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Qian Y, Peng Q, Qian Q, Gao X, Liu X, Li Y, Fan X, Cheng Y, Yuan N, Hadi S, Jin L, Wang S, Liu F. A methylation panel of 10 CpGs for accurate age inference via stepwise conditional epigenome-wide association study. Int J Legal Med 2025; 139:1193-1203. [PMID: 39633164 DOI: 10.1007/s00414-024-03365-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024]
Abstract
Estimating individual age from DNA methylation at age associated CpG sites may provide key information facilitating forensic investigations. Systematic marker screening and feature selection play a critical role in ensuring the performance of the final prediction model. In the discovery stage, we screened for 811876 CpGs from whole blood of 2664 Chinese individuals ranging from 18 to 83 years of age based on a stepwise conditional epigenome-wide association study (SCEWAS). The SCEWAS identified 28 CpGs showing genome-wide significant and independent effects. Further restricting this panel to 10 most informative CpGs showed a tolerable loss of information. A linear model consisting of these 10 CpGs could explain 93% of the age variance (R2 = 0.93) in the training set (n = 2664). In an independent test set of Chinese individuals (n = 648), this model also provided highly accurate predictions (R2 = 0.85, mean absolute deviation, MAD = 3.20 years). The model was additionally validated in a public dataset of multiple ancestral origins (86 Europeans, 14 Asians, and 273 Africans) and the prediction accuracy reduced significantly (R2 = 0.85, MAD = 6.21 years), as might be expected due to different genomic backgrounds, sample sizes, and age ranges. Our 10 CpG model also outperformed the recently proposed 9-CpG model constructed in 390 Chinese males (R2 = 0.79 in test set). We also demonstrated that our SCEWAS approach outperformed the traditional EWAS and the elastic net approach in obtaining a small set of most age informative CpGs. Overall, our systematic genome-wide feature selection identified a small panel of 10 CpGs for accurate age estimation with high potential in forensic applications.
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Affiliation(s)
- Yu Qian
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
- Beijing No.8 High School, Beijing, China
| | - Qianqian Peng
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Qili Qian
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Xingjian Gao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, Jiangsu, China
| | - Xinxuan Liu
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
| | - Yi Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
| | - Xiu Fan
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
| | - Yuan Cheng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
| | - Na Yuan
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China
| | - Sibte Hadi
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University of Security Sciences, Riyadh, 11452, Kingdom of Saudi Arabia
| | - Li Jin
- Human Phenome Institute, Fudan University, Shanghai, China
- Taizhou Institute of Health Sciences, Fudan University, Taizhou, Jiangsu, China
- State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Sijia Wang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
| | - Fan Liu
- Department of Forensic Sciences, College of Criminal Justice, Naif Arab University of Security Sciences, Riyadh, 11452, Kingdom of Saudi Arabia.
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Lin E, Yan YT, Chen MH, Yang AC, Kuo PH, Tsai SJ. Gene clusters linked to insulin resistance identified in a genome-wide study of the Taiwan Biobank population. Nat Commun 2025; 16:3525. [PMID: 40229288 PMCID: PMC11997021 DOI: 10.1038/s41467-025-58506-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 03/25/2025] [Indexed: 04/16/2025] Open
Abstract
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research.
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Affiliation(s)
- Eugene Lin
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC
| | - Yu-Ting Yan
- Department of Public Health & Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan, ROC
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Albert C Yang
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Po-Hsiu Kuo
- Department of Public Health & Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan, ROC.
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan, ROC.
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
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Wang X, Qu X, Liu X, Wang K, Yang Y, Zhang Y, Wang Z, Fan G, Li Y, Zeng Y, Chen H, Zhu T. KLF14 inhibits tumor progression via FOSL1 in glioma. Biochem Biophys Rep 2025; 41:101885. [PMID: 39678169 PMCID: PMC11638655 DOI: 10.1016/j.bbrep.2024.101885] [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: 07/30/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024] Open
Abstract
Background Glioma, the most frequent central nervous system malignancy, is often promoted by the overexpression of Fos-like antigen 1 (FOSL1). However, the regulation of FOSL1 remains unexplored. The present study aimed to investigate the regulatory mechanism of FOSL1 to identify potential therapeutic targets for glioblastoma. Methods This study's initial investigation utilized dual-luciferase reporter gene assays and quantitative polymerase chain reaction (qPCR) assays to establish that Kruppel-like factor 14 (KLF14) inhibits the transcription of FOSL1. Subsequent immunohistochemistry and western blotting (WB) assays on glioma tissues confirmed a negative association between FOSL1 and KLF14. This study generated KLF14 knockdown cells and double knockdown cells of KLF14 and FOSL1 and further assessed cell growth through various experimental methods. The impact of KLF14 on tumor cell migration via FOSL1 was determined using qPCR and WB assays. A xenograft tumor model was utilized to verify tumor growth suppression by KLF14. Results The present study demonstrated that KLF14 restrains FOSL1 transcription and is inversely correlated with FOSL1 in glioma tissues. KLF14 overexpression was found to counteract FOSL1's effect on cell migration and epithelial-to-mesenchymal transition in glioma cells, which coincided with decreased Snail2 and cluster of differentiation 44 (CD44) expressions. Further, KLF14 overexpression was shown to hinder tumor progression in vivo. Conclusion This study highlights that FOSL1 is negatively regulated by KLF14 in glioblastoma and suggests that KLF14 overexpression can mitigate tumor growth by inhibiting FOSL1, thus identifying KLF14 as a novel molecular target for treating glioblastoma. Further research into the interplay and regulatory dynamics between KLF14 and FOSL1 under varying stress conditions can enhance the precision of glioblastoma treatment.
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Affiliation(s)
- Xiaohua Wang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510006, China
- Department of General Internal Medicine, Linyi People's Hospital, No.27 Jiefang Road, Lanshan District, Linyi City, Shandong Province, 276003, China
| | - Xinjuan Qu
- Department of Neurology, Linyi Hospital of Traditional Chinese Medicine, Shandong, 276002, China
| | - Xuelai Liu
- Department of Neurology, Linyi Hospital of Traditional Chinese Medicine, Shandong, 276002, China
| | - Kaiyue Wang
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong Province, 276003, China
| | - Yongfang Yang
- Department of Rehabilitation, Linyi People's Hospital, Linyi, Shandong Province, 276003, China
| | - Yujuan Zhang
- Department of Acupuncture and Moxibustion, Linyi People's Hospital, Linyi, Shandong Province, 276003, China
| | - Zhenguo Wang
- Department of Neurology, Linyi Hospital of Traditional Chinese Medicine, Shandong, 276002, China
| | - Guangjian Fan
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200080, China
| | - Yuming Li
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200080, China
| | - Yuanyuan Zeng
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200080, China
| | - Hongwei Chen
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200080, China
- Department of Clinical Laboratory, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai 201600, China
| | - Ting Zhu
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200080, China
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Akinbiyi T, McPeek MS, Abney M. ADELLE: A global testing method for trans-eQTL mapping. PLoS Genet 2025; 21:e1011563. [PMID: 39792937 PMCID: PMC11756770 DOI: 10.1371/journal.pgen.1011563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/23/2025] [Accepted: 12/31/2024] [Indexed: 01/12/2025] Open
Abstract
Understanding the genetic regulatory mechanisms of gene expression is an ongoing challenge. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%-2% of 10,000 traits, among the 8 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. We also apply ADELLE to trans-eQTL mapping in the eQTLGen data, and for 1,451 previously identified trans-eQTLs, we discover trans association with additional expression traits beyond those previously identified. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.
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Affiliation(s)
- Takintayo Akinbiyi
- Department of Statistics, The University of Chicago, Chicago, Illinois, United States of America
| | - Mary Sara McPeek
- Department of Statistics, The University of Chicago, Chicago, Illinois, United States of America
- Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America
| | - Mark Abney
- Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America
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Ye H, Ding X, Lv X, Du Y, Guo R, Qiu J, Li R, Cao L. KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer. J Transl Med 2024; 22:923. [PMID: 39390559 PMCID: PMC11465826 DOI: 10.1186/s12967-024-05714-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 09/30/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Cervical cancer is the fourth leading cause of cancer-related death among women worldwide, and effective therapeutic strategies for its treatment are limited. Recent studies have indicated that ferroptosis, a form of regulated cell death, is a promising therapeutic strategy. KLF14 has been shown to regulate both cell proliferation and apoptosis in cervical cancer. However, its role in modulating lipid peroxidation and ferroptosis remains largely unexplored and enigmatic. METHODS SiHa and HeLa cells were transduced with lentiviral vectors to overexpress KLF14. Protein levels were analyzed via western blotting and immunohistochemistry (IHC). LDH assays, calcein-AM/propidium iodide (PI) staining, and generation of cell growth curves using a real-time cell analysis (RTCA) system were used to detect cell damage and proliferation. Cellular ROS, lipid ROS, transmission electron microscopy (TEM), and Fe2+ assays and a xenograft mouse model were used to measure the level of ferroptosis. Proteomics combined with bioinformatics methods was used to screen target genes regulated by KLF14, and CUT&Tag and dual-luciferase assays confirmed the repression of GPX4 by KLF14 via direct binding to its promoter. RESULTS KLF14 is abnormally expressed in various tumors and downregulated in cervical cancer. Overexpression of KLF14 induced ferroptosis and inhibited cell proliferation in vitro as well as xenograft tumorigenicity in vivo. Mechanistic studies revealed that KLF14 binds to the promoter of GPX4, suppressing its transcriptional activity and thereby decreasing its expression, which contributes to the induction of ferroptosis. Truncation and point mutation analyses of the GPX4 promoter revealed multiple binding sites for KLF14 within the - 1000 bp to + 35 bp region, which are responsible for its inhibitory effect on GPX4 transcription. Additionally, deletion of the zinc finger motif in KLF14 abolished its inhibitory effect on GPX4 promoter activity and cell proliferation. CONCLUSION Our data revealed a previously unidentified function of KLF14 in promoting ferroptosis, which results in the suppression of cell proliferation. Mechanistically, we revealed a novel regulatory mechanism by which KLF14 targets GPX4. These findings suggest a novel strategy to induce ferroptosis through the targeting of KLF14 in human cervical cancer cells.
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Affiliation(s)
- Hui Ye
- Oncology Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China
- Blood Center of Shandong Province, Jinan, 250014, China
| | - XuChao Ding
- Department of Blood Transfusion, Binzhou People's Hospital, Binzhou, 256601, China
| | - XinRan Lv
- Shandong Public Health Clinical Center, Shandong University, Shandong, 250013, China
| | - Ying Du
- Department of Laboratory Medicine, Linyi Peoples' Hospital, Linyi, 276003, China
| | - Rui Guo
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Jin Qiu
- Oncology Department, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - RuoNan Li
- Oncology Department, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - LiLi Cao
- Oncology Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China.
- Oncology Department, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, Laboratory of Clinical Immunology and Translational Medicine, Shandong Provincial University, Jinan, 250014, China.
- Shandong Lung Cancer Institute, Jinan, 250014, China.
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Ryba-Stanisławowska M, Słomiński B, Myśliwiec M. Association of KLF14 rs4731702 gene polymorphism with metabolic phenotype in young patients with type 1 diabetes. Diabetes Obes Metab 2024; 26:3663-3672. [PMID: 38894632 DOI: 10.1111/dom.15707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024]
Abstract
AIM To explore the potential association between the KLF14 rs4731702 polymorphism and metabolic syndrome traits among patients diagnosed with type 1 diabetes (T1D). METHODS The study group included 350 patients with T1D and 250 healthy control subjects. The analysis focused on the genotyping of KLF14 rs4731702 single nucleotide polymorphism (SNP), as well as evaluating serum concentrations of inflammatory markers, blood pressure, lipid profiles, and the quantitative status of CD4 + CD25highFOXP3+ T cells. RESULTS Patients with T1D carrying the T allele of KLF14 rs4731702 SNP had higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, as well as lower glycated haemoglobin and serum concentration of proinflammatory markers than C allele carriers. They also developed hypertension less often than carriers of the C allele. The analysis of CD4 + CD25highFOXP3+ regulatory T-cell status based on KLF14 genotype showed that, in T1D patients, those with the TT genotype had the highest frequency of these cells compared to carriers of the CC and CT genotypes. CONCLUSION Our study suggests that the T allele of the KLF14 rs4731702 SNP might confer a protective effect against the development of obesity, hypertension, dyslipidaemia, and chronic inflammatory state in patients diagnosed with T1D.
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Affiliation(s)
| | - Bartosz Słomiński
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Małgorzata Myśliwiec
- Chair & Clinics of Paediatrics, Diabetology and Endocrinology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Le J, Chen Y, Yang W, Chen L, Ye J. Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus. Acta Pharm Sin B 2024; 14:437-454. [PMID: 38322335 PMCID: PMC10840401 DOI: 10.1016/j.apsb.2023.09.004] [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: 05/26/2023] [Revised: 07/10/2023] [Accepted: 08/09/2023] [Indexed: 02/08/2024] Open
Abstract
Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
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Affiliation(s)
- Jiamei Le
- Shanghai Key Laboratory of Molecular Imaging, Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yilong Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Wei Yang
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Jianping Ye
- Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou 450007, China
- Research Center for Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, China
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He Y, Ma P, Luo Y, Gong X, Gao J, Sun Y, Chen P, Zhang S, Tian Y, Shi B, Zhang B. Novel Association of KLRC4-KLRK1 Gene Polymorphisms with Susceptibility and Progression of Antithyroid Drug-Induced Agranulocytosis. Exp Clin Endocrinol Diabetes 2024; 132:17-22. [PMID: 38237612 DOI: 10.1055/a-2206-2242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
OBJECTIVE Antithyroid drug (ATD)-induced agranulocytosis (TIA) is the most serious adverse effect during ATD treatment of Graves' disease (GD). Previously, the MICA gene was reported to be associated with TIA. MICA protein is an important ligand for the NKG2D protein, which is encoded by the KLRK1 gene and KLRC4-KLRK1 read-through transcription. This study further investigated the association between KLRC4-KLRK1 gene polymorphisms and susceptibility to TIA. METHODS Twenty-eight candidate single nucleotide polymorphisms (SNPs) on KLRC4-KLRK1 read-through transcription were evaluated by the iPLEX MassARRAY system in 209 GD control patients and 38 TIA cases. RESULTS A significant association of rs2734565 polymorphism with TIA was found (p=0.02, OR=1.80, 95% CI=1.09-2.96). The haplotype C-A-A-C-G, including rs2734565-C, was associated with a significantly higher risk of TIA (p=4.79E-09, OR=8.361, 95% CI=3.737-18.707). In addition, the interval time from hyperthyroidism to agranulocytosis onset was shorter in patients carrying the rs2734565-C allele than in non-carrying groups (45.00 (14.00-6570.00) d vs. 1080.00 (30.00-3600.00) d, p=0.046), and the interval from ATD treatment to agranulocytosis onset was also shorter in patients carrying rs2734565-C allele (29.00 (13.00-75.00) d vs. 57.50 (21.00-240.00) d, p=0.023). CONCLUSIONS The findings suggest that the KLRC4-KLRK1 gene polymorphism is associated with susceptibility and progression of ATD-induced agranulocytosis. Patients carrying the rs2734565-C allele had a higher susceptibility and faster onset time of TIA.
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Affiliation(s)
- Yayi He
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pan Ma
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
- Kunming Center for Medical Service Quality Assessment, Kunming, China
| | - Yuanlin Luo
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaojuan Gong
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Jiayang Gao
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Yuxin Sun
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Pu Chen
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Suliang Zhang
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Yuxin Tian
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
| | - Bingyin Shi
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Bao Zhang
- College of Medicine & Forensic, Health Science Center, Xi'an Jiaotong University, Xi'an, China
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Wang H, Akbari-Alavijeh S, Parhar RS, Gaugler R, Hashmi S. Partners in diabetes epidemic: A global perspective. World J Diabetes 2023; 14:1463-1477. [PMID: 37970124 PMCID: PMC10642420 DOI: 10.4239/wjd.v14.i10.1463] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/01/2023] [Accepted: 09/01/2023] [Indexed: 10/09/2023] Open
Abstract
There is a recent increase in the worldwide prevalence of both obesity and diabetes. In this review we assessed insulin signaling, genetics, environment, lipid metabolism dysfunction and mitochondria as the major determinants in diabetes and to identify the potential mechanism of gut microbiota in diabetes diseases. We searched relevant articles, which have key information from laboratory experiments, epidemiological evidence, clinical trials, experimental models, meta-analysis and review articles, in PubMed, MEDLINE, EMBASE, Google scholars and Cochrane Controlled Trial Database. We selected 144 full-length articles that met our inclusion and exclusion criteria for complete assessment. We have briefly discussed these associations, challenges, and the need for further research to manage and treat diabetes more efficiently. Diabetes involves the complex network of physiological dysfunction that can be attributed to insulin signaling, genetics, environment, obesity, mitochondria and stress. In recent years, there are intriguing findings regarding gut microbiome as the important regulator of diabetes. Valid approaches are necessary for speeding medical advances but we should find a solution sooner given the burden of the metabolic disorder - What we need is a collaborative venture that may involve laboratories both in academia and industries for the scientific progress and its application for the diabetes control.
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Affiliation(s)
- Huan Wang
- College of Bioscience and Biotechnology, Shenyang Agricultural University, Shenyang 110866, Liaoning Province, China
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Safoura Akbari-Alavijeh
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Department of Food Science and Technology, College of Agriculture, Isfahan University of Technology, Isfahan 84156-83111, Iran
| | - Ranjit S Parhar
- Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Randy Gaugler
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
| | - Sarwar Hashmi
- Rutgers Center for Vector Biology, Rutgers University, New Brunswick, NJ 08901, United States
- Research and Diagnostics, Ghazala and Sanya Hashmi Foundation, Holmdel, NJ 07733, United States
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10
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Li Y, Xiong Z, Zhang M, Hysi PG, Qian Y, Adhikari K, Weng J, Wu S, Du S, Gonzalez-Jose R, Schuler-Faccini L, Bortolini MC, Acuna-Alonzo V, Canizales-Quinteros S, Gallo C, Poletti G, Bedoya G, Rothhammer F, Wang J, Tan J, Yuan Z, Jin L, Uitterlinden AG, Ghanbari M, Ikram MA, Nijsten T, Zhu X, Lei Z, Jia P, Ruiz-Linares A, Spector TD, Wang S, Kayser M, Liu F. Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci. PLoS Genet 2023; 19:e1010786. [PMID: 37459304 PMCID: PMC10351707 DOI: 10.1371/journal.pgen.1010786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 05/16/2023] [Indexed: 07/20/2023] Open
Abstract
Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.
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Affiliation(s)
- Yi Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China
| | - Ziyi Xiong
- Department of Genetic Identification, Erasmus MC, University Medical Center, the Netherlands
- Department of Epidemiology, Erasmus MC, University Medical Center, the Netherlands
| | - Manfei Zhang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, China
| | - Pirro G. Hysi
- Department of Twin Research and Genetic Epidemiology, King’s College London, United Kingdom
| | - Yu Qian
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China
- Beijing No.8 High School, Beijing, China
| | - Kaustubh Adhikari
- Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, United Kingdom
- School of Mathematics and Statistics, Faculty of Science, Technology, Engineering and Mathematics, The Open University, United Kingdom
| | - Jun Weng
- Center for Biometrics and Security Research & National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, China
| | - Sijie Wu
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, China
| | - Siyuan Du
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- University of Chinese Academy of Sciences, China
| | - Rolando Gonzalez-Jose
- Instituto Patagonico de Ciencias Sociales y Humanas, Centro Nacional Patagonico, CONICET, Argentina
| | | | | | - Victor Acuna-Alonzo
- Molecular Genetics Laboratory, National School of Anthropology and History, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genomica de Poblaciones Aplicada a la Salud, Facultad de Quimica, UNAM-Instituto Nacional de Medicina Genomica, Mexico
| | - Carla Gallo
- Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Peru
| | - Giovanni Poletti
- Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Peru
| | - Gabriel Bedoya
- GENMOL (Genetica Molecular), Universidad de Antioquia, Medellin, Colombia
| | | | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, China
| | - Jingze Tan
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, China
| | - Ziyu Yuan
- Fudan-Taizhou Institute of Health Sciences, China
| | - Li Jin
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, China
- Fudan-Taizhou Institute of Health Sciences, China
| | - André G. Uitterlinden
- Department of Epidemiology, Erasmus MC, University Medical Center, the Netherlands
- Department of Internal Medicine, Erasmus MC, University Medical Center, the Netherlands
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC, University Medical Center, the Netherlands
| | - M. Arfan Ikram
- Department of Epidemiology, Erasmus MC, University Medical Center, the Netherlands
| | - Tamar Nijsten
- Department of Dermatology, Erasmus MC, University Medical Center, the Netherlands
| | - Xiangyu Zhu
- Center for Biometrics and Security Research & National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, China
- School of Artificial Intelligence, University of Chinese Academy of Sciences, China
| | - Zhen Lei
- Center for Biometrics and Security Research & National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, China
- School of Artificial Intelligence, University of Chinese Academy of Sciences, China
| | - Peilin Jia
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China
| | - Andres Ruiz-Linares
- Department of Genetics, Evolution and Environment, and UCL Genetics Institute, University College London, United Kingdom
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, China
- Aix-Marseille Universite, CNRS, EFS, ADES, France
| | - Timothy D. Spector
- Department of Twin Research and Genetic Epidemiology, King’s College London, United Kingdom
| | - Sijia Wang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, China
| | - Manfred Kayser
- Department of Genetic Identification, Erasmus MC, University Medical Center, the Netherlands
| | - Fan Liu
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China
- Department of Genetic Identification, Erasmus MC, University Medical Center, the Netherlands
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11
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Kruppel-like Factors in Skeletal Physiology and Pathologies. Int J Mol Sci 2022; 23:ijms232315174. [PMID: 36499521 PMCID: PMC9741390 DOI: 10.3390/ijms232315174] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 12/11/2022] Open
Abstract
Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.
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12
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Jersin RÅ, Jonassen LR, Dankel SN. The neutral amino acid transporter SLC7A10 in adipose tissue, obesity and insulin resistance. Front Cell Dev Biol 2022; 10:974338. [PMID: 36172277 PMCID: PMC9512047 DOI: 10.3389/fcell.2022.974338] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/26/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity, insulin resistance and type 2 diabetes represent major global health challenges, and a better mechanistic understanding of the altered metabolism in these conditions may give improved treatment strategies. SLC7A10, a member of the SLC7 subfamily of solute carriers, also named ASC-1 (alanine, serine, cysteine transporter-1), has recently been implicated as an important modulator of core processes in energy- and lipid metabolism, through its particularly high expression in adipocytes. In human cohorts, adipose SLC7A10 mRNA shows strong inverse correlations with insulin resistance, adipocyte size and components of the metabolic syndrome, strong heritability, and an association with type 2 diabetes risk alleles. SLC7A10 has been proposed as a marker of white as opposed to thermogenic beige and brown adipocytes, supported by increased formation of thermogenic beige adipocytes upon loss of Slc7a10 in mouse white preadipocytes. Overexpression of SLC7A10 in mature white adipocytes was found to lower the generation of reactive oxygen species (ROS) and stimulate mitochondrial respiratory capacity, while SLC7A10 inhibition had the opposite effect, indicating that SLC7A10 supports a beneficial increase in mitochondrial activity in white adipocytes. Consistent with these beneficial effects, inhibition of SLC7A10 was in mouse and human white adipocyte cultures found to increase lipid accumulation, likely explained by lowered serine uptake and glutathione production. Additionally, zebrafish with partial global Slc7a10b loss-of-function were found to have greater diet-induced body weight and larger visceral adipocytes compared to controls. However, challenging that SLC7A10 exerts metabolic benefits only in white adipocytes, suppression of SLC7A10 has been reported to decrease mitochondrial respiration and expression of thermogenic genes also in some beige and brown adipocyte cultures. Taken together, the data point to an important but complex role of SLC7A10 in metabolic regulation across different adipose tissue depots and adipocyte subtypes. Further research into SLC7A10 functions in specific adipocyte subtypes may lead to new precision therapeutics for mitigating the risk of insulin resistance and type 2 diabetes.
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Affiliation(s)
- Regine Åsen Jersin
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Laura Roxana Jonassen
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Simon Nitter Dankel
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
- *Correspondence: Simon Nitter Dankel,
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13
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Macias-Velasco JF, St Pierre CL, Wayhart JP, Yin L, Spears L, Miranda MA, Carson C, Funai K, Cheverud JM, Semenkovich CF, Lawson HA. Parent-of-origin effects propagate through networks to shape metabolic traits. eLife 2022; 11:e72989. [PMID: 35356864 PMCID: PMC9075957 DOI: 10.7554/elife.72989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 03/25/2022] [Indexed: 11/16/2022] Open
Abstract
Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these parent-of-origin effects phenomena. We propose that non-imprinted genes can generate complex parent-of-origin effects on metabolic traits through interactions with imprinted genes. Here, we employ data from mouse populations at different levels of intercrossing (F0, F1, F2, F16) of the LG/J and SM/J inbred mouse lines to test this hypothesis. Using multiple populations and incorporating genetic, genomic, and physiological data, we leverage orthogonal evidence to identify networks of genes through which parent-of-origin effects propagate. We identify a network comprised of three imprinted and six non-imprinted genes that show parent-of-origin effects. This epistatic network forms a nutritional responsive pathway and the genes comprising it jointly serve cellular functions associated with growth. We focus on two genes, Nnat and F2r, whose interaction associates with serum glucose levels across generations in high-fat-fed females. Single-cell RNAseq reveals that Nnat expression increases and F2r expression decreases in pre-adipocytes along an adipogenic trajectory, a result that is consistent with our observations in bulk white adipose tissue.
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Affiliation(s)
- Juan F Macias-Velasco
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
| | - Celine L St Pierre
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
| | - Jessica P Wayhart
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
| | - Li Yin
- Department of Medicine, Washington University School of MedicineSaint LouisUnited States
| | - Larry Spears
- Department of Medicine, Washington University School of MedicineSaint LouisUnited States
| | - Mario A Miranda
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
| | - Caryn Carson
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
| | - Katsuhiko Funai
- Diabetes and Metabolism Research Center, University of UtahSalt Lake CityUnited States
| | | | - Clay F Semenkovich
- Department of Medicine, Washington University School of MedicineSaint LouisUnited States
| | - Heather A Lawson
- Department of Genetics, Washington University School of MedicineSaint LouisUnited States
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14
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Lucknuch T, Praihirunkit P. Evaluation of Age-associated DNA Methylation Markers in Colorectal Cancer of Thai Population. FORENSIC SCIENCE INTERNATIONAL: REPORTS 2022. [DOI: 10.1016/j.fsir.2022.100265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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15
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Skaar DA, Dietze EC, Alva-Ornelas JA, Ann D, Schones DE, Hyslop T, Sistrunk C, Zalles C, Ambrose A, Kennedy K, Idassi O, Miranda Carboni G, Gould MN, Jirtle RL, Seewaldt VL. Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:6031. [PMID: 34885139 PMCID: PMC8656495 DOI: 10.3390/cancers13236031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 11/26/2021] [Indexed: 12/02/2022] Open
Abstract
Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that KCNK9 is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the KCNK9 gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the KCNK9 DMR predicts for increased TASK3 expression and mitochondrial membrane potential (p < 0.001). This is the first identification of the KCNK9 DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the KCNK9 DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.
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Affiliation(s)
- David A. Skaar
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA;
| | - Eric C. Dietze
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Jackelyn A. Alva-Ornelas
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - David Ann
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Dustin E. Schones
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Terry Hyslop
- Department of Biostatistics, School of Medicine, Duke University, Durham, NC 27710, USA;
| | - Christopher Sistrunk
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Carola Zalles
- Department of Pathology, Mercy Hospital, Miami, FL 33133, USA;
| | - Adrian Ambrose
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Kendall Kennedy
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Ombeni Idassi
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
| | - Gustavo Miranda Carboni
- Laboratory of Oncology, Department of Oncology, School of Medicine, University of Tennessee Health Science, Memphis, TN 38163, USA;
| | - Michael N. Gould
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA;
| | - Randy L. Jirtle
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA;
| | - Victoria L. Seewaldt
- Beckman Research Institute, Department of Population Sciences, City of Hope, Duarte, CA 91010, USA; (E.C.D.); (J.A.A.-O.); (D.A.); (D.E.S.); (C.S.); (A.A.); (K.K.); (O.I.)
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16
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Hoskins JW, Chung CC, O’Brien A, Zhong J, Connelly K, Collins I, Shi J, Amundadottir LT. Inferred expression regulator activities suggest genes mediating cardiometabolic genetic signals. PLoS Comput Biol 2021; 17:e1009563. [PMID: 34793442 PMCID: PMC8639061 DOI: 10.1371/journal.pcbi.1009563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 12/02/2021] [Accepted: 10/15/2021] [Indexed: 12/12/2022] Open
Abstract
Expression QTL (eQTL) analyses have suggested many genes mediating genome-wide association study (GWAS) signals but most GWAS signals still lack compelling explanatory genes. We have leveraged an adipose-specific gene regulatory network to infer expression regulator activities and phenotypic master regulators (MRs), which were used to detect activity QTLs (aQTLs) at cardiometabolic trait GWAS loci. Regulator activities were inferred with the VIPER algorithm that integrates enrichment of expected expression changes among a regulator's target genes with confidence in their regulator-target network interactions and target overlap between different regulators (i.e., pleiotropy). Phenotypic MRs were identified as those regulators whose activities were most important in predicting their respective phenotypes using random forest modeling. While eQTLs were typically more significant than aQTLs in cis, the opposite was true among candidate MRs in trans. Several GWAS loci colocalized with MR trans-eQTLs/aQTLs in the absence of colocalized cis-QTLs. Intriguingly, at the 1p36.1 BMI GWAS locus the EPHB2 cis-aQTL was stronger than its cis-eQTL and colocalized with the GWAS signal and 35 BMI MR trans-aQTLs, suggesting the GWAS signal may be mediated by effects on EPHB2 activity and its downstream effects on a network of BMI MRs. These MR and aQTL analyses represent systems genetic methods that may be broadly applied to supplement standard eQTL analyses for suggesting molecular effects mediating GWAS signals.
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Affiliation(s)
- Jason W. Hoskins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail: (JWH); (LTA)
| | - Charles C. Chung
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- Cancer Genome Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Aidan O’Brien
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Jun Zhong
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Katelyn Connelly
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Irene Collins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Jianxin Shi
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Laufey T. Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail: (JWH); (LTA)
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17
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Kim HI, Ye B, Staples J, Marcketta A, Gao C, Shuldiner AR, Van Hout CV. Genome-wide survey of parent-of-origin-specific associations across clinical traits derived from electronic health records. HGG ADVANCES 2021; 2:100039. [PMID: 35047837 PMCID: PMC8756508 DOI: 10.1016/j.xhgg.2021.100039] [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: 01/29/2021] [Accepted: 05/31/2021] [Indexed: 11/03/2022] Open
Abstract
Parent-of-origin (PoO) effects refer to the differential phenotypic impacts of genetic variants dependent on their parental inheritance due to imprinting. While PoO effects can influence complex traits, they may be poorly captured by models that do not differentiate the parental origin of the variant. The aim of this study was to conduct a genome-wide screen for PoO effects on a broad range of clinical traits derived from electronic health records (EHR) in the DiscovEHR study enriched with familial relationships. Using pairwise kinship estimates from genetic data and demographic data, we identified 22,051 offspring among 134,049 individuals in the DiscovEHR study. PoO of ~9 million variants was assigned in the offspring by comparing offspring and parental genotypes and haplotypes. We then performed genome-wide PoO association analyses across 154 quantitative and 611 binary traits extracted from EHR. Of the 732 significant PoO associations identified (p < 5 × 10-8), we attempted to replicate 274 PoO associations in the UK Biobank study with 5,015 offspring and replicated 9 PoO associations (p < 0.05). In summary, our study implements a bioinformatic and statistical approach to examine PoO effects genome-wide in a large population study enriched with familial relationships and systematically characterizes PoO effects on hundreds of clinical traits derived from EHR. Our results suggest that, while the statistical power to detect PoO effects remains modest yet, accurately modeling PoO effects has the potential to find new associations that may have been missed by the standard additive model, further enhancing the mechanistic understanding of genetic influence on complex traits.
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Affiliation(s)
- Hye In Kim
- Regeneron Genetics Center, Tarrytown, NY 10591, USA
| | - Bin Ye
- Regeneron Genetics Center, Tarrytown, NY 10591, USA
| | | | | | - Chuan Gao
- Regeneron Genetics Center, Tarrytown, NY 10591, USA
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18
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Du Z, Liu M, Wang Z, Lin Z, Feng Y, Tian D, Xia L. EZH2-mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARγ. Cell Prolif 2021; 54:e13072. [PMID: 34031939 PMCID: PMC8249795 DOI: 10.1111/cpr.13072] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Krüppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown. MATERIALS AND METHODS KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor γ (PPARγ) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis. RESULTS KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPARγ promoter activity. Inhibition of PPARγ blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPARγ-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPARγ downregulation. CONCLUSIONS KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPARγ axis might be a novel therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Zhipeng Du
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mei Liu
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Wang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuoying Lin
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yangyang Feng
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Limin Xia
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Ostinelli G, Vijay J, Vohl MC, Grundberg E, Tchernof A. AKR1C2 and AKR1C3 expression in adipose tissue: Association with body fat distribution and regulatory variants. Mol Cell Endocrinol 2021; 527:111220. [PMID: 33675863 PMCID: PMC8052191 DOI: 10.1016/j.mce.2021.111220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Changes in androgen dynamics within adipose tissue have been proposed as modulators of body fat accumulation. In this context, AKR1C2 likely plays a significant role by inactivating 5α-dihydrotestosterone. AIM To characterize AKR1C2 expression patterns across adipose depots and cell populations and to provide insight into the link with body fat distribution and genetic regulation. METHODS We used RNA sequencing data from severely obese patients to assess patterns of AKR1C2 and AKR1C3 expression in abdominal adipose tissue depots and cell fractions. We additionally used data from 856 women to assess AKR1C2 heritability and to link its expression in adipose tissue with body fat distribution. Further, we used public resources to study AKR1C2 genetic regulation as well as reference epigenome data for regulatory element profiling and functional interpretation of genetic data. RESULTS We found that mature adipocytes and adipocyte-committed adipocyte progenitor cells (APCs) had enriched expression of AKR1C2. We found adipose tissue AKR1C2 and AKR1C3 expression to be significantly and positively associated with percentage trunk fat mass in women. We identified strong genetic regulation of AKR1C2 by rs28571848 and rs34477787 located on the binding sites of two nuclear transcription factors, namely retinoid acid-related orphan receptor alpha and the glucocorticoid receptor. CONCLUSION We confirm the link between AKR1C2, adipogenic differentiation and adipose tissue distribution. We provide insight into genetic regulation of AKR1C2 by identifying regulatory variants mapping to binding sites for the glucocorticoid receptor and retinoid acid-related orphan receptor alpha which may in part mediate the effect of AKR1C2 expression on body fat distribution.
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Affiliation(s)
- Giada Ostinelli
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec-Université Laval, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, Québec, Canada; École de Nutrition, Université Laval, 2425 Rue de l'Agriculture, G1V 0A6, Québec City, Québec, Canada
| | - Jinchu Vijay
- Department of Human Genetics, McGill University, Montréal, Quebec, Canada
| | - Marie-Claude Vohl
- École de Nutrition, Université Laval, 2425 Rue de l'Agriculture, G1V 0A6, Québec City, Québec, Canada; Centre Nutrition, Santé et Societé (NUTRISS)-Insitut sur la Nutrition et les Aliments Fonctionnells (INAF), Université Laval, Québec City, Québec, Canada
| | - Elin Grundberg
- Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, MO, USA.
| | - Andre Tchernof
- Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec-Université Laval, 2725 Chemin Sainte-Foy, G1V 4G5, Québec City, Québec, Canada; École de Nutrition, Université Laval, 2425 Rue de l'Agriculture, G1V 0A6, Québec City, Québec, Canada.
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20
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Identifying Methylation Patterns in Dental Pulp Aging: Application to Age-at-Death Estimation in Forensic Anthropology. Int J Mol Sci 2021; 22:ijms22073717. [PMID: 33918302 PMCID: PMC8038189 DOI: 10.3390/ijms22073717] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 11/19/2022] Open
Abstract
Age-at-death estimation constitutes one of the key parameters for identification of human remains in forensic investigations. However, for applications in forensic anthropology, many current methods are not sufficiently accurate for adult individuals, leading to chronological age estimates erring by ±10 years. Based on recent trends in aging studies, DNA methylation has great potential as a solution to this problem. However, there are only a few studies that have been published utilizing DNA methylation to determine age from human remains. The aim of the present study was to expand the range of this work by analyzing DNA methylation in dental pulp from adult individuals. Healthy erupted third molars were extracted from individuals aged 22–70. DNA from pulp was isolated and bisulfite converted. Pyrosequencing was the chosen technique to assess DNA methylation. As noted in previous studies, we found that ELOVL2 and FHL2 CpGs played a role in age estimation. In addition, three new markers were evaluated—NPTX2, KLF14, and SCGN. A set of CpGs from these five loci was used in four different multivariate regression models, providing a Mean Absolute Error (MAE) between predicted and chronological age of 1.5–2.13 years. The findings from this research can improve age estimation, increasing the accuracy of identification in forensic anthropology.
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21
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Sinnott-Armstrong N, Naqvi S, Rivas M, Pritchard JK. GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background. eLife 2021; 10:e58615. [PMID: 33587031 PMCID: PMC7884075 DOI: 10.7554/elife.58615] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 01/18/2021] [Indexed: 12/30/2022] Open
Abstract
Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits-urate, IGF-1, and testosterone-with better-understood biology than most other complex traits. We find that many of the most significant hits are readily interpretable. We observe huge enrichment of associations near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of each trait, including differences in testosterone regulation between females and males. At the same time, even these molecular traits are highly polygenic, with many thousands of variants spread across the genome contributing to trait variance. In summary, for these three molecular traits we identify strong enrichment of signal in putative core gene sets, even while most of the SNP-based heritability is driven by a massively polygenic background.
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Affiliation(s)
| | - Sahin Naqvi
- Department of Genetics, Stanford UniversityStanfordUnited States
- Department of Chemical and Systems Biology, Stanford UniversityStanfordUnited States
| | - Manuel Rivas
- Department of Biomedical Data Sciences, Stanford UniversityStanfordUnited States
| | - Jonathan K Pritchard
- Department of Genetics, Stanford UniversityStanfordUnited States
- Department of Biology, Stanford UniversityStanfordUnited States
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22
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Huang LO, Rauch A, Mazzaferro E, Preuss M, Carobbio S, Bayrak CS, Chami N, Wang Z, Schick UM, Yang N, Itan Y, Vidal-Puig A, den Hoed M, Mandrup S, Kilpeläinen TO, Loos RJF. Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities. Nat Metab 2021; 3:228-243. [PMID: 33619380 DOI: 10.1038/s42255-021-00346-2] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 01/14/2021] [Indexed: 01/31/2023]
Abstract
Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.
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Affiliation(s)
- Lam O Huang
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Alexander Rauch
- Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- Molecular Endocrinology & Stem Cell Research Unit, Department of Endocrinology and Metabolism, Odense University Hospital and Steno Diabetes Center Odense and Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Eugenia Mazzaferro
- The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
| | - Michael Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Stefania Carobbio
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
| | - Cigdem S Bayrak
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Nathalie Chami
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Zhe Wang
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Ursula M Schick
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Nancy Yang
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Yuval Itan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Antonio Vidal-Puig
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
- University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
| | - Marcel den Hoed
- The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
| | - Susanne Mandrup
- Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Tuomas O Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA.
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA.
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA.
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23
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Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance. Nat Commun 2021; 12:74. [PMID: 33397965 PMCID: PMC7782476 DOI: 10.1038/s41467-020-20434-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 12/01/2020] [Indexed: 12/19/2022] Open
Abstract
The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.
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24
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Shahvazian E, Mahmoudi MB, Farashahi Yazd E, Gharibi S, Moghimi B, HosseinNia P, Mirzaei M. The KLF14 Variant is Associated with Type 2 Diabetes and HbA 1C Level. Biochem Genet 2021; 59:574-588. [PMID: 33389382 DOI: 10.1007/s10528-020-10015-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 10/30/2020] [Indexed: 12/20/2022]
Abstract
The purpose of this study was to scan variants in coding region of Krȕppel like factor14 (KLF14) locus and assess association related to type 2 diabetes (T2D) in Iranian population. We sequenced the coding region of KLF14 to scan variants in case-sibling study (92 individuals with T2D and 92 healthy older siblings). To confirm, we analyzed rs76603546 association with T2D in a larger unrelated case-control study by PCR-RFLP (475 cases and 512 controls). We analyzed the association of rs76603546 with HbA1C, BMI, fat mass, waist circumference, fasting glucose, cholesterol and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) using one-way ANOVA analysis. Also, association of genotypes with T2D adjusted for confounding variables was analyzed using logistic regression. HaploReg v 4.1 was used to predict rs76603546 possible function. Sequencing results analysis revealed the association of C allele of rs76603546, synonymous variant C>T, [OR 2.10 (1.38-3.20), P value < 0.001] and CC genotype of rs76603546 [OR 4.3 (1.79-10.23), P value = 0.001] with susceptibility to T2D. PCR-Restriction Fragment Length Polymorphism (RFLP) results analysis confirmed the association of rs76603546 with T2D [C allele, OR 1.91 (1.59-2.29), P value = 0.002, CC genotype, OR 3.27 (2.26-4.73), P value = 0.002 and TC genotype, OR 1.74 (1.31-2.31), P value = 0.001]. The CC genotype of rs76603546 is associated with HbA1C level (P value < 0.001) and BMI (P value = 0.02). After adjustment with confounding variables, we observed association of CC genotype with T2D [OR 2.542 (1.25-3.77), P value = 0.03]. Among over 220 SNPs, rs76603546 was associated with T2D, HbA1C and BMI in our study.
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Affiliation(s)
- Ensieh Shahvazian
- Department of Genetics, Faculty of Medicine, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohammad Bagher Mahmoudi
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ehsan Farashahi Yazd
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. .,Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. .,Yazd Reproductive Sciences Institute, Bu-Ali Ave., Timsar Fallahi St., Safaeieh, Yazd, Iran.
| | - Saba Gharibi
- Department of Genetics, Faculty of Medicine, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Bahram Moghimi
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Masoud Mirzaei
- Yazd Cardiovascular Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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25
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Molecular and evolutionary processes generating variation in gene expression. Nat Rev Genet 2020; 22:203-215. [PMID: 33268840 DOI: 10.1038/s41576-020-00304-w] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2020] [Indexed: 12/18/2022]
Abstract
Heritable variation in gene expression is common within and between species. This variation arises from mutations that alter the form or function of molecular gene regulatory networks that are then filtered by natural selection. High-throughput methods for introducing mutations and characterizing their cis- and trans-regulatory effects on gene expression (particularly, transcription) are revealing how different molecular mechanisms generate regulatory variation, and studies comparing these mutational effects with variation seen in the wild are teasing apart the role of neutral and non-neutral evolutionary processes. This integration of molecular and evolutionary biology allows us to understand how the variation in gene expression we see today came to be and to predict how it is most likely to evolve in the future.
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26
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Hongfang G, Khan R, Raza SHA, Nurgulsim K, Suhail SM, Rahman A, Ahmed I, Ijaz A, Ahmad I, Linsen Z. Transcriptional regulation of adipogenic marker genes for the improvement of intramuscular fat in Qinchuan beef cattle. Anim Biotechnol 2020; 33:776-795. [PMID: 33151113 DOI: 10.1080/10495398.2020.1837847] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The intramuscular fat content plays a crucial role in meat quality traits. Increasing the degree of adipogenesis in beef cattle leads to an increase in the content of intramuscular fat. Adipogenesis a complex biochemical process which is under firm genetic control. Over the last three decades, the Qinchuan beef cattle have been extensively studied for the improvement of meat production and quality traits. In this study, we reviewed the literature regarding adipogenesis and intramuscular fat deposition. Then, we summarized the research conducted on the transcriptional regulation of key adipogenic marker genes, and also reviewed the roles of adipogenic marker genes in adipogenesis of Qinchuan beef cattle. This review will elaborate our understanding regarding transcriptional regulation which is a vital physiological process regulated by a cascade of transcription factors (TFs), key target marker genes, and regulatory proteins. This synergistic action of TFs and target genes ensures the accurate and diverse transmission of the genetic information for the accomplishment of central physiological processes. This information will provide an insight into the transcriptional regulation of the adipogenic marker genes and its role in bovine adipogenesis for the breed improvement programs especially for the trait of intramuscular fat deposition.
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Affiliation(s)
- Guo Hongfang
- Medical College of Xuchang University, Xuchang City, Henan Province, P. R. China
| | - Rajwali Khan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China.,Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Kaster Nurgulsim
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
| | - Syed Muhammad Suhail
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Abdur Rahman
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Ijaz Ahmed
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Asim Ijaz
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Iftikhar Ahmad
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, Pakistan
| | - Zan Linsen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, P. R. China
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27
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Prevention of Diabetes and Cardiovascular Disease in Obesity. Int J Mol Sci 2020; 21:ijms21218178. [PMID: 33142938 PMCID: PMC7663329 DOI: 10.3390/ijms21218178] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
Obesity is one of the major risk factors for the development of both impaired glucose tolerance (IGT, or prediabetes) and type 2 diabetes (T2D), and its prevalence worldwide drives toward an increased rate of cardiovascular morbidity and mortality. Given the estimations of the World Health Organization (WHO) and the recommendation of the Diabetes Prevention Program (DPP), where IGT and diabetes are considered as risk factors for the development of cardiovascular complications and obesity, the development of diabetes should be treated because of its potential reversibility. In this view, several interventions such as diet, lifestyle changes, and pharmacological treatment are effective, including bariatric metabolic surgery (BMS), which is the most incisive way to efficiently lower body weight. In this review, we sought to summarize some of the major aspects linked to diabetes prevention in overweight/obesity, focusing on the use of surgery; we also attempted to elucidate molecular pathways involved in a variety of obesity-induced processes able to favor the progression of chronic diseases, such as diabetes and its complications.
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28
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The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 2020; 369:1318-1330. [PMID: 32913098 PMCID: PMC7737656 DOI: 10.1126/science.aaz1776] [Citation(s) in RCA: 2714] [Impact Index Per Article: 542.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
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29
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Pereira M, Ko JH, Logan J, Protheroe H, Kim KB, Tan ALM, Croucher PI, Park KS, Rotival M, Petretto E, Bassett JD, Williams GR, Behmoaras J. A trans-eQTL network regulates osteoclast multinucleation and bone mass. eLife 2020; 9:55549. [PMID: 32553114 PMCID: PMC7351491 DOI: 10.7554/elife.55549] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 06/12/2020] [Indexed: 12/11/2022] Open
Abstract
Functional characterisation of cell-type-specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1 knockout mice displayed abnormal bone phenotypes. We report opposing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast multinucleation and bone mass.
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Affiliation(s)
- Marie Pereira
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom.,Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Jeong-Hun Ko
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom.,Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - John Logan
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Hayley Protheroe
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Kee-Beom Kim
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
| | | | - Peter I Croucher
- The Garvan Institute of Medical Research and St. Vincent's Clinical School, University of NewSouth Wales Medicine, Sydney, Australia
| | - Kwon-Sik Park
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United States
| | - Maxime Rotival
- Human Evolutionary Genetics Unit, Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, Paris, France
| | | | - Jh Duncan Bassett
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Graham R Williams
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Jacques Behmoaras
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom
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Abstract
Cardiovascular diseases are the leading cause of death worldwide. Complex diseases with highly heterogenous disease progression among patient populations, cardiovascular diseases feature multifactorial contributions from both genetic and environmental stressors. Despite significant effort utilizing multiple approaches from molecular biology to genome-wide association studies, the genetic landscape of cardiovascular diseases, particularly for the nonfamilial forms of heart failure, is still poorly understood. In the past decade, systems-level approaches based on omics technologies have become an important approach for the study of complex traits in large populations. These advances create opportunities to integrate genetic variation with other biological layers to identify and prioritize candidate genes, understand pathogenic pathways, and elucidate gene-gene and gene-environment interactions. In this review, we will highlight some of the recent progress made using systems genetics approaches to uncover novel mechanisms and molecular bases of cardiovascular pathophysiological manifestations. The key technology and data analysis platforms necessary to implement systems genetics will be described, and the current major challenges and future directions will also be discussed. For complex cardiovascular diseases, such as heart failure, systems genetics represents a powerful strategy to obtain mechanistic insights and to develop individualized diagnostic and therapeutic regiments, paving the way for precision cardiovascular medicine.
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Affiliation(s)
- Christoph D. Rau
- Departments of Anesthesiology, Medicine, Physiology
- Current address: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Aldons J. Lusis
- Department of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Yibin Wang
- Departments of Anesthesiology, Medicine, Physiology
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31
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Yang Q, Civelek M. Transcription Factor KLF14 and Metabolic Syndrome. Front Cardiovasc Med 2020; 7:91. [PMID: 32548128 PMCID: PMC7274157 DOI: 10.3389/fcvm.2020.00091] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome (MetSyn) is a combination of metabolic abnormalities that lead to the development of cardiovascular disease (CVD) and Type 2 Diabetes (T2D). Although various criteria for defining MetSyn exist, common abnormalities include abdominal obesity, elevated serum triglyceride, insulin resistance, and blood glucose, decreased high-density lipoprotein cholesterol (HDL-C), and hypertension. MetSyn prevalence has been increasing with the rise of obesity worldwide, with significantly higher prevalence in women compared with men and in Hispanics compared with Whites. Affected individuals are at a higher risk of developing T2D (5-fold) and CVD (2-fold). Heritability estimates for individual components of MetSyn vary between 40 and 70%, suggesting a strong contribution of an individual's genetic makeup to disease pathology. The advent of next-generation sequencing technologies has enabled large-scale genome-wide association studies (GWAS) into the genetics underlying MetSyn pathogenesis. Several such studies have implicated the transcription factor KLF14, a member of the Krüpple-like factor family (KLF), in the development of metabolic diseases, including obesity, insulin resistance, and T2D. How KLF14 regulates these metabolic traits and increases the risk of developing T2D, atherosclerosis, and liver dysfunction is still unknown. There have been some debate and controversial results with regards to its expression profile and functionality in various tissues, and a systematic review of current knowledge on KLF14 is lacking. Here, we summarize the research progress made in understanding the function of KLF14 and describe common attributes of its biochemical, physiological, and pathophysiological roles. We also discuss the current challenges in understanding the role of KLF14 in metabolism and provide suggestions for future directions.
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Affiliation(s)
- Qianyi Yang
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
| | - Mete Civelek
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
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32
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IRF4 and STAT3 activities are associated with the imbalanced differentiation of T-cells in responses to inhalable particulate matters. Respir Res 2020; 21:123. [PMID: 32448264 PMCID: PMC7245756 DOI: 10.1186/s12931-020-01368-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 04/22/2020] [Indexed: 12/23/2022] Open
Abstract
Background Particulate Matter (PM) is known to cause inflammatory responses in human. Although prior studies verified the immunogenicity of PM in cell lines and animal models, the effectors of PM exposure in the respiratory system and the regulators of the immunogenicity of PM is not fully elucidated. Methods To identify the potential effector of PM exposure in human respiratory system and to better understand the biology of the immunogenicity of PM, We performed gene-expression profiling of peripheral blood mononuclear cells from 171 heathy subjects in northern China to identify co-expressed gene modules associated with PM exposure. We inferred transcription factors regulating the co-expression and validated the association to T-cell differentiation in both primary T-cells and mice treated with PM. Results We report two transcription factors, IRF4 and STAT3, as regulators of the gene expression in response to PM exposure in human. We confirmed that the activation of IRF4 and STAT3 by PM is strongly associated with imbalanced differentiation of T-cells in the respiratory tracts in a time-sensitive manner in mouse. We also verified the consequential inflammatory responses of the PM exposure. Moreover, we show that the protein levels of phosphorylated IRF4 and STAT3 increase with PM exposure. Conclusions Our study suggests the regulatory activities of IRF4 and STAT3 are associated with the Th17-mediated inflammatory responses to PM exposure in the respiratory tracts, which informs the biological background of the immunogenicity of particulate matters.
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Gao X, Liu S, Song H, Feng X, Duan M, Huang L, Zhou F. AgeGuess, a Methylomic Prediction Model for Human Ages. Front Bioeng Biotechnol 2020; 8:80. [PMID: 32211384 PMCID: PMC7075810 DOI: 10.3389/fbioe.2020.00080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
Aging was a biological process under regulations from both inherited genetic factors and various molecular modifications within cells during the lifespan. Multiple studies demonstrated that the chronological age may be accurately predicted using the methylomic data. This study proposed a three-step feature selection algorithm AgeGuess for the age regression problem. AgeGuess selected 107 methylomic features as the gender-independent age biomarkers and the Support Vector Regressor (SVR) model using these biomarkers achieved 2.0267 in the mean absolute deviation (MAD) compared with the real chronological ages. Another regression algorithm Ridge achieved a slightly better MAD 1.9859 using the same biomarkers. The gender-independent age prediction models may be further improved by establishing two gender-specific models. And it's interesting to observe that there were only two methylation biomarkers shared by the two gender-specific biomarker sets and these two biomarkers were within the two known age-associated biomarker genes CALB1 and KLF14.
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Affiliation(s)
- Xiaoqian Gao
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
| | - Shuai Liu
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
| | - Haoqiu Song
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China.,College of Computer Science, Hubei University of Technology, Wuhan, China
| | - Xin Feng
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
| | - Meiyu Duan
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
| | - Lan Huang
- Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
| | - Fengfeng Zhou
- BioKnow Health Informatics Laboratory Key Laboratory of Symbolic Computation and Knowledge Engineering, College of Computer Science and Technology, Ministry of Education, Jilin University, Changchun, China
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34
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Chen X, Shi W, Zhang H. The role of KLF14 in multiple disease processes. Biofactors 2020; 46:276-282. [PMID: 31925990 DOI: 10.1002/biof.1612] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022]
Abstract
Kruppel-like factor 14 (KLF14) is a newly identified member of the KLF family. Expression of KLF14 is induced by TGF-β in intrauterine and ectodermal tissue. Initial researches on KLF14 focused on its role in lipid and glucose metabolism. In recent years, however, the role of KLF14 in regulating cell signaling pathways, cell proliferation and differentiation has been explored. Moreover, the research has gradually extended into the field of tumorigenesis and immune regulation. This paper aims to briefly review the functions of KLF14 in physiologyical and pathological process.
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Affiliation(s)
- Xiaoyan Chen
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjie Shi
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Zhang
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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35
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Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17020493. [PMID: 31941024 PMCID: PMC7013753 DOI: 10.3390/ijerph17020493] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022]
Abstract
During puberty, a woman’s breasts are vulnerable to environmental damage (“window of vulnerability”). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.
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36
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Vijay J, Gauthier MF, Biswell RL, Louiselle DA, Johnston JJ, Cheung WA, Belden B, Pramatarova A, Biertho L, Gibson M, Simon MM, Djambazian H, Staffa A, Bourque G, Laitinen A, Nystedt J, Vohl MC, Fraser JD, Pastinen T, Tchernof A, Grundberg E. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat Metab 2020; 2:97-109. [PMID: 32066997 PMCID: PMC7025882 DOI: 10.1038/s42255-019-0152-6] [Citation(s) in RCA: 274] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depot-specific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status and those include a population of potential dysfunctional CD8+ T cells expressing metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, which shares common features with beige preadipocytes. Our human single-cell transcriptome atlas across fat depots provides a resource to dissect functional genomics of metabolic disease.
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Affiliation(s)
- Jinchu Vijay
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, Québec, Canada
| | | | - Rebecca L Biswell
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Daniel A Louiselle
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Jeffrey J Johnston
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Warren A Cheung
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Bradley Belden
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Albena Pramatarova
- McGill University and Genome Québec Innovation Centre, Montreal, Québec, Canada
| | - Laurent Biertho
- Québec Heart and Lung Institute, Université Laval, Québec, Québec, Canada
| | - Margaret Gibson
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | | | - Haig Djambazian
- McGill University and Genome Québec Innovation Centre, Montreal, Québec, Canada
| | - Alfredo Staffa
- McGill University and Genome Québec Innovation Centre, Montreal, Québec, Canada
| | - Guillaume Bourque
- Department of Human Genetics, McGill University, Montreal, Québec, Canada
- McGill University and Genome Québec Innovation Centre, Montreal, Québec, Canada
| | | | | | - Marie-Claude Vohl
- Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, Québec, Canada
| | - Jason D Fraser
- Department of Surgery, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Tomi Pastinen
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - André Tchernof
- Québec Heart and Lung Institute, Université Laval, Québec, Québec, Canada.
| | - Elin Grundberg
- Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, USA.
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Schröder J, Schüller V, May A, Gerges C, Anders M, Becker J, Hess T, Kreuser N, Thieme R, Ludwig KU, Noder T, Venerito M, Veits L, Schmidt T, Fuchs C, Izbicki JR, Hölscher AH, Dakkak D, Jansen-Winkeln B, Moulla Y, Lyros O, Niebisch S, Mehdorn M, Lang H, Lorenz D, Schumacher B, Mayershofer R, Vashist Y, Ott K, Vieth M, Weismüller J, Mangold E, Nöthen MM, Moebus S, Knapp M, Neuhaus H, Rösch T, Ell C, Gockel I, Schumacher J, Böhmer AC. Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data. PLoS One 2019; 14:e0227072. [PMID: 31891614 PMCID: PMC6938334 DOI: 10.1371/journal.pone.0227072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/10/2019] [Indexed: 01/29/2023] Open
Abstract
Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10-8) and novel candidate loci (5×10-8 ≤ P ≤ 5×10-5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10-7 and rs1540, Pcombined = 4.16×10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.
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Affiliation(s)
- Julia Schröder
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Vitalia Schüller
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Andrea May
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christian Gerges
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Jessica Becker
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Timo Hess
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Center for Human Genetics, University Hospital Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Kerstin U. Ludwig
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Claudia Fuchs
- Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Arnulf H. Hölscher
- Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Dani Dakkak
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Yusef Moulla
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Hauke Lang
- Department of General, Visceral, and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Dietmar Lorenz
- Department of General, Visceral, and Thoracic Surgery, Klinikum Darmstadt, Darmstadt, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | | | - Yogesh Vashist
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
- Kantonsspital Aarau, Aarau, Switzerland
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral, and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | | | - Elisabeth Mangold
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Markus M. Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Susanne Moebus
- Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, University of Essen, Essen, Germany
| | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Horst Neuhaus
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | | | - Anne C. Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
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Wong KH, Levy‐Sakin M, Ma W, Gonzaludo N, Mak AC, Vaka D, Poon A, Chu C, Lao R, Balamir M, Grenville Z, Wong N, Kane JP, Kwok P, Malloy MJ, Pullinger CR. Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis. Mol Genet Genomic Med 2019; 7:e1007. [PMID: 31617323 PMCID: PMC6900368 DOI: 10.1002/mgg3.1007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/18/2019] [Accepted: 09/25/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis. OBJECTIVE We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds. METHODS We applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL. RESULTS In the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs. CONCLUSIONS While the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.
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Affiliation(s)
- Karen H.Y. Wong
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - Michal Levy‐Sakin
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - Walfred Ma
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - Nina Gonzaludo
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - Angel C.Y. Mak
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
- Lung Biology CenterUniversity of CaliforniaSan FranciscoCAUSA
| | - Dedeepya Vaka
- Institute for Human GeneticsUniversity of CaliforniaSan FranciscoCAUSA
| | - Annie Poon
- Institute for Human GeneticsUniversity of CaliforniaSan FranciscoCAUSA
| | - Catherine Chu
- Institute for Human GeneticsUniversity of CaliforniaSan FranciscoCAUSA
| | - Richard Lao
- Institute for Human GeneticsUniversity of CaliforniaSan FranciscoCAUSA
| | - Melek Balamir
- Department of Internal MedicineIstanbul UniversityIstanbulTurkey
| | - Zoe Grenville
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - Nicolas Wong
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
| | - John P. Kane
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
- Department of MedicineUniversity of CaliforniaSan FranciscoCAUSA
- Department of Biochemistry and BiophysicsUniversity of CaliforniaSan FranciscoCAUSA
| | - Pui‐Yan Kwok
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
- Institute for Human GeneticsUniversity of CaliforniaSan FranciscoCAUSA
- Department of DermatologyUniversity of CaliforniaSan FranciscoCAUSA
| | - Mary J. Malloy
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
- Department of MedicineUniversity of CaliforniaSan FranciscoCAUSA
- Department of PediatricsUniversity of CaliforniaSan FranciscoCAUSA
| | - Clive R. Pullinger
- Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoCAUSA
- Department of Physiological NursingUniversity of CaliforniaSan FranciscoCAUSA
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Xiong Z, Dankova G, Howe LJ, Lee MK, Hysi PG, de Jong MA, Zhu G, Adhikari K, Li D, Li Y, Pan B, Feingold E, Marazita ML, Shaffer JR, McAloney K, Xu SH, Jin L, Wang S, de Vrij FMS, Lendemeijer B, Richmond S, Zhurov A, Lewis S, Sharp GC, Paternoster L, Thompson H, Gonzalez-Jose R, Bortolini MC, Canizales-Quinteros S, Gallo C, Poletti G, Bedoya G, Rothhammer F, Uitterlinden AG, Ikram MA, Wolvius E, Kushner SA, Nijsten TEC, Palstra RJTS, Boehringer S, Medland SE, Tang K, Ruiz-Linares A, Martin NG, Spector TD, Stergiakouli E, Weinberg SM, Liu F, Kayser M. Novel genetic loci affecting facial shape variation in humans. eLife 2019; 8:e49898. [PMID: 31763980 PMCID: PMC6905649 DOI: 10.7554/elife.49898] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 11/22/2019] [Indexed: 12/14/2022] Open
Abstract
The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.
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Affiliation(s)
- Ziyi Xiong
- Department of Genetic IdentificationErasmus MC University Medical Center RotterdamRotterdamNetherlands
- Department of EpidemiologyErasmus MC University Medical Center RotterdamRotterdamNetherlands
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of GenomicsUniversity of Chinese Academy of Sciences (CAS)BeijingChina
| | - Gabriela Dankova
- Department of Genetic IdentificationErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Laurence J Howe
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
| | - Myoung Keun Lee
- Center for Craniofacial and Dental Genetics, Department of Oral BiologyUniversity of PittsburghPittsburghUnited States
| | - Pirro G Hysi
- Department of Twin Research and Genetic EpidemiologyKing’s College LondonLondonUnited Kingdom
| | - Markus A de Jong
- Department of Genetic IdentificationErasmus MC University Medical Center RotterdamRotterdamNetherlands
- Department of Oral & Maxillofacial Surgery, Special Dental Care, and OrthodonticsErasmus MC University Medical Center RotterdamRotterdamNetherlands
- Department of Biomedical Data SciencesLeiden University Medical CenterLeidenNetherlands
| | - Gu Zhu
- QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Kaustubh Adhikari
- Department of Genetics, Evolution, and EnvironmentUniversity College LondonLondonUnited Kingdom
| | - Dan Li
- CAS Key Laboratory of Computational BiologyChinese Academy of Sciences (CAS)ShanghaiChina
- CAS-MPG Partner Institute for Computational Biology (PICB)Chinese Academy of Sciences (CAS)ShanghaiChina
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological SciencesChinese Academy of Sciences (CAS)ShanghaiChina
| | - Yi Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of GenomicsUniversity of Chinese Academy of Sciences (CAS)BeijingChina
| | - Bo Pan
- Department of Auricular ReconstructionPlastic Surgery HospitalBeijingChina
| | - Eleanor Feingold
- Center for Craniofacial and Dental Genetics, Department of Oral BiologyUniversity of PittsburghPittsburghUnited States
| | - Mary L Marazita
- Center for Craniofacial and Dental Genetics, Department of Oral BiologyUniversity of PittsburghPittsburghUnited States
- Department of Human GeneticsUniversity of PittsburghPittsburghUnited States
| | - John R Shaffer
- Center for Craniofacial and Dental Genetics, Department of Oral BiologyUniversity of PittsburghPittsburghUnited States
- Department of Human GeneticsUniversity of PittsburghPittsburghUnited States
| | | | - Shu-Hua Xu
- CAS Key Laboratory of Computational BiologyChinese Academy of Sciences (CAS)ShanghaiChina
- CAS-MPG Partner Institute for Computational Biology (PICB)Chinese Academy of Sciences (CAS)ShanghaiChina
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological SciencesChinese Academy of Sciences (CAS)ShanghaiChina
- School of Life Science and TechnologyShanghaiTech UniversityShanghaiChina
- Center for Excellence in Animal Evolution and GeneticsChinese Academy of SciencesKunmingChina
| | - Li Jin
- CAS Key Laboratory of Computational BiologyChinese Academy of Sciences (CAS)ShanghaiChina
- CAS-MPG Partner Institute for Computational Biology (PICB)Chinese Academy of Sciences (CAS)ShanghaiChina
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological SciencesChinese Academy of Sciences (CAS)ShanghaiChina
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life SciencesFudan UniversityShanghaiChina
| | - Sijia Wang
- CAS Key Laboratory of Computational BiologyChinese Academy of Sciences (CAS)ShanghaiChina
- CAS-MPG Partner Institute for Computational Biology (PICB)Chinese Academy of Sciences (CAS)ShanghaiChina
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological SciencesChinese Academy of Sciences (CAS)ShanghaiChina
- Center for Excellence in Animal Evolution and GeneticsChinese Academy of SciencesKunmingChina
| | - Femke MS de Vrij
- Department of PsychiatryErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Bas Lendemeijer
- Department of PsychiatryErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Stephen Richmond
- Applied Clinical Research and Public Health, University Dental SchoolCardiff UniversityCardiffUnited Kingdom
| | - Alexei Zhurov
- Applied Clinical Research and Public Health, University Dental SchoolCardiff UniversityCardiffUnited Kingdom
| | - Sarah Lewis
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
| | - Gemma C Sharp
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
- School of Oral and Dental SciencesUniversity of BristolBristolUnited Kingdom
| | - Lavinia Paternoster
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
| | - Holly Thompson
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
| | - Rolando Gonzalez-Jose
- Instituto Patagonico de Ciencias Sociales y Humanas, CENPAT-CONICETPuerto MadrynArgentina
| | | | - Samuel Canizales-Quinteros
- UNAM-Instituto Nacional de Medicina Genomica, Facultad de QuımicaUnidad de Genomica de Poblaciones Aplicada a la SaludMexico CityMexico
| | - Carla Gallo
- Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y FilosofıaUniversidad Peruana Cayetano HerediaLimaPeru
| | - Giovanni Poletti
- Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias y FilosofıaUniversidad Peruana Cayetano HerediaLimaPeru
| | - Gabriel Bedoya
- GENMOL (Genetica Molecular)Universidad de AntioquiaMedellınColombia
| | | | - André G Uitterlinden
- Department of EpidemiologyErasmus MC University Medical Center RotterdamRotterdamNetherlands
- Department of Internal MedicineErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - M Arfan Ikram
- Department of EpidemiologyErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Eppo Wolvius
- Department of Oral & Maxillofacial Surgery, Special Dental Care, and OrthodonticsErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Steven A Kushner
- Department of PsychiatryErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Tamar EC Nijsten
- Department of DermatologyErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Robert-Jan TS Palstra
- Department of BiochemistryErasmus MC University Medical Center RotterdamRotterdamNetherlands
| | - Stefan Boehringer
- Department of Biomedical Data SciencesLeiden University Medical CenterLeidenNetherlands
| | | | - Kun Tang
- CAS Key Laboratory of Computational BiologyChinese Academy of Sciences (CAS)ShanghaiChina
- CAS-MPG Partner Institute for Computational Biology (PICB)Chinese Academy of Sciences (CAS)ShanghaiChina
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological SciencesChinese Academy of Sciences (CAS)ShanghaiChina
| | - Andres Ruiz-Linares
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life SciencesFudan UniversityShanghaiChina
- Aix-Marseille Université, CNRS, EFS, ADESMarseilleFrance
| | | | - Timothy D Spector
- Department of Twin Research and Genetic EpidemiologyKing’s College LondonLondonUnited Kingdom
| | - Evie Stergiakouli
- Medical Research Council Integrative Epidemiology Unit, Population Health SciencesUniversity of BristolBristolUnited Kingdom
- School of Oral and Dental SciencesUniversity of BristolBristolUnited Kingdom
| | - Seth M Weinberg
- Center for Craniofacial and Dental Genetics, Department of Oral BiologyUniversity of PittsburghPittsburghUnited States
- Department of Human GeneticsUniversity of PittsburghPittsburghUnited States
- Department of AnthropologyUniversity of PittsburghPittsburghUnited States
| | - Fan Liu
- Department of Genetic IdentificationErasmus MC University Medical Center RotterdamRotterdamNetherlands
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of GenomicsUniversity of Chinese Academy of Sciences (CAS)BeijingChina
| | - Manfred Kayser
- Department of Genetic IdentificationErasmus MC University Medical Center RotterdamRotterdamNetherlands
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Klf14 is an imprinted transcription factor that regulates placental growth. Placenta 2019; 88:61-67. [PMID: 31675530 DOI: 10.1016/j.placenta.2019.09.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Imprinted genes are preferentially expressed from one parentally inherited allele, and many are crucial to the regulation of placental function and fetal growth. Murine Krüppel-like factor 14 (Klf14) is a maternally expressed imprinted transcription factor that is a component of the Mest imprinted gene cluster on mouse chromosome 6. We sought to determine if loss of Klf14 expression alters the course of normal mouse extraembryonic development. We also used high-throughput RNA sequencing (RNAseq) to identify a set of differentially expressed genes (DEGs) in placentas with loss of Klf14. METHODS We generated a Klf14 knockout (Klf14null) mouse using recombineering and transgenic approaches. To identify DEGs in the mouse placenta we compared mRNA transcriptomes derived from 17.5dpc Klf14matKO and wild-type littermate placentas by RNAseq. Candidate DEGs were confirmed with quantitative reverse transcription PCR (qPCR) on an independent cohort of male and female gestational age matched Klf14matKO placentas. RESULTS We found that 17.5dpc placentas inheriting a maternal null allele (Klf14matKO) had a modest overgrowth phenotype and a near complete ablation of Klf14 expression. However, there was no effect on fetal growth. We identified 20 DEGs differentially expressed in Klf14matKO placentas by RNAseq, and subsequently validated five that are highly upregulated (Begain, Col26a1, Fbln5, Gdf10, and Nell1) by qPCR. The most enriched functional gene-networks included those classified as regulating cellular development and metabolism. CONCLUSION These results suggest that loss of the maternal Klf14 locus in the mouse placenta acts results in changes in gene expression patterns that modulate placental growth.
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Zhao Z, Tian H, Shi B, Jiang Y, Liu X, Hu J. Transcriptional Regulation of the Bovine Fatty Acid Transport Protein 1 Gene by Krüppel-Like Factors 15. Animals (Basel) 2019; 9:ani9090654. [PMID: 31491871 PMCID: PMC6769441 DOI: 10.3390/ani9090654] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 12/27/2022] Open
Abstract
Simple Summary The nutritional value and qualities of beef are enhanced when the unsaturated fatty acid content is increased. Fatty acid transport protein 1 (FATP1), also called SLC27A1, an integral membrane protein that facilitates long-chain fatty acid influx, is involved in the genetic network for oleic acid synthesis in beef. Polymorphisms in bovine SLC27A1 gene are most significantly associated with oleic acid. Its expression exhibits significant positive correlations with bovine intramuscular fat content in the longissimus thoracis muscle. However, the transcription factors that contribute to the control and regulation of its expression have not been characterized extensively. In this study, we determined the tissue distribution of SLC27A1 mRNA and found that bovine SLC27A1 was highly expressed in subcutaneous adipose tissue and the longissimus thoracis muscle. Furthermore, we analyzed the molecular mechanisms involved in SLC27A1 regulation and found that the transcriptional activity of SLC27A1 gene was dependent on KLF15 transcription factor. These results may lead to an enhanced understanding of the regulation of SLC27A1 expression in other models, as well as provide new insights into the regulatory mechanism and biological functions of the SLC27A1 gene in determining the lipid composition in beef. Abstract Oleic acid is a major monounsaturated fatty acid, which accounts for about 33% of the fatty acid content in beef and is considered to have the least negative effect on serum cholesterol levels. Fatty acid transport protein 1 (FATP1), an integral membrane protein that facilitates long-chain fatty acid (LCFA) influx, is involved in the genetic network for oleic acid synthesis in beef. Its expression exhibits significant positive correlations with intramuscular fat (IMF) content in the longissimus thoracis. However, the expression mechanism of SLC27A1 or FATP1 is still unclear. To elucidate the molecular mechanisms involved in bovine SLC27A1 regulation, we cloned and characterized the promoter region of SLC27A1. By applying 5′-rapid amplification of cDNA end analysis, we identified two alternative splice variants of this gene. Using a series of 5′ deletion promoter plasmids in luciferase reporter assays, we found that the core promoter was 96 base pairs upstream from the transcription initiation site. Electrophoretic mobility shift assay combined with a site-directed mutation experiment demonstrated that KLF15 binding to the promoter region drives the SLC27A1 transcription. KLF15 plays an essential role in adipogenesis and skeletal muscle lipid flux. Thus, these results might provide further information on the regulatory roles of SLC27A1 gene in mediating the lipid composition in beef.
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Affiliation(s)
- Zhidong Zhao
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Hongshan Tian
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Bingang Shi
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Yanyan Jiang
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Xiu Liu
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
| | - Jiang Hu
- College of Animal Science and Technology & Gansu Key Laboratory of Herbivorous Animal Biotechnology, Gansu Agricultural University, Lanzhou 730070, China.
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Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173074. [PMID: 31450859 PMCID: PMC6747190 DOI: 10.3390/ijerph16173074] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/14/2019] [Accepted: 08/20/2019] [Indexed: 12/15/2022]
Abstract
DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined "epigenetic clock", with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.
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Baliga NS, Björkegren JLM, Boeke JD, Boutros M, Crawford NPS, Dudley AM, Farber CR, Jones A, Levey AI, Lusis AJ, Mak HC, Nadeau JH, Noyes MB, Petretto E, Seyfried NT, Steinmetz LM, Vonesch SC. The State of Systems Genetics in 2017. Cell Syst 2019; 4:7-15. [PMID: 28125793 DOI: 10.1016/j.cels.2017.01.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cell Systems invited 16 experts to share their views on the field of systems genetics. In questions repeated in the headings, we asked them to define systems genetics, highlight its relevance to researchers outside the field, discuss what makes a strong systems genetics paper, and paint a picture of where the field is heading in the coming years. Their responses, ordered by the journal but otherwise unedited, make it clear that deciphering genotype to phenotype relationships is a central challenge of systems genetics and will require understanding how networks and higher-order properties of biological systems underlie complex traits. In addition, our experts illuminate the applications and relevance of systems genetics to human disease, the gut microbiome, development of tools that connect the global research community, sustainability, drug discovery, patient-specific disease and network models, and personalized treatments. Finally, a table of suggested reading provides a sample of influential work in the field.
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Affiliation(s)
| | - Johan L M Björkegren
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Estonia
| | - Jef D Boeke
- Institute for Systems Genetics, NYU Langone Medical Center, New York, NY, USA
| | - Michael Boutros
- German Cancer Research Center (DKFZ) and Heidelberg University, Germany
| | | | - Aimée M Dudley
- Pacific Northwest Research Institute, Seattle, Washington, USA
| | - Charles R Farber
- Departments of Public Health Sciences and Biochemistry and Molecular Genetics, Center for Public Health Genomics, University of Virginia, Charlottesville VA, 22908, USA
| | - Allan Jones
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
| | - Allan I Levey
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Aldons J Lusis
- Department of Medicine; Department of Microbiology, Immunology and Molecular Genetics; Department of Human Genetics, University of California Los Angeles, California, USA
| | - H Craig Mak
- Cell Systems, Cell Press, Cambridge, MA, USA.
| | - Joseph H Nadeau
- Pacific Northwest Research Institute, Seattle, Washington, USA
| | - Marcus B Noyes
- Institute for Systems Genetics, NYU Langone Medical Center, New York, NY, USA
| | - Enrico Petretto
- Cardiovascular & Metabolic Disorders Program and Centre for Computational Biology, Duke-National University of Singapore (NUS) Medical School, Singapore
| | - Nicholas T Seyfried
- Department of Biochemistry and Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Lars M Steinmetz
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany; Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sibylle C Vonesch
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
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Ling C, Rönn T. Epigenetics in Human Obesity and Type 2 Diabetes. Cell Metab 2019; 29:1028-1044. [PMID: 30982733 PMCID: PMC6509280 DOI: 10.1016/j.cmet.2019.03.009] [Citation(s) in RCA: 552] [Impact Index Per Article: 92.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/05/2019] [Accepted: 03/18/2019] [Indexed: 12/16/2022]
Abstract
Epigenetic mechanisms control gene activity and the development of an organism. The epigenome includes DNA methylation, histone modifications, and RNA-mediated processes, and disruption of this balance may cause several pathologies and contribute to obesity and type 2 diabetes (T2D). This Review summarizes epigenetic signatures obtained from human tissues of relevance for metabolism-i.e., adipose tissue, skeletal muscle, pancreatic islets, liver, and blood-in relation to obesity and T2D. Although this research field is still young, these comprehensive data support not only a role for epigenetics in disease development, but also epigenetic alterations as a response to disease. Genetic predisposition, as well as aging, contribute to epigenetic variability, and several environmental factors, including exercise and diet, further interact with the human epigenome. The reversible nature of epigenetic modifications holds promise for future therapeutic strategies in obesity and T2D.
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Affiliation(s)
- Charlotte Ling
- Epigenetics and Diabetes Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
| | - Tina Rönn
- Epigenetics and Diabetes Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden
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Allum F, Hedman ÅK, Shao X, Cheung WA, Vijay J, Guénard F, Kwan T, Simon MM, Ge B, Moura C, Boulier E, Rönnblom L, Bernatsky S, Lathrop M, McCarthy MI, Deloukas P, Tchernof A, Pastinen T, Vohl MC, Grundberg E. Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements. Nat Commun 2019; 10:1209. [PMID: 30872577 PMCID: PMC6418220 DOI: 10.1038/s41467-019-09184-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 02/25/2019] [Indexed: 12/16/2022] Open
Abstract
Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (Ntotal~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.
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Affiliation(s)
- Fiona Allum
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Åsa K Hedman
- Department of Medicine Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, 171 76, Sweden
| | - Xiaojian Shao
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Warren A Cheung
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
- Children's Mercy Hospitals and Clinics, Kansas City, MO, 64108, USA
| | - Jinchu Vijay
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Frédéric Guénard
- Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, QC, G1V 0A6, Canada
| | - Tony Kwan
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Marie-Michelle Simon
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Bing Ge
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Cristiano Moura
- Department of Epidemiology, McGill University, Montréal, QC, H3A 1A2, Canada
| | - Elodie Boulier
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Lars Rönnblom
- Department of Medical Sciences, Uppsala University, Uppsala, 751 85, Sweden
| | - Sasha Bernatsky
- Department of Epidemiology, McGill University, Montréal, QC, H3A 1A2, Canada
| | - Mark Lathrop
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
| | - Mark I McCarthy
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Old Road, Headington, Oxford, OX3 7LJ, UK
- Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - André Tchernof
- Québec Heart and Lung Institute, Université Laval, Québec, QC, G1V 0A6, Canada
| | - Tomi Pastinen
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada
- Children's Mercy Hospitals and Clinics, Kansas City, MO, 64108, USA
| | - Marie-Claude Vohl
- Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, QC, G1V 0A6, Canada
| | - Elin Grundberg
- Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada.
- McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada.
- Children's Mercy Hospitals and Clinics, Kansas City, MO, 64108, USA.
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46
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Qin H, Niu T, Zhao J. Identifying Multi-Omics Causers and Causal Pathways for Complex Traits. Front Genet 2019; 10:110. [PMID: 30847004 PMCID: PMC6393387 DOI: 10.3389/fgene.2019.00110] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 01/30/2019] [Indexed: 12/23/2022] Open
Abstract
The central dogma of molecular biology delineates a unidirectional causal flow, i.e., DNA → RNA → protein → trait. Genome-wide association studies, next-generation sequencing association studies, and their meta-analyses have successfully identified ~12,000 susceptibility genetic variants that are associated with a broad array of human physiological traits. However, such conventional association studies ignore the mediate causers (i.e., RNA, protein) and the unidirectional causal pathway. Such studies may not be ideally powerful; and the genetic variants identified may not necessarily be genuine causal variants. In this article, we model the central dogma by a mediate causal model and analytically prove that the more remote an omics level is from a physiological trait, the smaller the magnitude of their correlation is. Under both random and extreme sampling schemes, we numerically demonstrate that the proteome-trait correlation test is more powerful than the transcriptome-trait correlation test, which in turn is more powerful than the genotype-trait association test. In conclusion, integrating RNA and protein expressions with DNA data and causal inference are necessary to gain a full understanding of how genetic causal variants contribute to phenotype variations.
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Affiliation(s)
- Huaizhen Qin
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, United States
| | - Tianhua Niu
- Department of Global Biostatistics and Data Science, Tulane University, New Orleans, LA, United States
- Department of Biochemistry and Molecular Biology, Tulane University School Medicine, New Orleans, LA, United States
| | - Jinying Zhao
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, FL, United States
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47
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Hsieh PN, Fan L, Sweet DR, Jain MK. The Krüppel-Like Factors and Control of Energy Homeostasis. Endocr Rev 2019; 40:137-152. [PMID: 30307551 PMCID: PMC6334632 DOI: 10.1210/er.2018-00151] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 10/05/2018] [Indexed: 12/16/2022]
Abstract
Nutrient handling by higher organisms is a complex process that is regulated at the transcriptional level. Studies over the past 15 years have highlighted the critical importance of a family of transcriptional regulators termed the Krüppel-like factors (KLFs) in metabolism. Within an organ, distinct KLFs direct networks of metabolic gene targets to achieve specialized functions. This regulation is often orchestrated in concert with recruitment of tissue-specific transcriptional regulators, particularly members of the nuclear receptor family. Upon nutrient entry into the intestine, gut, and liver, KLFs control a range of functions from bile synthesis to intestinal stem cell maintenance to effect nutrient acquisition. Subsequently, coordinated KLF activity across multiple organs distributes nutrients to sites of storage or liberates them for use in response to changes in nutrient status. Finally, in energy-consuming organs like cardiac and skeletal muscle, KLFs tune local metabolic programs to precisely match substrate uptake, flux, and use, particularly via mitochondrial function, with energetic demand; this is achieved in part via circulating mediators, including glucocorticoids and insulin. Here, we summarize current understanding of KLFs in regulation of nutrient absorption, interorgan circulation, and tissue-specific use.
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Affiliation(s)
- Paishiun N Hsieh
- Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Liyan Fan
- Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - David R Sweet
- Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Mukesh K Jain
- Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio.,Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio
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48
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Liu F, Chen Y, Zhu G, Hysi PG, Wu S, Adhikari K, Breslin K, Pospiech E, Hamer MA, Peng F, Muralidharan C, Acuna-Alonzo V, Canizales-Quinteros S, Bedoya G, Gallo C, Poletti G, Rothhammer F, Bortolini MC, Gonzalez-Jose R, Zeng C, Xu S, Jin L, Uitterlinden AG, Ikram MA, van Duijn CM, Nijsten T, Walsh S, Branicki W, Wang S, Ruiz-Linares A, Spector TD, Martin NG, Medland SE, Kayser M. Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair. Hum Mol Genet 2019; 27:559-575. [PMID: 29220522 PMCID: PMC5886212 DOI: 10.1093/hmg/ddx416] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 11/29/2017] [Indexed: 01/18/2023] Open
Abstract
Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62–0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans.
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Affiliation(s)
- Fan Liu
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.,University of Chinese Academy of Sciences, Beijing, China
| | - Yan Chen
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Gu Zhu
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Pirro G Hysi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Sijie Wu
- University of Chinese Academy of Sciences, Beijing, China.,Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Kaustubh Adhikari
- Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK
| | - Krystal Breslin
- Department of Biology, Indiana-University-Purdue-University-Indianapolis (IUPUI), Indianapolis, IN, USA
| | - Ewelina Pospiech
- Institute of Zoology and Biomedical Research, Faculty of Biology and Earth Sciences, Jagiellonian University, Kraków, Poland.,Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland
| | - Merel A Hamer
- Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Fuduan Peng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Charanya Muralidharan
- Department of Biology, Indiana-University-Purdue-University-Indianapolis (IUPUI), Indianapolis, IN, USA
| | - Victor Acuna-Alonzo
- Laboratorio de Genética Molecular, Escuela Nacional de Antropologia e Historia, México City, México
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica, México City, México
| | - Gabriel Bedoya
- GENMOL (Genética Molecular), Universidad de Antioquia, Medellín, Colombia
| | - Carla Gallo
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Giovanni Poletti
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Perú
| | | | - Maria Catira Bortolini
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil
| | - Rolando Gonzalez-Jose
- Instituto Patagónico de Ciencias Sociales y Humanas, CENPAT-CONICET, Puerto Madryn, Argentina
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Shuhua Xu
- University of Chinese Academy of Sciences, Beijing, China.,Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.,School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Li Jin
- University of Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - André G Uitterlinden
- Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Tamar Nijsten
- Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Susan Walsh
- Department of Biology, Indiana-University-Purdue-University-Indianapolis (IUPUI), Indianapolis, IN, USA
| | - Wojciech Branicki
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.,Central Forensic Laboratory of the Police, Warsaw, Poland
| | - Sijia Wang
- University of Chinese Academy of Sciences, Beijing, China.,Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Andrés Ruiz-Linares
- Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK.,Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.,Laboratory of Biocultural Anthropology, Law, Ethics, and Health (Centre National de la Recherche Scientifique and Etablissement Français du Sang), Aix-Marseille Université, Marseille, France
| | - Timothy D Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Nicholas G Martin
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sarah E Medland
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Manfred Kayser
- Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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49
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Wu G, Yuan S, Chen Z, Chen G, Fan Q, Dong H, Ye F, Li J, Zhu X. The KLF14 Transcription Factor Regulates Glycolysis by Downregulating LDHB in Colorectal Cancer. Int J Biol Sci 2019; 15:628-635. [PMID: 30745849 PMCID: PMC6367579 DOI: 10.7150/ijbs.30652] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 11/29/2018] [Indexed: 12/24/2022] Open
Abstract
The Krüppel-like transcription factor 14 (KLF14) is a critical regulator of a wide array of biological processes. However, the role of KLF14 in colorectal cancer (CRC) isn't fully investigated. This study aimed to explore the clinicopathological significance and potential role of KLF14 in the carcinogenesis and progression of CRC. A tissue microarray consisting of 185 samples from stage I-III CRC patients was adopted to analyze the correlation between KLF14 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The underlying mechanisms of altered KLF14 expression on glycolysis were studied using in vitro and patients' samples. The results showed that KLF14 expression was downregulated in CRC than their normal controls. Low KLF14 expression correlated with advanced T stage (P< 0.001) and N stage (P= 0.040), and larger tumor size (P= 0.008). Lost KLF14 expression implied shorter OS and DFS after colectomy in both univariate and multivariate survival analysis (P<0.05). Experimentally, restore KLF14 expression significantly decreased the rate of glycolysis both in vitro and in patients' sample. Mechanically, KLF14 regulated glycolysis by downregulating glycolytic enzyme LDHB. Collectively, KLF14 is a novel prognostic biomarker for survival in CRC, and downregulation of KLF14 in CRC prompts glycolysis by target LDHB. Hence, KLF14 could constitute potential prognostic predictors and therapeutic targets for CRC.
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Affiliation(s)
- Guiyang Wu
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Shichao Yuan
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Zaiping Chen
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Guoping Chen
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Qinghao Fan
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Hao Dong
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Fubo Ye
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jing Li
- Departments of CyberKnife, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Xiongwen Zhu
- Department of General Surgery, Taizhou Municipal Hospital, Medical School of Taizhou University, Taizhou 318000, Zhejiang Province, China
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50
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Witka BZ, Oktaviani DJ, Marcellino M, Barliana MI, Abdulah R. Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors. Diabetes Metab Syndr Obes 2019; 12:2689-2706. [PMID: 31908510 PMCID: PMC6927489 DOI: 10.2147/dmso.s230061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a major cause of mortality worldwide. There are several types of diabetes, with type 2 diabetes mellitus (T2DM) being the most common. Many factors, including environmental and genetic factors, are involved in the etiology of the disease. Numerous studies have reported the role of genetic polymorphisms in the initiation and development of T2DM. While genome-wide association studies have identified around more than 200 susceptibility loci, it remains unclear whether these loci are correlated with the pathophysiology of the disease. The present review aimed to elucidate the potential genetic mechanisms underlying T2DM. We found that some genetic polymorphisms were related to T2DM, either in the form of single-nucleotide polymorphisms or direct amino acid changes in proteins. These polymorphisms are potential predictors for the management of T2DM.
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Affiliation(s)
- Beska Z Witka
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Dede J Oktaviani
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Marcellino Marcellino
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Melisa I Barliana
- Departement of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
- Correspondence: Melisa I Barliana Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor45363, Indonesia Email
| | - Rizky Abdulah
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
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