational diabetes mellitus (GDM) has been studied in a group of Bangladeshi women. METHODS In this case-control study, 212 GDM patients and 256 control subjects were genotyped for rs7756992 and rs7754840 by PCR-RFLP and TaqMan™ allelic discrimination assay method respectively. Genotyping results were confirmed by DNA sequencing and replicated TaqMan™ assay. The odds ratios and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and GDM. RESULTS The genotype frequencies of rs7756992-AA/AG/GG in the GDM group and the control group were 37%/48%, 53%/45%, 10%/7% and those of rs7754840-CC/CG/GG were 51%/55%, 40.1%/39.8%, 9%/5% respectively. Under dominant and log additive models rs7756992 was revealed significantly associated with GDM after being adjusted for family history of diabetes (FHD) and gravidity. Conversely, rs7754840 was significantly associated (P = 0.047) with GDM only under the recessive model after the same adjustment. The risk allele frequency of both SNPs was higher in the GDM group but significantly (P = 0.029) increased prevalence was observed in the rs7756992 G allele. When positive FHD and risk alleles of these SNPs were synergistically present in any pregnant woman, the chance of developing GDM was augmented by many folds. The codominant model revealed 2.5 and 2.1 folds increase in odds by AG (rs7756992) and GC (rs7754840) genotypes and 3.7 and 4.5 folds by GG (rs7756992) and CC (rs7754840) genotypes respectively. A significant 2.7 folds (P = 0.038) increase in odds of GDM resulted from the interaction of rs7756992 and family history of diabetes under the dominant model. The cumulative effect of multigravidity and risk alleles of these SNPs increased the odds of GDM more than 1.5 folds in different genotypes. CONCLUSION This study not only revealed a significant association between rs7756992 and rs7754840 with GDM but also provided the possibility as potential markers for foretelling about GDM and type 2 diabetes mellitus in Bangladeshi women.
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Affiliation(s)
- U S Mahzabin Amin
- Molecular Biotechnology Division, National Institute of Biotechnology (NIB), Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh
| | - Nahid Parvez
- Molecular Biotechnology Division, National Institute of Biotechnology (NIB), Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh
| | - Tahia Anan Rahman
- Molecular Biotechnology Division, National Institute of Biotechnology (NIB), Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh
| | - Md Rakibul Hasan
- Department of Endocrinology and Metabolism, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Keshob Chandra Das
- Molecular Biotechnology Division, National Institute of Biotechnology (NIB), Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh
| | - Sharmin Jahan
- Department of Endocrinology and Metabolism, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Muhammad Abul Hasanat
- Department of Endocrinology and Metabolism, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
| | - Zeba I Seraj
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Md Salimullah
- Molecular Biotechnology Division, National Institute of Biotechnology (NIB), Ganakbari, Ashulia, Savar, Dhaka, 1349, Bangladesh.
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10
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Leite LCG, Dos Santos MC, Duarte NE, Horimoto ARVR, Crispim F, Vieira Filho JPB, Dal Fabbro AL, Franco LJ, Moises RS. Association of fat mass and obesity-associated (FTO) gene rs9939609 with obesity-related traits and glucose intolerance in an indigenous population, the Xavante. Diabetes Metab Syndr 2022; 16:102358. [PMID: 34920192 DOI: 10.1016/j.dsx.2021.102358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 11/02/2021] [Accepted: 11/30/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND AND AIMS Common variants in fat mass and obesity-associated (FTO) gene have been implicated as a susceptibility locus for obesity and type 2 diabetes in different populations. Here, in an indigenous population-based study, we examined whether FTO rs9939609 has a role in susceptibility to glucose intolerance and obesity. METHODS The study population comprised 949 full Xavante indigenous people (465 men) aged 18-99 years. The participants were submitted to clinical examination, anthropometrical measures and basal and 2-h post 75g oral glucose load capillary glucose measurements. FTO rs9939609 was genotyped and logistic regression was carried out to test the additive effect of the risk allele. RESULTS The frequency of the minor allele of the FTO rs9939609 (0.06) was lower in Xavante than observed in some populations. A significant association between the variant and overweight was observed (OR = 1.56 (95% CI:1.06-2.29, p = 0.02), using an additive model of inheritance, adjusted by age and gender and considering the family structure. We found no associations with obesity or glucose intolerance. CONCLUSIONS The FTO rs9939609 is associated with overweight, but not with obesity or glucose intolerance. The low frequency of the A allele suggests that it is not an important risk determinant for these conditions in Xavante indigenous people.
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Affiliation(s)
- Lanna C G Leite
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
| | - Marcia C Dos Santos
- Division of Endocrinology, Faculdade de Medicina, Instituto de Ciências da Saúde,Universidade Federal Do Pará, Belém, PA, Brazil
| | - Nubia E Duarte
- Departamento de Matemáticas y Estadística, Universidad Nacional de Colombia, Manizales, Caldas, Colombia
| | - Andrea R V R Horimoto
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, United States
| | - Felipe Crispim
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - João Paulo B Vieira Filho
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Amaury L Dal Fabbro
- Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Laércio J Franco
- Department of Social Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Regina S Moises
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil
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11
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Izaola-Jáuregui O, Primo-Martín D, López JJ, de Luis-Román DA. The risk variant of CDKAL1 (rs7756992) impairs fasting glucose levels and insulin resistance improvements after a partial meal-replacement hypocaloric diet. ENDOCRINOL DIAB NUTR 2021; 68:548-556. [PMID: 34872638 DOI: 10.1016/j.endien.2020.08.017] [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: 12/30/2019] [Accepted: 08/27/2020] [Indexed: 06/13/2023]
Abstract
BACKGROUND The CDKAL1 (CDK5 Regulatory Subunit Associated Protein 1 Like 1) gene encodes cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated proten1 like 1. This protein has been shown to contribute to the glucose-dependent regulation of insulin secretion in pancreatic islets. AIMS The aim of our study was to analyze the effects of the rs7756992 genetic variant of CDKAL1 gene on fasting glucose and insulin resistance after weight loss secondary to partial meal replacement hypocaloric diet (pMRHD). METHODS This was a non-randomized, single-treatment study with a formula-diet in 44 obese subjects. The patients received nutritional education and a modified diet with two intakes of a normocaloric hyperproteic formula for 3-months. Anthropometric parameter and biochemical profile were measured at basal time and after 3 months. The variant of CDKAL1 gene rs7756992 was assessed. RESULTS The following genetic distribution was observed; [27AA (61.3%), 12 AG (27.3%) and 5 GG (11.4%)]. After the pMRHD, body weight, the body mass index (BMI), fat mass, waist circumference and blood pressure decreased in both genotypes. Non-G allele carriers showed a significant improvement in fasting glucose levels (AA vs. AG + GG) (-6.1 ± 1.4 md/dl vs. -1.2 ± 0.7 mg/dl; p = 0.01), fasting insulin levels (-3.6 ± 0.2 mU/l vs. -1.3 ± 0.6 mU/l; p = 0.02) and HOMA-IR (-1.2 ± 0.2 units vs. -0.3 ± 0.2 units; p = 0.01). Fasting plasma glucose levels were higher in G allele carriers than non G allele carriers. CONCLUSIONS Our data suggest that the genetic variant (rs7756992) of CDKAL1 gene is associated with glycaemic status after a pMRHD, with greater improvements in fasting glucose, insulin and HOMA-IR in subjects without the G allele.
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Affiliation(s)
- Olatz Izaola-Jáuregui
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - David Primo-Martín
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - Juan José López
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain
| | - Daniel Antonio de Luis-Román
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
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12
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Cao J, Yan W, Ma X, Huang H, Yan H. Insulin-like Growth Factor 2 mRNA-Binding Protein 2-a Potential Link Between Type 2 Diabetes Mellitus and Cancer. J Clin Endocrinol Metab 2021; 106:2807-2818. [PMID: 34061963 PMCID: PMC8475209 DOI: 10.1210/clinem/dgab391] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Indexed: 12/12/2022]
Abstract
CONTEXT Type 2 diabetes mellitus (T2DM) and cancer share a variety of risk factors and pathophysiological features. It is becoming increasingly accepted that the 2 diseases are related, and that T2DM increases the risk of certain malignancies. OBJECTIVE This review summarizes recent advancements in the elucidation of functions of insulin-like growth factor 2 (IGF-2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) in T2DM and cancer. METHODS A PubMed review of the literature was conducted, and search terms included IGF2BP2, IMP2, or p62 in combination with cancer or T2DM. Additional sources were identified through manual searches of reference lists. The increased risk of multiple malignancies and cancer-associated mortality in patients with T2DM is believed to be driven by insulin resistance, hyperinsulinemia, hyperglycemia, chronic inflammation, and dysregulation of adipokines and sex hormones. Furthermore, IGF-2 is oncogenic, and its loss-of-function splice variant is protective against T2DM, which highlights the pivotal role of this growth factor in the pathogenesis of these 2 diseases. IGF-2 mRNA-binding proteins, particularly IGF2BP2, are also involved in T2DM and cancer, and single-nucleotide variations (formerly single-nucleotide polymorphisms) of IGF2BP2 are associated with both diseases. Deletion of the IGF2BP2 gene in mice improves their glucose tolerance and insulin sensitivity, and mice with transgenic p62, a splice variant of IGF2BP2, are prone to diet-induced fatty liver disease and hepatocellular carcinoma, suggesting the biological significance of IGF2BP2 in T2DM and cancer. CONCLUSION Accumulating evidence has revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis. This review provides insight into the potential involvement of this RNA binding protein in the link between T2DM and cancer.
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Affiliation(s)
- Junguo Cao
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
- Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg 69120, Germany
| | - Weijia Yan
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
| | - Xiujian Ma
- Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Haiyan Huang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130000, China
| | - Hong Yan
- Shaanxi Eye Hospital (Xi’an People’s Hospital), Affiliated Guangren Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 71004, Shaanxi Province, China
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13
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Yin XY, Chen P, Zhu HW, Yin XL, Ye G, Chi YY, Kang ZP, Sun HY, Hou WL, Guan LY, Zhu ZH, Tang Z, Wang J, Zhang GY, Jia QF, Hui L. The type 2 diabetes mellitus susceptibility gene CDKAL1 polymorphism is associated with depressive symptom in first-episode drug-naive schizophrenic patients. Hum Psychopharmacol 2021; 36:e2790. [PMID: 33856697 DOI: 10.1002/hup.2790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Patients with schizophrenia have an increased prevalence of type 2 diabetes mellitus that has shown a significant association with the rs7754840 polymorphism in the gene encoding the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1). OBJECTIVE To examine whether this polymorphism was involved in the susceptibility in first-episode drug-naive schizophrenic patients (FDSP), and further influenced their clinical symptoms. METHODS This polymorphism was genotyped in 239 FDSP and 368 healthy controls. The clinical symptoms in FDSP were assessed using the Positive and Negative Syndrome Scale (PANSS) five-factor models. RESULTS There was no significant difference in the allelic and genotypic frequencies of this polymorphism between two groups (both p > 0.05) after adjusting for covariates. However, the PANSS depressive score significantly differed by genotype in FDSP after adjusting for covariates (F = 5.25, p = 0.006). This significant difference also persisted after Bonferroni correction (p < 0.05). FDSP with C/C genotype had significantly higher PANSS depressive score than those with C/G genotype (p = 0.007) and those with G/G genotype (p = 0.005). Moreover, further stepwise multivariate regression analysis showed the significant association between the rs7754840 polymorphism and PANSS depressive score in FDSP (β = -1.07, t = -2.75, p = 0.007). CONCLUSIONS Our findings demonstrated that although the CDKAL1 rs7754840 polymorphism did not contribute to the susceptibility to FDSP, it might be implicated in depressive symptoms in this patient group.
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Affiliation(s)
- Xu Yuan Yin
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Peng Chen
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Hai Wen Zhu
- Department of Laboratory Medicine, Suzhou Municipal Hospital North, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, PR China
| | - Xiao Li Yin
- Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Gang Ye
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Yu Yan Chi
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Zhao Peng Kang
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Hong Yan Sun
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Wen Long Hou
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Lu Yang Guan
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Zhen Hua Zhu
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Zhen Tang
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Jing Wang
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Guang Ya Zhang
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Qiu Fang Jia
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
| | - Li Hui
- Research Center of Biological Psychiatry, Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Soochow Unversity, Suzhou, Jiangsu, PR China
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14
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Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels and is influenced by both genetic and environmental factors. It is treated with various classes of oral antidiabetic drugs, however, response to treatment is highly variable with patients failing to achieve adequate glycemic control. Treatment response variability has been associated with single nucleotide polymorphisms (SNPs) which influence the pharma-cokinetics and pharmacodynamics of drug(s). The aim of this study was to evaluate the genetic association of 17 SNPs and the response to metformin therapy in patients diagnosed with diabetes from the indigenous Nguni population of South Africa. One hundred and forty indigenous African patients diagnosed with T2DM were recruited and genotyped using the MassARRAY® system. Therapeutic response of patients was ascertained by a change in Hb A1c. Two SNPs (rs1801282 and rs6265) were monomorphic. All other variants were within the Hardy-Weinberg equilibrium (HWE). The T allele of the SLC variant rs316009 [odds ratio (OR) = 0.25, 95% confidence interval (95% CI) = 0.01-0.09, p value = 0.044] and the CT genotype of the PCK1 variant rs4810083 (OR = 2.80, 95% CI = 1.01-7.79, p value = 0.049) were associated with an improved response to treatment after adjustment. No association was observed with post Bonferroni correction. Moreover, this study provides important additional data regarding possible associations between genetic variants and metformin therapy outcomes. In addition, this is one of the first studies providing genetic data from the understudied indigenous sub-Saharan African populations.
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15
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Zapater JL, Lednovich KR, Layden BT. The Role of Hexokinase Domain Containing Protein-1 in Glucose Regulation During Pregnancy. Curr Diab Rep 2021; 21:27. [PMID: 34232412 PMCID: PMC8867521 DOI: 10.1007/s11892-021-01394-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/28/2021] [Indexed: 01/22/2023]
Abstract
PURPOSE OF REVIEW Gestational diabetes mellitus (GDM) is a common pregnancy complication conferring an increased risk to the individual of developing type 2 diabetes. As such, a thorough understanding of the pathophysiology of GDM is warranted. Hexokinase domain containing protein-1 (HKDC1) is a recently discovered protein containing hexokinase activity which has been shown to be associated with glucose metabolism during pregnancy. Here, we discuss recent evidence suggesting roles for the novel HKDC1 in gestational glucose homeostasis and the development of GDM and overt diabetes. RECENT FINDINGS Genome-wide association studies identified variants of the HKDC1 gene associated with maternal glucose metabolism. Studies modulating HKDC1 protein expression in pregnant mice demonstrate that HKDC1 has roles in whole-body glucose utilization and nutrient balance, with liver-specific HKDC1 influencing insulin sensitivity, glucose tolerance, gluconeogenesis, and ketone production. HKDC1 has important roles in maintaining maternal glucose homeostasis extending beyond traditional hexokinase functions and may serve as a potential therapeutic target.
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Affiliation(s)
- Joseph L Zapater
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Kristen R Lednovich
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Brian T Layden
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA.
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16
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Xu J, Wijesekara N, Regeenes R, Rijjal DA, Piro AL, Song Y, Wu A, Bhattacharjee A, Liu Y, Marzban L, Rocheleau JV, Fraser PE, Dai FF, Hu C, Wheeler MB. Pancreatic β cell-selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis. JCI Insight 2021; 6:143037. [PMID: 34027899 PMCID: PMC8262350 DOI: 10.1172/jci.insight.143037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 04/21/2021] [Indexed: 01/25/2023] Open
Abstract
GWAS have shown that the common R325W variant of SLC30A8 (ZnT8) increases the risk of type 2 diabetes (T2D). However, ZnT8 haploinsufficiency is protective against T2D in humans, counterintuitive to earlier work in humans and mouse models. Therefore, whether decreasing ZnT8 activity is beneficial or detrimental to β cell function, especially under conditions of metabolic stress, remains unknown. In order to examine whether the existence of human islet amyloid polypeptide (hIAPP), a coresident of the insulin granule, affects the role of ZnT8 in regulating β cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B+/– hIAPP) or null ZnT8 (ZnT8B–/– hIAPP) expression specifically in β cells. We showed that ZnT8B–/– hIAPP mice on a high-fat diet had intensified amyloid deposition and further impaired glucose tolerance and insulin secretion compared with control, ZnT8B–/–, and hIAPP mice. This can in part be attributed to impaired glucose sensing and islet cell synchronicity. Importantly, ZnT8B+/– hIAPP mice were also glucose intolerant and had reduced insulin secretion and increased amyloid aggregation compared with controls. These data suggest that loss of or reduced ZnT8 activity in β cells heightened the toxicity induced by hIAPP, leading to impaired β cell function and glucose homeostasis associated with metabolic stress.
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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, Shanghai, China.,Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Nadeeja Wijesekara
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto Western Hospital, Toronto, Ontario Canada
| | - Romario Regeenes
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Dana Al Rijjal
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Anthony L Piro
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Youchen Song
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Anne Wu
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Alpana Bhattacharjee
- Division of Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto General Hospital, Toronto, Ontario, Canada
| | - Ying Liu
- Division of Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto General Hospital, Toronto, Ontario, Canada
| | - Lucy Marzban
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jonathan V Rocheleau
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.,Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Paul E Fraser
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto Western Hospital, Toronto, Ontario Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Feihan F Dai
- Department of Physiology, University of Toronto, Toronto, Ontario, 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, Shanghai, China.,Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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17
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Izaola-Jáuregui O, Primo-Martín D, López JJ, de Luis-Román DA. The risk variant of CDKAL1 (rs7756992) impairs fasting glucose levels and insulin resistance improvements after a partial meal-replacement hypocaloric diet. ENDOCRINOL DIAB NUTR 2021; 68:S2530-0164(21)00038-0. [PMID: 33965365 DOI: 10.1016/j.endinu.2020.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND The CDKAL1 (CDK5 Regulatory Subunit Associated Protein 1 Like 1) gene encodes cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated proten1 like 1. This protein has been shown to contribute to the glucose-dependent regulation of insulin secretion in pancreatic islets. AIMS The aim of our study was to analyze the effects of the rs7756992 genetic variant of CDKAL1 gene on fasting glucose and insulin resistance after weight loss secondary to partial meal replacement hypocaloric diet (pMRHD). METHODS This was a non-randomized, single-treatment study with a formula-diet in 44 obese subjects. The patients received nutritional education and a modified diet with two intakes of a normocaloric hyperproteic formula for 3-months. Anthropometric parameter and biochemical profile were measured at basal time and after 3 months. The variant of CDKAL1 gene rs7756992 was assessed. RESULTS The following genetic distribution was observed; [27AA (61.3%), 12 AG (27.3%) and 5 GG (11.4%)]. After the pMRHD, body weight, the body mass index (BMI), fat mass, waist circumference and blood pressure decreased in both genotypes. Non-G allele carriers showed a significant improvement in fasting glucose levels (AA vs. AG + GG) (-6.1 ± 1.4 md/dL vs. -1.2 ± 0.7 mg/dl; p = 0.01), fasting insulin levels (-3.6 ± 0.2 mU/L vs. -1.3 ± 0.6 mU/L; p = 0.02) and HOMA-IR (-1.2 ± 0.2 units vs. -0.3 ± 0.2 units; p = 0.01). Fasting plasma glucose levels were higher in G allele carriers than non G allele carriers. CONCLUSIONS Our data suggest that the genetic variant (rs7756992) of CDKAL1 gene is associated with glycaemic status after a pMRHD, with greater improvements in fasting glucose, insulin and HOMA-IR in subjects without the G allele.
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Affiliation(s)
- Olatz Izaola-Jáuregui
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid. Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - David Primo-Martín
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid. Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - Juan José López
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid. Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - Daniel Antonio de Luis-Román
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valladolid. Centro de Investigación de Endocrinología y Nutrición Clínica, Facultad de Medicina, Universidad de Valladolid, Valladolid, España.
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Wang J, Chen L, Qiang P. The role of IGF2BP2, an m6A reader gene, in human metabolic diseases and cancers. Cancer Cell Int 2021; 21:99. [PMID: 33568150 PMCID: PMC7876817 DOI: 10.1186/s12935-021-01799-x] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
The human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) is an RNA-binding protein that regulates multiple biological processes. Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene. Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases such as diabetes, obesity and fatty liver through post-transcriptional regulation of numerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 is an N6-methyladenosine (m6A) reader that participates in the development and progression of cancers by communicating with different RNAs such as microRNAs (miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Additionally, IGF2BP2 is an independent prognostic factor for multiple cancer types. In this review, we summarize the current knowledge on IGF2BP2 with regard to diverse human metabolic diseases and its potential for cancer prognosis.
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Affiliation(s)
- Jinyan Wang
- Department of Oncology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, China.,The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Lijuan Chen
- Department of Gynecology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, 215600, Jiangsu, People's Republic of China.
| | - Ping Qiang
- Department of Gynecology, Zhangjiagang First People's Hospital, Zhangjiagang Affiliated Hospital of Soochow University, Zhangjiagang, 215600, Jiangsu, People's Republic of China.
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19
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Ruan D, Zhuang Z, Ding R, Qiu Y, Zhou S, Wu J, Xu C, Hong L, Huang S, Zheng E, Cai G, Wu Z, Yang J. Weighted Single-Step GWAS Identified Candidate Genes Associated with Growth Traits in a Duroc Pig Population. Genes (Basel) 2021; 12:genes12010117. [PMID: 33477978 PMCID: PMC7835741 DOI: 10.3390/genes12010117] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 12/17/2022] Open
Abstract
Growth traits are important economic traits of pigs that are controlled by several major genes and multiple minor genes. To better understand the genetic architecture of growth traits, we performed a weighted single-step genome-wide association study (wssGWAS) to identify genomic regions and candidate genes that are associated with days to 100 kg (AGE), average daily gain (ADG), backfat thickness (BF) and lean meat percentage (LMP) in a Duroc pig population. In this study, 3945 individuals with phenotypic and genealogical information, of which 2084 pigs were genotyped with a 50 K single-nucleotide polymorphism (SNP) array, were used for association analyses. We found that the most significant regions explained 2.56–3.07% of genetic variance for four traits, and the detected significant regions (>1%) explained 17.07%, 18.59%, 23.87% and 21.94% for four traits. Finally, 21 genes that have been reported to be associated with metabolism, bone growth, and fat deposition were treated as candidate genes for growth traits in pigs. Moreover, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses implied that the identified genes took part in bone formation, the immune system, and digestion. In conclusion, such full use of phenotypic, genotypic, and genealogical information will accelerate the genetic improvement of growth traits in pigs.
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Affiliation(s)
- Donglin Ruan
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Zhanwei Zhuang
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Rongrong Ding
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Yibin Qiu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Shenping Zhou
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Jie Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Cineng Xu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Linjun Hong
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Sixiu Huang
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Enqin Zheng
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Gengyuan Cai
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
| | - Zhenfang Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
- Correspondence: (Z.W.); (J.Y.)
| | - Jie Yang
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (D.R.); (Z.Z.); (R.D.); (Y.Q.); (S.Z.); (J.W.); (C.X.); (L.H.); (S.H.); (E.Z.); (G.C.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
- Correspondence: (Z.W.); (J.Y.)
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20
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Li Y, He S, Li C, Shen K, Yang M, Tao W, Yang Y, Shi L, Yao Y. Evidence of association between single-nucleotide polymorphisms in lipid metabolism-related genes and type 2 diabetes mellitus in a Chinese population. Int J Med Sci 2021; 18:356-363. [PMID: 33390804 PMCID: PMC7757135 DOI: 10.7150/ijms.53004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/09/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Type 2 diabetes mellitus (T2DM) is a complex chronic metabolic disorder triggered by insulin resistance in peripheral tissues. Evidence has shown that lipid metabolism and related genetic factors lead to insulin resistance. Hence, it is meaningful to investigate the association between single-nucleotide polymorphisms (SNPs) in lipid metabolism-related genes and T2DM. Methods: A total of 1,194 subjects with T2DM and 1,274 Non-diabetic subjects (NDM) were enrolled. Five SNPs in three genes (rs864745 in JAZF1, rs35767 in IGF1, and rs4376068, rs4402960, and rs6769511 in IGF2BP2) that contribute to insulin resistance involving lipid metabolism were genotyped using the MassArray method in a Chinese population. Results: The allele and genotypes of rs6769511 in IGF2BP2 were associated with T2DM (P=0.009 and P=0.002, respectively). In inheritance model analysis, compared with the T/T-C/T genotype, the C/C genotype of rs6769511 in IGF2BP2 was a risk factor for the development of T2DM (P<0.001, odds ratio [OR] =1.76; 95% confidence interval [CI]: 1.29-2.42). Haplotype analysis revealed associations of the rs4376068-rs4402960-rs6769511 haplotypes in IGF2BP2 with the development of T2DM (P=0.015). Additionally, rs4376068C-rs4402960T-rs6769511C was a risk haplotype for T2DM (OR=1.179; 95% CI: 1.033-1.346). Conclusion: The rs6769511 in IGF2BP2 was associated with T2DM susceptibility, and the rs4376068-rs4402960-rs6769511 haplotypes in IGF2BP2 was associated with the development of T2DM in a Chinese population.
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Affiliation(s)
- Yiping Li
- Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province & The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China
| | - Siqi He
- Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province & The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China.,Dali University, Dali 671000, Yunnan, China
| | - Chuanyin Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Keyu Shen
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Man Yang
- Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province & The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China
| | - Wenyu Tao
- Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province & The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China
| | - Ying Yang
- Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province & The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
| | - Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, Yunnan, China
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Jan A, Saeed M, Afridi MH, Khuda F, Shabbir M, Khan H, Ali S, Hassan M, Akbar R. Association of HLA-B Gene Polymorphisms with Type 2 Diabetes in Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan. J Diabetes Res 2021; 2021:6669731. [PMID: 34258292 PMCID: PMC8254654 DOI: 10.1155/2021/6669731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 04/20/2021] [Accepted: 06/07/2021] [Indexed: 11/26/2022] Open
Abstract
Human leukocyte antigen (HLA) system is the most polymorphic and gene dense region of human DNA that has shown many disease associations. It has been further divided into HLA classes I, II, and III. Polymorphism in HLA class II genes has been reported to play an important role in the pathogenesis of type 1 diabetes (T1D). It also showed association with T2D in different ethnic populations. However, a little is known about the relationship of HLA class I gene polymorphism and T2D. This study has evaluated the association of HLA-B (class I gene) variants with T2D in Pashtun ethnic population of Khyber Pakhtunkhwa. In the first phase of the study, whole exome sequencing (WES) of 2 pooled DNA samples was carried out, and DNA pools used were constructed from 100 diabetic cases and 100 control subjects. WES results identified a total of n = 17 SNPs in HLA-B gene. In the next phase, first 5 out of n = 17 reported SNPs were genotyped using MassARRAY® system in order to validate WES results and to confirm association of selected SNPs with T2D. Minor allele frequencies (MAFs) and selected SNPs×T2D association were determined using chi-square test and logistic regression analysis. The frequency of minor C allele was significantly higher in the T2D group as compared to control group (45.0% vs. 13.0%) (p = 0.006) for rs2308655 in HLA-B gene. No significant difference in MAF distribution between cases and controls was observed for rs1051488, rs1131500, rs1050341, and rs1131285 (p > 0.05). Binary logistic regression analyses showed significant results for SNP rs2308655 (OR = 2.233, CI (95%) = 1.223-4.077, and p = 0.009), while no considerable association was observed for the other 4 SNPs. However, when adjusted for these variants, the association of rs2308655 further strengthened significantly (adjusted OR = 7.485, CI (95%) = 2.353-23.812, and p = 0.001), except for rs1131500, which has no additive effect. In conclusion, the finding of this study suggests rs2308655 variant in HLA-B gene as risk variant for T2D susceptibility in Pashtun population.
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Affiliation(s)
- Asif Jan
- Department of Pharmacy, University of Peshawar, Pakistan
| | - Muhammad Saeed
- Department of Pharmacy, University of Peshawar, Pakistan
| | | | - Fazli Khuda
- Department of Pharmacy, University of Peshawar, Pakistan
| | - Muhammad Shabbir
- Internal Medicine, College of Medicine, Shaqra University, Saudi Arabia
| | - Hamayun Khan
- Department of Pharmacy, University of Peshawar, Pakistan
| | - Sajid Ali
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan
| | | | - Rani Akbar
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
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22
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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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Liju S, Chidambaram M, Mohan V, Radha V. Impact of type 2 diabetes variants identified through genome-wide association studies in early-onset type 2 diabetes from South Indian population. Genomics Inform 2020; 18:e27. [PMID: 33017871 PMCID: PMC7560451 DOI: 10.5808/gi.2020.18.3.e27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
The prevalence of early-onset type 2 diabetes (EOT2D) is increasing in Asian countries. Genome-wide association studies performed in European and various other populations have identified associations of numerous variants with type 2 diabetes in adults. However, the genetic component of EOT2D which is still unexplored could have similarities with late-onset type 2 diabetes. Here in the present study we aim to identify the association of variants with EOT2D in South Indian population. Twenty-five variants from 18 gene loci were genotyped in 1,188 EOT2D and 1,183 normal glucose tolerant subjects using the MassARRAY technology. We confirm the association of the HHEX variant rs1111875 with EOT2D in this South Indian population and also the association of CDKN2A/2B (rs7020996) and TCF7L2 (rs4506565) with EOT2D. Logistic regression analyses of the TCF7L2 variant rs4506565(A/T), showed that the heterozygous and homozygous carriers for allele ‘T’ have odds ratios of 1.47 (95% confidence interval [CI], 1.17 to 1.83; p = 0.001) and 1.65 (95% CI, 1.18 to 2.28; p = 0.006) respectively, relative to AA homozygote. For the HHEX variant rs1111875 (T/C), heterozygous and homozygous carriers for allele ‘C’ have odds ratios of 1.13 (95% CI, 0.91 to 1.42; p = 0.27) and 1.58 (95% CI, 1.17 to 2.12; p = 0.003) respectively, relative to the TT homozygote. For CDKN2A/2B variant rs7020996, the heterozygous and homozygous carriers of allele ‘C’ were protective with odds ratios of 0.65 (95% CI, 0.51 to 0.83; p = 0.0004) and 0.62 (95% CI, 0.27 to 1.39; p = 0.24) respectively, relative to TT homozygote. This is the first study to report on the association of HHEX variant rs1111875 with EOT2D in this population.
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Affiliation(s)
- Samuel Liju
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
| | - Manickam Chidambaram
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
| | - Viswanathan Mohan
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India.,Dr. Mohan's Diabetes Specialties Centre, ICMR Centre for Diabetes Advanced Research and WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, Chennai 600086, India
| | - Venkatesan Radha
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
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Cho HW, Jin HS, Eom YB. The interaction between FTO rs9939609 and physical activity is associated with a 2-fold reduction in the risk of obesity in Korean population. Am J Hum Biol 2020; 33:e23489. [PMID: 32865273 DOI: 10.1002/ajhb.23489] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/29/2020] [Accepted: 07/29/2020] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE FTO (fat mass and obesity-associated) gene is a well-known genetic risk factor for obesity. We investigated whether physical activity modulates the effect of FTO rs9939609 on obesity in Korean population. METHODS The study analyzed the correlation between physical activity and obesity in 8840 individuals representing the Korea Association Resource (KARE). The association between obesity-related traits and single-nucleotide polymorphisms (SNPs) was assessed using linear regression models. Physical activity was defined as 3 hours or more of daily intense activity. RESULTS Participants carrying rs9939609 (AT+AA) genotypes showed higher BMI compared with those carrying the wild-type (TT) homozygote. The highest significant association was observed between obesity-related traits (ß = .334, P value = 1.76 × 10-6 ). FTO rs9939609 (AT+AA) increased the risk of obesity (OR = 1.42, CI [1.13-1.79]), which was correlated with BMI correlations. However, active exercise by subjects carrying the same genotype reduced the risk of obesity by nearly 2-fold (OR = 0.62, CI [0.25-0.84]). In contrast, TT genotype was not statistically significant in reducing the risk of obesity in the active exercise group. CONCLUSIONS Our results support a previous finding correlating FTO and obesity-related traits and suggest that the interaction with genetic variation and physical activity is an important risk factor for obesity.
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Affiliation(s)
- Hye-Won Cho
- Department of Medical Sciences, College of Medical Sciences, Soonchunhyang University, Asan, Republic of Korea
| | - Hyun-Seok Jin
- Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Republic of Korea
| | - Yong-Bin Eom
- Department of Medical Sciences, College of Medical Sciences, Soonchunhyang University, Asan, Republic of Korea
- Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan, Republic of Korea
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Krentz NAJ, Gloyn AL. Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol 2020; 16:202-212. [PMID: 32099086 DOI: 10.1038/s41574-020-0325-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/17/2020] [Indexed: 12/30/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent multifactorial disease that has both genetic and environmental risk factors, resulting in impaired glucose homeostasis. Genome-wide association studies (GWAS) have identified over 400 genetic signals that are associated with altered risk of T2DM. Human physiology and epigenomic data support a central role for the pancreatic islet in the pathogenesis of T2DM. This Review focuses on the promises and challenges of moving from genetic associations to molecular mechanisms and highlights efforts to identify the causal variant and effector transcripts at T2DM GWAS susceptibility loci. In addition, we examine current human models that are used to study both β-cell development and function, including EndoC-β cell lines and human induced pluripotent stem cell-derived β-like cells. We use examples of four T2DM susceptibility loci (CDKAL1, MTNR1B, SLC30A8 and PAM) to emphasize how a holistic approach involving genetics, physiology, and cellular and developmental biology can disentangle disease mechanisms at T2DM GWAS signals.
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Affiliation(s)
- Nicole A J Krentz
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
| | - Anna L Gloyn
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
- Stanford Diabetes Research Centre, Stanford University, Stanford, CA, USA.
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Obesity-related loci in TMEM18, CDKAL1 and FAIM2 are associated with obesity and type 2 diabetes in Chinese Han patients. BMC MEDICAL GENETICS 2020; 21:65. [PMID: 32228543 PMCID: PMC7106578 DOI: 10.1186/s12881-020-00999-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 03/16/2020] [Indexed: 12/18/2022]
Abstract
Background Several obesity susceptibility loci in genes, including GNPDA2, SH2B1, TMEM18, MTCH2, CDKAL1, FAIM2, and MC4R, have been identified by genome-wide association studies. The purpose of this study was to investigate whether these loci are associated with the concurrence of obesity and type 2 diabetes in Chinese Han patients. Methods Using the SNaPshot technique, we genotyped seven single nucleotide polymorphisms (SNPs) in 439 Chinese patients living in Northeast China who presented at The Second Hospital of Jilin University. We analyzed the associations between these seven alleles and clinical characteristics. Results Risk alleles near TMEM18 (rs6548238) were associated with increased waist circumference, waist/hip ratio, body mass index (BMI), fasting plasma glucose, hemoglobin A1c, diastolic blood pressure, triglycerides, total cholesterol, and low-density lipoprotein-cholesterol; risk alleles of CDKAL1 (rs7754840) were associated with increased waist circumference and waist/hip ratio; and FAIM2 (rs7138803) risk alleles were linked to increased BMI, diastolic blood pressure, and triglycerides (all P < 0.05). After adjusting for sex and age, loci near TMEM18 (rs6548238) and FAIM2 (rs7138803), but not SH2B1 (rs7498665), near GNPDA2 (rs10938397), MTCH2 (rs10838738) and near MC4R (rs12970134), were associated with increased risk for type 2 diabetes in obese individuals. Conclusion We found that loci near TMEM18 (rs6548238), CDKAL1 (rs7754840), and FAIM2 (rs7138803) may be associated with obesity-related indicators, and loci near TMEM18 (rs6548238) and FAIM2 (rs7138803) may increase susceptibility of concurrent type 2 diabetes associated with obesity.
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Park S, Lee K, Park IB, Kim NH, Cho S, Rhee WJ, Oh Y, Choi J, Nam S, Lee DH. The profiles of microRNAs from urinary extracellular vesicles (EVs) prepared by various isolation methods and their correlation with serum EV microRNAs. Diabetes Res Clin Pract 2020; 160:108010. [PMID: 31987752 DOI: 10.1016/j.diabres.2020.108010] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/16/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022]
Abstract
AIMS MicroRNAs (miRNAs) that circulate in biological fluids are frequently enclosed in extracellular vesicles (EVs). However, urinary EVs and their cargo miRNAs have not been systematically studied according to their EV isolation methods. METHODS In type 2 diabetes mellitus persons with diabetic nephropathy (n = 4), we compared miRNA species in urine EVs prepared by ultracentrifugation (UC), qEV original size exclusion column (qEV), ExoQuick-TC Plus (ExoQuick), and ultrafiltration using Amicon Ultra centrifugal filter devices (Amicons) 10 K and 100 K. EV miRNAs were profiled by next-generation sequencing (NGS). Additionally, we evaluated the correlations of EV miRNA expression between the urine and serum samples isolated by UC. RESULTS From each of 100 ml of urine, the UC method yielded the highest number of EV miRNA species (233 ± 37.3), with the ExoQuick yielded the lowest (103 ± 17.4). Urine EV miRNA profiles were highly correlated between UC, qEV, ExoQuick and Amicon 10 K methods. EV miRNA profiles between the urine and serum samples showed variable correlations between the patients (paired sample number = 3, r = 0.39-0.72). CONCLUSIONS UC, qEV, ExoQuick, and Amicon 10 K are acceptable for urinary EV isolation to profile miRNAs. Urine- and serum-derived EV miRNA profiles have variable correlations depending on specific patients.
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Affiliation(s)
- Sungjin Park
- Department of Genome Medicine and Science, Gachon University College of Medicine, Incheon, Republic of Korea; Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | - Kiyoung Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Ie Byung Park
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seongcheol Cho
- Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea
| | - Won Jong Rhee
- Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea; Division of Bioengineering, Incheon National University, Incheon, Republic of Korea
| | - Yujin Oh
- Gachon Biomedical & Convergence Institute, Gachon University Lee Gil Ya Cancer and Diabetes Institute, Incheon, Republic of Korea
| | - Jimin Choi
- Gachon Biomedical & Convergence Institute, Gachon University Lee Gil Ya Cancer and Diabetes Institute, Incheon, Republic of Korea
| | - Seungyoon Nam
- Department of Genome Medicine and Science, Gachon University College of Medicine, Incheon, Republic of Korea; Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology, Gachon University, Incheon, Republic of Korea; Department of Life Sciences, Gachon University, Seongnam, Republic of Korea.
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; Department of Internal Medicine, Gachon University College of Medicine, Incheon, Republic of Korea; Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology, Gachon University, Incheon, Republic of Korea.
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Rosik J, Szostak B, Machaj F, Pawlik A. The role of genetics and epigenetics in the pathogenesis of gestational diabetes mellitus. Ann Hum Genet 2019; 84:114-124. [DOI: 10.1111/ahg.12356] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 09/07/2019] [Accepted: 09/09/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Jakub Rosik
- Department of Physiology Pomeranian Medical University Szczecin Poland
| | - Bartosz Szostak
- Department of Physiology Pomeranian Medical University Szczecin Poland
| | - Filip Machaj
- Department of Physiology Pomeranian Medical University Szczecin Poland
| | - Andrzej Pawlik
- Department of Physiology Pomeranian Medical University Szczecin Poland
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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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Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes. J Clin Med 2019; 8:jcm8030393. [PMID: 30901912 PMCID: PMC6463061 DOI: 10.3390/jcm8030393] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/17/2022] Open
Abstract
Precision medicine is a scientific and medical practice for personalized therapy based on patients’ individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.
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Modeling Heterogeneity in the Genetic Architecture of Ethnically Diverse Groups Using Random Effect Interaction Models. Genetics 2019; 211:1395-1407. [PMID: 30796011 PMCID: PMC6456318 DOI: 10.1534/genetics.119.301909] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 01/24/2019] [Indexed: 01/08/2023] Open
Abstract
In humans, most genome-wide association studies have been conducted using data from Caucasians and many of the reported findings have not replicated in other populations. This lack of replication may be due to statistical issues (small sample sizes or confounding) or perhaps more fundamentally to differences in the genetic architecture of traits between ethnically diverse subpopulations. What aspects of the genetic architecture of traits vary between subpopulations and how can this be quantified? We consider studying effect heterogeneity using Bayesian random effect interaction models. The proposed methodology can be applied using shrinkage and variable selection methods, and produces useful information about effect heterogeneity in the form of whole-genome summaries (e.g., the proportions of variance of a complex trait explained by a set of SNPs and the average correlation of effects) as well as SNP-specific attributes. Using simulations, we show that the proposed methodology yields (nearly) unbiased estimates when the sample size is not too small relative to the number of SNPs used. Subsequently, we used the methodology for the analyses of four complex human traits (standing height, high-density lipoprotein, low-density lipoprotein, and serum urate levels) in European-Americans (EAs) and African-Americans (AAs). The estimated correlations of effects between the two subpopulations were well below unity for all the traits, ranging from 0.73 to 0.50. The extent of effect heterogeneity varied between traits and SNP sets. Height showed less differences in SNP effects between AAs and EAs whereas HDL, a trait highly influenced by lifestyle, exhibited a greater extent of effect heterogeneity. For all the traits, we observed substantial variability in effect heterogeneity across SNPs, suggesting that effect heterogeneity varies between regions of the genome.
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32
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Zhao T, Huang Q, Su Y, Sun W, Huang Q, Wei W. Zinc and its regulators in pancreas. Inflammopharmacology 2019; 27:453-464. [PMID: 30756223 DOI: 10.1007/s10787-019-00573-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/02/2019] [Indexed: 12/12/2022]
Abstract
Studies have demonstrated that susceptibility to type 2 diabetes (T2D) is influenced by common polymorphism in the zinc transporter 8 gene SLC30A8, providing novel insight into the role of zinc in diabetes. Intriguingly, zinc participates in every step of the process, including insulin synthesis, crystallization, storage, secretion and signaling. Zinc deficiency or overload is associated with various disorders, such as diabetes, cardiovascular disease and obesity. Zinc supplementation is considered as an effective means of treating or preventing T2D in people with certain SLC30A8 genotypes. Three important protein families-zinc transporters (ZnTs), zinc importers (ZiPs) and metallothionein (MT)-participate in maintaining zinc homeostasis. Here, we review research on the physiological characteristics of zinc and its role in the pancreas and homeostasis regulation mechanisms, along with the latest research on the structure and function of ZnT/ZiP and MT. In addition, we summarize the advancements in research on SLC30A8 gene polymorphism in search of a mechanism to explain the relationship between the R risk allele and zinc transporter activity.
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Affiliation(s)
- Tianjiao Zhao
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Qiongfang Huang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Yangni Su
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Wuyi Sun
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Qiong Huang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
| | - Wei Wei
- Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei, 230032, 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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34
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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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35
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Johns EC, Denison FC, Norman JE, Reynolds RM. Gestational Diabetes Mellitus: Mechanisms, Treatment, and Complications. Trends Endocrinol Metab 2018; 29:743-754. [PMID: 30297319 DOI: 10.1016/j.tem.2018.09.004] [Citation(s) in RCA: 488] [Impact Index Per Article: 69.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 08/29/2018] [Accepted: 09/06/2018] [Indexed: 12/12/2022]
Abstract
Gestational diabetes mellitus (GDM) is the most common metabolic disturbance during pregnancy. The prevalence is rising and correlates with the increase in maternal obesity over recent decades. The etiology of GDM is complex, with genetic and environmental factors implicated in mechanistic and epidemiological studies. GDM begets important short- and long-term health risks for the mother, developing fetus, and offspring. This includes the high likelihood of subsequent maternal type 2 diabetes (T2DM), and possible adverse cardiometabolic phenotypes in the offspring. The most clinically and cost-effective methods of screening for GDM remain uncertain. Whilst treatments with lifestyle and pharmacological interventions have demonstrated short-term benefits, the long-term impact for the offspring of intrauterine exposure to antidiabetic medication remains unclear.
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MESH Headings
- Diabetes Complications/etiology
- Diabetes, Gestational/diagnosis
- Diabetes, Gestational/drug therapy
- Diabetes, Gestational/etiology
- Female
- Humans
- Hypertension, Pregnancy-Induced/etiology
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Infant, Newborn
- Infant, Newborn, Diseases/etiology
- Infant, Newborn, Diseases/metabolism
- Infant, Newborn, Diseases/pathology
- Infant, Newborn, Diseases/physiopathology
- Obstetric Labor Complications/etiology
- Pregnancy
- Prenatal Exposure Delayed Effects/chemically induced
- Prenatal Exposure Delayed Effects/metabolism
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Affiliation(s)
- Emma C Johns
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK
| | - Fiona C Denison
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK
| | - Jane E Norman
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK
| | - Rebecca M Reynolds
- Tommy's Centre for Maternal and Fetal Health, MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK; BHF/University Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
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Yokoyama N, Ishimura T, Oda T, Ogawa S, Yamamoto K, Fujisawa M. Association of the PCK2 Gene Polymorphism With New-onset Glucose Intolerance in Japanese Kidney Transplant Recipients. Transplant Proc 2018; 50:1045-1049. [PMID: 29731064 DOI: 10.1016/j.transproceed.2018.01.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 01/22/2018] [Indexed: 01/18/2023]
Abstract
BACKGROUND New-onset diabetes mellitus after transplantation (NODAT) is a risk factor for both cardiovascular disease and poor graft survival after kidney transplantation (KTx). In this study, we identified single-nucleotide polymorphisms (SNPs) in genes involved in glucose metabolism and examined the correlation between these SNPs and glucose intolerance after KTx. METHODS Thirty-eight patients with normal glucose tolerance before KTx were included in this study. Patients with plasma glucose levels of >140 mg/dL at 120 minutes on the 75-g oral glucose tolerance test at 1 year after KTx were classified as having new-onset impaired glucose tolerance (NIGT). We identified 8 SNPs in 7 genes that are involved in glucose metabolism among the patients included in this study, and compared the prevalence rate of NIGT among SNPs in each gene. RESULTS Of the 38 patients, 11 (28.9%) were diagnosed with NIGT. For rs4982856 in the PCK2 gene, the distribution of genotypes among the total patient population was as follows: T/T, 12 (31.6%); T/C, 22 (57.9%); and C/C, 4 (10.5%). Seven of 11 patients with NIGT had the T/T genotype of rs4982856, whereas only 5 of 27 patients with normal glucose tolerance had this genotype. The T allele frequency of the rs4982856 was significantly higher in the NIGT group than in the normal group (81.8 vs 52.8%, respectively; P = .015). CONCLUSION Our study indicates that the T allele of the rs4982856 SNP in the PCK2 gene may be a risk factor for glucose intolerance after KTx.
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Affiliation(s)
- N Yokoyama
- Division of Urology, Department of Surgery Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - T Ishimura
- Division of Urology, Department of Surgery Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - T Oda
- Division of Urology, Department of Surgery Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - S Ogawa
- Division of Urology, Department of Surgery Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - K Yamamoto
- Department of Pharmacy, Kobe University Hospital, Kobe, Japan
| | - M Fujisawa
- Division of Urology, Department of Surgery Related, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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FTO, GCKR, CDKAL1 and CDKN2A/B gene polymorphisms and the risk of gestational diabetes mellitus: a meta-analysis. Arch Gynecol Obstet 2018; 298:705-715. [PMID: 30074065 DOI: 10.1007/s00404-018-4857-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 07/28/2018] [Indexed: 01/11/2023]
Abstract
PURPOSE Studies had examined the associations between genetic polymorphisms and the risk of gestational diabetes mellitus (GDM). However, conclusions of these studies were controversial due to the smaller sample size and limited statistical power. We carried out a meta-analysis with the aim of providing a more comprehensive summary of the currently available research to evaluate the relationship between FTO, GCKR, CDKAL1 and CDKN2A/B gene polymorphisms and GDM risk. METHODS Literature search was carried out in the PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure and Wangfang databases up to November 2017. Data were extracted by two independent reviewers and statistical analyses were performed with STATA software. Pooled odds ratios and 95% confidence intervals were calculated by Z test to assess the association between genetic polymorphisms and GDM risk. Stratified analysis was performed based on ethnicity. Heterogeneity and publication bias between studies were evaluated by Cochran's Q test and Egger regression test, respectively. RESULTS 14 eligible studies were included. CDKAL1 rs7754840 and rs7756992 showed significant correlation with GDM risk under the allele, recessive, dominant, homozygote and heterozygote models. GCKR rs780094 and CDKN2A/B rs10811661 also showed the same association under the allele, recessive and heterozygote models. No associations between FTO rs9939609 and rs8050136, GCKR rs1260326 and GDM risk were found. CONCLUSIONS Our meta-analysis showed that two SNPs in particular(rs7754840 and rs7756992 in CDKAL1) were very strongly associated with GDM risk. GCKR rs780094 and CDKN2A/B rs10811661 polymorphisms were moderately associated with GDM risk.
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Dziewulska A, Dobosz AM, Dobrzyn A. High-Throughput Approaches onto Uncover (Epi)Genomic Architecture of Type 2 Diabetes. Genes (Basel) 2018; 9:E374. [PMID: 30050001 PMCID: PMC6115814 DOI: 10.3390/genes9080374] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/20/2018] [Accepted: 07/23/2018] [Indexed: 12/20/2022] Open
Abstract
Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.
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Affiliation(s)
- Anna Dziewulska
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland.
| | - Aneta M Dobosz
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland.
| | - Agnieszka Dobrzyn
- Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland.
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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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Ningombam SS, Rajkumari S, Chhungi V, Newmei MK, Devi NK, Mondal PR, Saraswathy KN. Type 2 diabetes and FTO rs9939609 gene polymorphism: a study among the two tribal population groups of Manipur, North East India. Int J Diabetes Dev Ctries 2018. [DOI: 10.1007/s13410-018-0634-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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The Roles of Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 in Cancer and Cancer Stem Cells. Stem Cells Int 2018; 2018:4217259. [PMID: 29736175 PMCID: PMC5874980 DOI: 10.1155/2018/4217259] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/12/2017] [Accepted: 01/04/2018] [Indexed: 12/14/2022] Open
Abstract
RNA-binding proteins (RBPs) mediate the localization, stability, and translation of the target transcripts and fine-tune the physiological functions of the proteins encoded. The insulin-like growth factor (IGF) 2 mRNA-binding protein (IGF2BP, IMP) family comprises three RBPs, IGF2BP1, IGF2BP2, and IGF2BP3, capable of associating with IGF2 and other transcripts and mediating their processing. IGF2BP2 represents the least understood member of this family of RBPs; however, it has been reported to participate in a wide range of physiological processes, such as embryonic development, neuronal differentiation, and metabolism. Its dysregulation is associated with insulin resistance, diabetes, and carcinogenesis and may potentially be a powerful biomarker and candidate target for relevant diseases. This review summarizes the structural features, regulation, and functions of IGF2BP2 and their association with cancer and cancer stem cells.
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Cyrus C, Ismail MH, Chathoth S, Vatte C, Hasen M, Al Ali A. Analysis of the Impact of Common Polymorphisms of theFTOandMC4RGenes with the Risk of Severe Obesity in Saudi Arabian Population. Genet Test Mol Biomarkers 2018; 22:170-177. [DOI: 10.1089/gtmb.2017.0218] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Affiliation(s)
- Cyril Cyrus
- Department of Genetic Research, Institute for Research and Medical Consultation, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mona H. Ismail
- Department of Internal Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Al-Khobar, Saudi Arabia
| | - Shahanas Chathoth
- Department of Genetic Research, Institute for Research and Medical Consultation, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Chittibabu Vatte
- Department of Genetic Research, Institute for Research and Medical Consultation, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Majd Hasen
- Department of Internal Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Al-Khobar, Saudi Arabia
| | - Amein Al Ali
- Department of Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Inferring genetic origins and phenotypic traits of George Bähr, the architect of the Dresden Frauenkirche. Sci Rep 2018; 8:2115. [PMID: 29391530 PMCID: PMC5794802 DOI: 10.1038/s41598-018-20180-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 01/11/2018] [Indexed: 12/25/2022] Open
Abstract
For historic individuals, the outward appearance and other phenotypic characteristics remain often non-resolved. Unfortunately, images or detailed written sources are only scarcely available in many cases. Attempts to study historic individuals with genetic data so far focused on hypervariable regions of mitochondrial DNA and to some extent on complete mitochondrial genomes. To elucidate the potential of in-solution based genome-wide SNP capture methods - as now widely applied in population genetics - we extracted DNA from the 17th century remains of George Bähr, the architect of the Dresdner Frauenkirche. We were able to identify the remains to be of male origin, showing sufficient DNA damage, deriving from a single person and being thus likely authentic. Furthermore, we were able to show that George Bähr had light skin pigmentation and most likely brown eyes. His genomic DNA furthermore points to a Central European origin. We see this analysis as an example to demonstrate the prospects that new in-solution SNP capture methods can provide for historic cases of forensic interest, using methods well established in ancient DNA (aDNA) research and population genetics.
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Sikhayeva N, Iskakova A, Saigi-Morgui N, Zholdybaeva E, Eap CB, Ramanculov E. Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study. BMC MEDICAL GENETICS 2017; 18:76. [PMID: 28738793 PMCID: PMC5525290 DOI: 10.1186/s12881-017-0443-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 07/13/2017] [Indexed: 02/06/2023]
Abstract
Background We evaluated the associations between single nucleotide polymorphisms and different clinical parameters related to type 2 diabetes mellitus (T2DM), obesity risk, and metabolic syndrome (MS) in a Kazakh cohort. Methods A total of 1336 subjects, including 408 T2DM patients and 928 control subjects, were recruited from an outpatient clinic and genotyped for 32 polymorphisms previously associated with T2DM and obesity-related phenotypes in other ethnic groups. For association studies, the chi-squared test or Fisher’s exact test for binomial variables were used. Logistic regression was conducted to explore associations between the studied SNPs and the risk of developing T2DM, obesity, and MS, after adjustments for age and sex. Results After excluding four SNPs due to Hardy-Weinberg disequilibrium, significant associations in age-matched cohorts were found betweenT2DM and the following SNPs: rs9939609 (FTO), rs13266634 (SLC30A8), rs7961581 (TSPAN8/LGR5), and rs1799883 (FABP2). In addition, examination of general unmatched T2DM and control cohorts revealed significant associations between T2DM and SNPsrs1799883 (FABP2) and rs9939609 (FTO). Furthermore, polymorphisms in the FTO gene were associated with increased obesity risk, whereas polymorphisms in the FTO and FABP2 genes were also associated with the risk of developing MS in general unmatched cohorts. Conclusion We confirmed associations between polymorphisms within the SLC30A8, TSPAN8/LGR5, FABP2, and FTO genes and susceptibility to T2DM in a Kazakh cohort, and revealed significant associations with anthropometric and metabolic traits. In particular, FTO and FABP2 gene polymorphisms were significantly associated with susceptibility to MS and obesity in this cohort. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0443-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nurgul Sikhayeva
- National Center for Biotechnology, 13/5 Korgalzhyn str, Astana, 010000, Kazakhstan. .,L.N. Gumilyov Eurasian National University, Astana, Kazakhstan.
| | - Aisha Iskakova
- National Center for Biotechnology, 13/5 Korgalzhyn str, Astana, 010000, Kazakhstan
| | - Nuria Saigi-Morgui
- Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly-Lausanne, Switzerland
| | - Elena Zholdybaeva
- National Center for Biotechnology, 13/5 Korgalzhyn str, Astana, 010000, Kazakhstan
| | - Chin-Bin Eap
- Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, 1008, Prilly-Lausanne, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
| | - Erlan Ramanculov
- National Center for Biotechnology, 13/5 Korgalzhyn str, Astana, 010000, Kazakhstan.,L.N. Gumilyov Eurasian National University, Astana, Kazakhstan.,School of Science and Technology, Nazarbayev University, Astana, Kazakhstan
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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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Abdelmajed SS, Youssef M, Zaki ME, Abu-Mandil Hassan N, Ismail S. Association analysis of FTO gene polymorphisms and obesity risk among Egyptian children and adolescents. Genes Dis 2017; 4:170-175. [PMID: 30258920 PMCID: PMC6146173 DOI: 10.1016/j.gendis.2017.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/26/2017] [Indexed: 11/29/2022] Open
Abstract
Obesity is a common disorder that has a significant impact on human health as it may lead to many serious diseases and sometimes morbidity. Previous genome-wide association studies (GWAS) confirmed that there is a relationship between some variants in the first intron of the fat mass and obesity associated (FTO) gene and obesity in adults and children in different ethnic groups. In our study, the association of the FTO rs9939609 and rs17817449 variants with obesity was investigated in Egyptian children and adolescents. We examined rs9939609 and rs17817449 polymorphisms in 100 control and 100 obese cases, we used the restriction fragment length polymorphism (RFLP) technique to genotype the samples. The current study showed that there were no significant differences (P > 0.05) between the cases and controls in both variants of rs17817449 and rs9939609 polymorphisms. However, there were significant correlations between rs17817449 and cholesterol and between rs9939609 and LDL. In Current Study although the two variants (rs9939609 and rs17817449) didn't show an association with obesity, but there was a correlation between the lipid profile and these two variants.
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Affiliation(s)
| | - Mohamed Youssef
- Organic chemistry Department, Faculty of science, Cairo University, Egypt
| | - Moushira Erfan Zaki
- Biological Anthropology Department, Medical Research Division, National Research Centre, Egypt
| | | | - Somaia Ismail
- Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Giza, Egypt
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Yu ACS, Li JW, Chan TF. Using genetics to inform new therapeutics for diabetes. Expert Rev Endocrinol Metab 2017; 12:159-169. [PMID: 30063460 DOI: 10.1080/17446651.2017.1323631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The genetic architecture of diabetes has been extensively studied. Numerous genetic markers for diabetes have been reported. However, the translation of such knowledge into clinical interventions has been inadequate. Areas covered: We performed a literature search on various frontiers in diabetes treatment that could be improved using genetic information: (1) understanding the mechanisms of existing antidiabetic drugs, (2) repurposing existing drugs for the treatment of diabetes, (3) complementing clinical trial findings; (4) finding novel treatment approaches; (5) better estimation of the efficacy of metabolic surgery. Expert commentary: The translation of genetic information to clinical intervention requires further study, including the development of an appropriate genetic risk score algorithm for type 2 diabetes. Genomic studies provide empirical explanations for clinical trial findings. Moreover, the mechanisms of antidiabetic drugs should be thoroughly investigated to enable clinical trials and pharmacogenomics studies of these drugs. As metabolic surgery becomes more prevalent for the treatment of diabetes, genetic approaches may improve patient prioritization.
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Affiliation(s)
- Allen Chi-Shing Yu
- a School of Life Sciences , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
| | - Jing-Woei Li
- a School of Life Sciences , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
- b Faculty of Medicine , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
| | - Ting-Fung Chan
- a School of Life Sciences , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
- c CUHK-BGI Innovation Institute of Transomics , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
- d Hong Kong Institute of Diabetes and Obesity , The Chinese University of Hong Kong , Shatin , Hong Kong SAR
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Wong WP, Allen NB, Meyers MS, Link EO, Zhang X, MacRenaris KW, El Muayed M. Exploring the Association Between Demographics, SLC30A8 Genotype, and Human Islet Content of Zinc, Cadmium, Copper, Iron, Manganese and Nickel. Sci Rep 2017; 7:473. [PMID: 28352089 PMCID: PMC5428289 DOI: 10.1038/s41598-017-00394-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 02/23/2017] [Indexed: 12/30/2022] Open
Abstract
A widely prevalent single nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM. ZnT8 is mostly expressed in pancreatic insulin-producing islets of Langerhans. The effect of this variant on the divalent metal profile in human islets is unknown. Additionally, essential and non-essential divalent metal content of human islets under normal environmental exposure conditions has not been described. We therefore examined the correlation of zinc and other divalent metals in human islets with rs13266634 genotype and demographic characteristics. We found that the diabetes risk genotype C/C at rs13266634 is associated with higher islet Zn concentration (C/C genotype: 16792 ± 1607, n = 22, C/T genotype: 11221 ± 1245, n = 18 T/T genotype: 11543 ± 6054, n = 3, all values expressed as mean nmol/g protein ± standard error of the mean, p = 0.040 by ANOVA). A positive correlation between islet cadmium content and both age (p = 0.048, R2 = 0.09) and female gender (women: 36.88 ± 4.11 vs men: 21.22 ± 3.65 nmol/g protein, p = 0.007) was observed. Our results suggest that the T2DM risk allele C is associated with higher islet zinc levels and support prior evidence of cadmium's higher bioavailability in women and its long tissue half-life.
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Affiliation(s)
- Winifred P Wong
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Norrina B Allen
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Matthew S Meyers
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Emma O Link
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Xiaomin Zhang
- Division of Transplant Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Keith W MacRenaris
- The Chemistry of Life Processes Institute and Department of Chemistry, Northwestern University, Evanston, IL, 60208, USA
| | - Malek El Muayed
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
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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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Culhane-Pera KA, Straka RJ, Moua M, Roman Y, Vue P, Xiaaj K, Lo MX, Lor M. Engaging Hmong adults in genomic and pharmacogenomic research: Toward reducing health disparities in genomic knowledge using a community-based participatory research approach. J Community Genet 2017; 8:117-125. [PMID: 28074382 DOI: 10.1007/s12687-017-0292-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 01/01/2017] [Indexed: 01/10/2023] Open
Abstract
Advancing precision medicine relies in part on examining populations that may exhibit unique genetic variants that impact clinical outcomes. Failure to include diverse populations in genomic-based research represents a health disparity. We implemented a community-based participatory research (CBPR) process with the Hmong community in Minnesota, who were refugees from Laos, in order to assess the feasibility of conducting genomic and pharmacogenomic-based research for genetic variants that are relevant to the Hmong community. Our Hmong Genomics Board, consisting of Hmong and non-Hmong professionals, used CBPR principles and built on previous formative research to create and implement culturally and linguistically appropriate informed consent processes for Hmong people at six community venues. The Board chose genetic variants for diabetes risk and warfarin response as relevant to the community. The Institutional Review Board approved aggregate but not individual return of results. Two hundred thirty-seven Hmong participants with mean (range) age of 30.2 (18-81) years and diverse levels of education (22% without and 75% with high-school education) provided saliva for genetic (DNA) analyses. Eighty-five percent of participants agreed to store DNA for future analyses, 82% agreed to share DNA with other researchers, and 78% agreed to be contacted for future studies. Twenty-five elders refused to participate because they wanted individual results. Aggregate results were shared with all participants. This CBPR approach proved highly successful to obtain informed consent and recruit a sample from the Hmong community for a genomic and pharmacogenomic study. Investment in the CBPR process may prove successful to address the gap of genomic information in under-represented communities.
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Affiliation(s)
| | - Robert J Straka
- Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota, 7-115 Weaver-Densford Hall, 308 Harvard St SE, Minneapolis, MN, 55455, USA
| | - MaiKia Moua
- Benton County Health Services, 530 NW 27th St, Corvallis, OR, 97330, USA
| | - Youssef Roman
- Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota, 7-115 Weaver-Densford Hall, 308 Harvard St SE, Minneapolis, MN, 55455, USA
| | - Pachia Vue
- University of Minnesota Medical Center-Fairview Campus, 2450 Riverside Ave, Minneapolis, MN, 55454, USA
| | - Kang Xiaaj
- West Side Community Health Services, 153 Cesar Chavez St, Saint Paul, MN, 55107, USA
| | - May Xia Lo
- Phalen Family Pharmacy, 1001 Johnson Parkway, St Paul, MN, 55106, USA
| | - Mai Lor
- Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota, 7-115 Weaver-Densford Hall, 308 Harvard St SE, Minneapolis, MN, 55455, USA
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