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Nikpour M, Morrisroe K, Calderone A, Yates D, Silman A. Occupational dust and chemical exposures and the development of autoimmune rheumatic diseases. Nat Rev Rheumatol 2025; 21:137-156. [PMID: 39910253 DOI: 10.1038/s41584-024-01216-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2024] [Indexed: 02/07/2025]
Abstract
Although the association between certain occupational exposures and the development of autoimmune rheumatic disease was first described over a century ago, this association has only become more widely recognized in the past 10 years because of the use of high-silica-content engineered stone in construction and home renovation. There is now a substantial and growing body of evidence that occupational dust and chemical exposure, be it through mining, stonemasonry, building or other trades, increases the risk of various systemic autoimmune rheumatic diseases (SARDs) including rheumatoid arthritis and systemic sclerosis. Although the pathogenic mechanisms of silica-induced autoimmunity are not fully elucidated, it is thought that alveolar macrophage ingestion of silica and the ensuing phagosomal damage is an initiating event that ultimately leads to production of autoantibodies and immune-mediated tissue injury. The purportedly causal association between occupational exposure to chemicals, such as organic solvents, and an increased risk of SARDs is less frequently recognized compared with silica dust, and its immunopathogenesis is less well understood. An appreciation of the importance of occupational dust and chemical exposures in the development of SARDs has implications for workplace health and safety regulations and offers a unique opportunity to better understand autoimmune disease pathogenesis and implement preventative strategies.
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Affiliation(s)
- Mandana Nikpour
- University of Sydney Musculoskeletal Research Flagship Centre and School of Public Health, Camperdown, Sydney, New South Wales, Australia.
- Department of Rheumatology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.
| | - Kathleen Morrisroe
- Department of Medicine, The University of Melbourne at St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
- Department of Rheumatology, St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
| | - Alicia Calderone
- Department of Rheumatology, St Vincent's Hospital (Melbourne), Fitzroy, Victoria, Australia
| | - Deborah Yates
- Asbestos & Dust Diseases Research Institute, Concord, New South Wales, Australia
- Respiratory & Sleep Medicine, Macquarie University Hospital, Macquarie University, New South Wales, Australia
| | - Alan Silman
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
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2
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Allen LA, Taylor PN, Gillespie KM, Oram RA, Dayan CM. Maternal type 1 diabetes and relative protection against offspring transmission. Lancet Diabetes Endocrinol 2023; 11:755-767. [PMID: 37666263 DOI: 10.1016/s2213-8587(23)00190-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 09/06/2023]
Abstract
Type 1 diabetes is around twice as common in the offspring of men with type 1 diabetes than in the offspring of women with type 1 diabetes, but the reasons for this difference are unclear. This Review summarises the evidence on the rate of transmission of type 1 diabetes to the offspring of affected fathers compared with affected mothers. The findings of nine major studies are presented, describing the magnitude of the effect observed and the relative strengths and weaknesses of these studies. This Review also explores possible underlying mechanisms for this effect, such as genetic mechanisms (eg, the selective loss of fetuses with high-risk genes in mothers with type 1 diabetes, preferential transmission of susceptibility genes from fathers, and parent-of-origin effects influencing gene expression), environmental exposures (eg, exposure to maternal hyperglycaemia, exogenous insulin exposure, and transplacental antibody transfer), and maternal microchimerism. Understanding why type 1 diabetes is more common in the offspring of men versus women with type 1 diabetes will help in the identification of individuals at high risk of the disease and can pave the way in the development of interventions that mimic the protective elements of maternal type 1 diabetes to reduce the risk of disease in individuals at high risk.
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Affiliation(s)
- Lowri A Allen
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK.
| | - Peter N Taylor
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK
| | - Kathleen M Gillespie
- Diabetes and Metabolism, Bristol Medical School, University of Bristol, Southmead Hospital, Bristol, UK
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK
| | - Colin M Dayan
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK
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3
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Chen S, Xi M, Gao F, Li M, Dong T, Geng Z, Liu C, Huang F, Wang J, Li X, Wei P, Miao F. Evaluation of mulberry leaves’ hypoglycemic properties and hypoglycemic mechanisms. Front Pharmacol 2023; 14:1045309. [PMID: 37089923 PMCID: PMC10117911 DOI: 10.3389/fphar.2023.1045309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/31/2023] [Indexed: 04/08/2023] Open
Abstract
The effectiveness of herbal medicine in treating diabetes has grown in recent years, but the precise mechanism by which it does so is still unclear to both medical professionals and diabetics. In traditional Chinese medicine, mulberry leaf is used to treat inflammation, colds, and antiviral illnesses. Mulberry leaves are one of the herbs with many medicinal applications, and as mulberry leaf study grows, there is mounting evidence that these leaves also have potent anti-diabetic properties. The direct role of mulberry leaf as a natural remedy in the treatment of diabetes has been proven in several studies and clinical trials. However, because mulberry leaf is a more potent remedy for diabetes, a deeper understanding of how it works is required. The bioactive compounds flavonoids, alkaloids, polysaccharides, polyphenols, volatile oils, sterols, amino acids, and a variety of inorganic trace elements and vitamins, among others, have been found to be abundant in mulberry leaves. Among these compounds, flavonoids, alkaloids, polysaccharides, and polyphenols have a stronger link to diabetes. Of course, trace minerals and vitamins also contribute to blood sugar regulation. Inhibiting alpha glucosidase activity in the intestine, regulating lipid metabolism in the body, protecting pancreatic -cells, lowering insulin resistance, accelerating glucose uptake by target tissues, and improving oxidative stress levels in the body are some of the main therapeutic properties mentioned above. These mechanisms can effectively regulate blood glucose levels. The therapeutic effects of the bioactive compounds found in mulberry leaves on diabetes mellitus and their associated molecular mechanisms are the main topics of this paper’s overview of the state of the art in mulberry leaf research for the treatment of diabetes mellitus.
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Affiliation(s)
- Sikai Chen
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Miaomiao Xi
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
- Xi’an TANK Medicinal Biology Institute, Xi’an, China
| | - Feng Gao
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Min Li
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - TaiWei Dong
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhixin Geng
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Chunyu Liu
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Fengyu Huang
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jing Wang
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xingyu Li
- Shaanxi University of Chinese Medicine, Xianyang, China
| | - Peifeng Wei
- Shaanxi University of Chinese Medicine, Xianyang, China
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
- *Correspondence: Peifeng Wei, ; Feng Miao,
| | - Feng Miao
- The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
- *Correspondence: Peifeng Wei, ; Feng Miao,
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Micro-RNA Implications in Type-1 Diabetes Mellitus: A Review of Literature. Int J Mol Sci 2021; 22:ijms222212165. [PMID: 34830046 PMCID: PMC8621893 DOI: 10.3390/ijms222212165] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/24/2021] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
Type-1 diabetes mellitus (T1DM) is one of the most well-defined and complex metabolic disorders, characterized by hyperglycemia, with a constantly increasing incidence in children and adolescents. While current knowledge regarding the molecules related to the pathogenesis and diagnosis of T1DM is vast, the discovery of new molecules, such as micro ribonucleic acids (micro-RNAs, miRNAs), as well as their interactions with T1DM, has spurred novel prospects in the diagnosis of the disease. This review aims at summarizing current knowledge regarding miRNAs' biosynthesis and action pathways and their role as gene expression regulators in T1DM. MiRNAs follow a complex biosynthesis pathway, including cleaving and transport from nucleus to cytoplasm. After assembly of their final form, they inhibit translation or cause messenger RNA (mRNA) degradation, resulting in the obstruction of protein synthesis. Many studies have reported miRNA involvement in T1DM pathogenesis, mainly through interference with pancreatic b-cell function, insulin production and secretion. They are also found to contribute to β-cell destruction, as they aid in the production of autoreactive agents. Due to their elevated accumulation in various biological specimens, as well as their involvement in T1DM pathogenesis, their role as biomarkers in early preclinical T1DM diagnosis is widely hypothesized, with future studies concerning their diagnostic value deemed a necessity.
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Lecamwasam A, Novakovic B, Meyer B, Ekinci EI, Dwyer KM, Saffery R. DNA methylation profiling identifies epigenetic differences between early versus late stages of diabetic chronic kidney disease. Nephrol Dial Transplant 2021; 36:2027-2038. [PMID: 33146725 DOI: 10.1093/ndt/gfaa226] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND We investigated a cross-sectional epigenome-wide association study of patients with early and late diabetes-associated chronic kidney disease (CKD) to identify possible epigenetic differences between the two groups as well as changes in methylation across all stages of diabetic CKD. We also evaluated the potential of using a panel of identified 5'-C-phosphate-G-3' (CpG) sites from this cohort to predict the progression of diabetic CKD. METHODS This cross-sectional study recruited 119 adults. DNA was extracted from blood using the Qiagen QIAampDNA Mini Spin Kit. Genome-wide methylation analysis was performed using Illumina Infinium MethylationEPIC BeadChips (HM850K). Intensity data files were processed and analysed using the minfi and MissMethyl packages for R. We examined the degree of methylation of CpG sites in early versus late diabetic CKD patients for CpG sites with an unadjusted P-value <0.01 and an absolute change in methylation of 5% (n = 239 CpG sites). RESULTS Hierarchical clustering of the 239 CpG sites largely separated the two groups. A heat map for all 239 CpG sites demonstrated distinct methylation patterns in the early versus late groups, with CpG sites showing evidence of progressive change. Based on our differentially methylated region (DMR) analysis of the 239 CpG sites, we highlighted two DMRs, namely the cysteine-rich secretory protein 2 (CRISP2) and piwi-like RNA-mediated gene silencing 1 (PIWIL1) genes. The best predictability for the two groups involved a receiver operating characteristics curve of eight CpG sites alone and achieved an area under the curve of 0.976. CONCLUSIONS We have identified distinct DNA methylation patterns between early and late diabetic CKD patients as well as demonstrated novel findings of potential progressive methylation changes across all stages (1-5) of diabetic CKD at specific CpG sites. We have also identified associated genes CRISP2 and PIWIL1, which may have the potential to act as stage-specific diabetes-associated CKD markers, and showed that the use of a panel of eight identified CpG sites alone helps to increase the predictability for the two groups.
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Affiliation(s)
| | - Boris Novakovic
- Epigenetics Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Braydon Meyer
- Epigenetics Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Elif I Ekinci
- Department of Endocrinology, Austin Health, Melbourne, Victoria, Australia.,Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Karen M Dwyer
- School of Medicine, Faculty of Health, Deakin University, Melbourne, Victoria, Australia
| | - Richard Saffery
- Epigenetics Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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6
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Margaritis K, Margioula-Siarkou G, Margioula-Siarkou C, Petousis S, Kotanidou EP, Christoforidis A, Pavlou E, Galli-Tsinopoulou A. Circulating serum and plasma levels of micro-RNA in type-1 diabetes in children and adolescents: A systematic review and meta-analysis. Eur J Clin Invest 2021; 51:e13510. [PMID: 33565089 DOI: 10.1111/eci.13510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/05/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Type 1 diabetes mellitus (T1DM) is a complex metabolic disorder characterized by hyperglycaemia, with constantly increasing incidence in paediatric population. The discovery of new molecules, such as microRNAs, and their possible interactions with T1DM create novel aspects in the diagnosis of the disease. METHODS This systematic review and meta-analysis adhered to PRISMA guidelines. MEDLINE, SCOPUS, Cochrane CENTRAL and Clinicaltrials.gov. were searched up to 20 April 2020. Inclusion criteria for individual studies were quantification of microRNAs in serum/plasma samples and study groups consisting of children and adolescents with T1DM and healthy controls. Primary outcome of the study was the qualitative expression of microRNAs between the two groups. Statistical analysis was performed with Comprehensive Meta-Analysis Software v3.0. Methodological quality of included studies was assessed using Newcastle-Ottawa scale. RESULTS A total of 484 studies were retrieved from the initial search of the databases. These were subsequently limited to seven included studies. Seven microRNAs demonstrated contrasting expression between the two groups, with two of them showing significant overexpression in T1DM group (miR-181:95% CI: 0.429 to 1.341 P < .001, miR-210:95% CI: 0.381 to 0.852, P < .001) and one micro-RNA being significantly overexpressed in control group (miR-375:95% CI: 0.293 to 1.459, P = .003). CONCLUSION A total of three micro-RNA molecules appeared to have a significantly different expression in T1DM patients, serving as a possible diagnostic panel of biomarkers. These findings may contribute as reference for future research to further support the use of microRNAs as a novel diagnostic tool in T1DM.
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Affiliation(s)
- Kosmas Margaritis
- 2nd Department of Paediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Georgia Margioula-Siarkou
- 2nd Department of Obstetrics and Gynecology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, Thessaloniki, Greece
| | - Chrysoula Margioula-Siarkou
- 2nd Department of Obstetrics and Gynecology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, Thessaloniki, Greece
| | - Stamatios Petousis
- 2nd Department of Obstetrics and Gynecology, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, Thessaloniki, Greece
| | - Eleni P Kotanidou
- 2nd Department of Paediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Athanasios Christoforidis
- 1st Department of Paediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, Ippokratio General Hospital, Thessaloniki, Greece
| | - Evangelos Pavlou
- 2nd Department of Paediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Paediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA University General Hospital, Thessaloniki, Greece
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7
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Di Ciaula A, Portincasa P. Relationships between emissions of toxic airborne molecules and type 1 diabetes incidence in children: An ecologic study. World J Diabetes 2021; 12:673-684. [PMID: 33995854 PMCID: PMC8107975 DOI: 10.4239/wjd.v12.i5.673] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/17/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 1 diabetes originates from gene-environment interactions, with increasing incidence over time. AIM To identify correlates of childhood type 1 diabetes in European countries using an ecological approach. Several environmental variables potentially influencing the onset of type 1 diabetes have been previously evaluated. However, the relationships between epidemiologic data and exposure to toxic airborne molecules are scarcely studied. METHODS We employed an ecological model to explore, in a wide time period (1990-2018), associations between type 1 diabetes incidence in 19 European countries (systematic literature review) and the nationwide production of five widely diffused air pollutants: particulate matter < 10 μm (PM10), nitrogen oxides (NO), non-methane volatile organic compounds (VOCs), sulphur oxide (SO2), and ammonia. RESULTS Data confirm a raising incidence of type 1 diabetes in 18 out of 19 explored countries. The average difference (last vs first report, all countries) was +6.9 × 100000/year, with values ranging from -1.4 (Germany) to +16.6 (Sweden) per 100000/year. Although the overall production of pollutants decreased progressively from 1990 to 2018, type 1 diabetes incidence was positively associated with the nationwide emissions of PM10, VOCs, and NO but not with those of SO2 and ammonia. Type 1 diabetes incidence was significantly higher in countries with high emissions than in those with low emissions of PM10 (27.5 ± 2.4 vs 14.6 ± 2.4 × 100000 residents, respectively), VOCs (24.5 ± 4.4 vs 13.2 ± 1.7 × 100000 residents, respectively), and NO (26.6 ± 3 vs 13.4 ± 2.4 × 100000 residents, respectively), but not of SO2 or ammonia. CONCLUSION Evidence justify further studies to explore better links between long-term air quality and type 1 diabetes onset at the individual level, which should include exposures during pregnancy. In this respect, type 1 diabetes could be, at least in part, a preventable condition. Thus, primary prevention policies acting through a marked abatement of pollutant emissions might attenuate future type 1 diabetes incidence throughout Europe.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari 70124, Italy
- International Society of Doctors for Environment (ISDE), Via XXV Aprile n.34 – 52100 Arezzo, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari 70124, Italy
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8
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Parveen N, Dhawan S. DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis. Front Endocrinol (Lausanne) 2021; 12:651258. [PMID: 34025578 PMCID: PMC8137853 DOI: 10.3389/fendo.2021.651258] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/21/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.
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Affiliation(s)
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States
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9
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The function and regulation of TET2 in innate immunity and inflammation. Protein Cell 2020; 12:165-173. [PMID: 33085059 PMCID: PMC7895883 DOI: 10.1007/s13238-020-00796-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/15/2020] [Indexed: 02/08/2023] Open
Abstract
TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
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10
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Lecamwasam AR, Mohebbi M, Ekinci EI, Dwyer KM, Saffery R. Identification of Potential Biomarkers of Chronic Kidney Disease in Individuals with Diabetes: Protocol for a Cross-sectional Observational Study. JMIR Res Protoc 2020; 9:e16277. [PMID: 32734931 PMCID: PMC7428908 DOI: 10.2196/16277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 05/03/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
Background The importance of identifying people with diabetes and progressive kidney dysfunction relates to the excess morbidity and mortality of this group. Rates of cardiovascular disease are much higher in people with both diabetes and kidney dysfunction than in those with only one of these conditions. By the time these people are identified in current clinical practice, proteinuria and renal dysfunction are already established, limiting the effectiveness of therapeutic interventions. The identification of an epigenetic or blood metabolite signature or gut microbiome profile may identify those with diabetes at risk of progressive chronic kidney disease, in turn providing targeted intervention to improve patient outcomes. Objective This study aims to identify potential biomarkers in people with diabetes and chronic kidney disease (CKD) associated with progressive renal injury and to distinguish between stages of chronic kidney disease. Three sources of biomarkers will be explored, including DNA methylation profiles in blood lymphocytes, the metabolomic profile of blood-derived plasma and urine, and the gut microbiome. Methods The cross-sectional study recruited 121 people with diabetes and varying stages (stages 1-5) of chronic kidney disease. Single-point data collection included blood, urine, and fecal samples in addition to clinical data such as anthropometric measurements and biochemical parameters. Additional information obtained from medical records included patient demographics, medical comorbidities, and medications. Results Data collection commenced in January 2018 and was completed in June 2018. At the time of submission, 121 patients had been recruited, and 119 samples remained after quality control. There were 83 participants in the early diabetes-associated CKD group with a mean estimated glomerular filtration rate (eGFR) of 61.2 mL/min/1.73 m2 (early CKD group consisting of stage 1, 2, and 3a CKD), and 36 participants in the late diabetic CKD group with a mean eGFR of 23.9 mL/min/1.73 m2 (late CKD group, consisting of stage 3b, 4, and 5), P<.001. We have successfully obtained DNA for methylation and microbiome analyses using the biospecimens collected via this protocol and are currently analyzing these results together with the metabolome of this cohort of individuals with diabetic CKD. Conclusions Recent advances have improved our understanding of the epigenome, metabolomics, and the influence of the gut microbiome on the incidence of diseases such as cancers, particularly those related to environmental exposures. However, there is a paucity of literature surrounding these influencers in renal disease. This study will provide insight into the fundamental understanding of the pathophysiology of CKD in individuals with diabetes, especially in novel areas such as epigenetics, metabolomics, and the kidney-gut axis. International Registered Report Identifier (IRRID) DERR1-10.2196/16277
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Affiliation(s)
- Ashani R Lecamwasam
- Epigenetics Research, Murdoch Children's Research Institute, Victoria, Australia.,Department of Endocrinology, Austin Health, Victoria, Australia.,School of Medicine, Faculty of Health, Deakin University, Victoria, Australia
| | | | - Elif I Ekinci
- Department of Endocrinology, Austin Health, Victoria, Australia.,Department of Medicine, The University of Melbourne, Victoria, Australia
| | - Karen M Dwyer
- School of Medicine, Faculty of Health, Deakin University, Victoria, Australia
| | - Richard Saffery
- Epigenetics Research, Murdoch Children's Research Institute, Victoria, Australia.,Department of Paediatrics, The University of Melbourne, Victoria, Australia
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11
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Sheehan A, Freni Sterrantino A, Fecht D, Elliott P, Hodgson S. Childhood type 1 diabetes: an environment-wide association study across England. Diabetologia 2020; 63:964-976. [PMID: 31980846 PMCID: PMC7145790 DOI: 10.1007/s00125-020-05087-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Type 1 diabetes is an autoimmune disease affecting ~400,000 people across the UK. It is likely that environmental factors trigger the disease process in genetically susceptible individuals. We assessed the associations between a wide range of environmental factors and childhood type 1 diabetes incidence in England, using an agnostic, ecological environment-wide association study (EnWAS) approach, to generate hypotheses about environmental triggers. METHODS We undertook analyses at the local authority district (LAD) level using a national hospital episode statistics-based incident type 1 diabetes dataset comprising 13,948 individuals with diabetes aged 0-9 years over the period April 2000 to March 2011. We compiled LAD level estimates for a range of potential demographic and environmental risk factors including meteorological, land use and environmental pollution variables. The associations between type 1 diabetes incidence and risk factors were assessed via Poisson regression, disease mapping and ecological regression. RESULTS Case counts by LAD varied from 1 to 236 (median 33, interquartile range 24-46). Overall type 1 diabetes incidence was 21.2 (95% CI 20.9, 21.6) per 100,000 individuals. The EnWAS and disease mapping indicated that 15 out of 53 demographic and environmental risk factors were significantly associated with diabetes incidence, after adjusting for multiple testing. These included air pollutants (particulate matter, nitrogen dioxide, nitrogen oxides, carbon monoxide; all inversely associated), as well as lead in soil, radon, outdoor light at night, overcrowding, population density and ethnicity. Disease mapping revealed spatial heterogeneity in type 1 diabetes risk. The ecological regression found an association between type 1 diabetes and the living environment domain of the Index of Multiple Deprivation (RR 0.995; 95% credible interval [CrI] 0.991, 0.998) and radon potential class (RR 1.044; 95% CrI 1.015, 1.074). CONCLUSIONS/INTERPRETATION Our analysis identifies a range of demographic and environmental factors associated with type 1 diabetes in children in England.
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Affiliation(s)
- Annalisa Sheehan
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Anna Freni Sterrantino
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK
- UK Small Area Health Statistics Unit, School of Public Health, Imperial College London, London, UK
| | - Daniela Fecht
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK
- UK Small Area Health Statistics Unit, School of Public Health, Imperial College London, London, UK
| | - Paul Elliott
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK
- UK Small Area Health Statistics Unit, School of Public Health, Imperial College London, London, UK
- Imperial College NIHR Biomedical Research Centre, Imperial College London, London, UK
| | - Susan Hodgson
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.
- UK Small Area Health Statistics Unit, School of Public Health, Imperial College London, London, UK.
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12
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Xie Z, Chang C, Huang G, Zhou Z. The Role of Epigenetics in Type 1 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1253:223-257. [PMID: 32445098 DOI: 10.1007/978-981-15-3449-2_9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the interaction between genetic alterations and environmental factors. More than 60 susceptible genes or loci of T1D have been identified. Among them, HLA regions are reported to contribute about 50% of genetic susceptibility in Caucasians. There are many environmental factors involved in the pathogenesis of T1D. Environmental factors may change the expression of genes through epigenetic mechanisms, thus inducing individuals with susceptible genes to develop T1D; however, the underlying mechanisms remain poorly understood. The major epigenetic modifications include DNA methylation, histone modification, and non-coding RNA. There has been extensive research on the role of epigenetic mechanisms including aberrant DNA methylation, histone modification, and microRNA in the pathogenesis of T1D. DNA methylation and microRNA have been proposed as biomarkers to predict islet β cell death, which needs further confirmation before any clinical application can be developed. Small molecule inhibitors of histone deacetylases, histone methylation, and DNA methylation are potentially important for preventing T1D or in the reprogramming of insulin-producing cells. This chapter mainly focuses on T1D-related DNA methylation, histone modification, and non-coding RNA, as well as their possible translational potential in the early diagnosis and treatment of T1D.
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Affiliation(s)
- Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Christopher Chang
- Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, 33021, USA.,Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, CA, 95616, USA
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, Hunan, China.
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13
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Smail HO. The epigenetics of diabetes, obesity, overweight and cardiovascular disease. AIMS GENETICS 2019; 6:36-45. [PMID: 31663031 PMCID: PMC6803788 DOI: 10.3934/genet.2019.3.36] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 07/25/2019] [Indexed: 02/06/2023]
Abstract
The objectives of this review were once to understand the roles of the epigenetics mechanism in different types of diabetes, obesity, overweight, and cardiovascular disease. Epigenetics represents a phenomenon of change heritable phenotypic expression of genetic records taking place except changes in DNA sequence. Epigenetic modifications can have an impact on a whole of metabolic disease with the aid of specific alteration of candidate genes based totally on the change of the target genes. In this review, I summarized the new findings in DNA methylation, histone modifications in each type of diabetes (type 1 and type 2), obesity, overweight, and cardiovascular disease. The involvement of histone alterations and DNA methylation in the development of metabolic diseases is now widely accepted recently many novel genes have been demonstrated that has roles in diabetes pathway and it can be used for detection prediabetic; however Over the modern-day years, mass spectrometry-based proteomics techniques positioned and mapped one-of a kind range of histone modifications linking obesity and metabolic diseases. The main point of these changes is rapidly growing; however, their points and roles in obesity are no longer properly understood in obesity. Furthermore, epigenetic seen in cardiovascular treatment revealed a massive quantity of modifications affecting the improvement and development of cardiovascular disease. In addition, epigenetics are moreover involved in cardiovascular risk factors such as smoking. The aberrant epigenetic mechanisms that make a contribution to cardiovascular disease.
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Affiliation(s)
- Harem Othman Smail
- Department of Biology, Faculty of science and health, Koya University Koya KOY45, Kurdistan Region-F.R. Iraq
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14
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Stefan-Lifshitz M, Karakose E, Cui L, Ettela A, Yi Z, Zhang W, Tomer Y. Epigenetic modulation of β cells by interferon-α via PNPT1/mir-26a/TET2 triggers autoimmune diabetes. JCI Insight 2019; 4:126663. [PMID: 30721151 DOI: 10.1172/jci.insight.126663] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/29/2019] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β cells. Mounting evidence supports a central role for β cell alterations in triggering the activation of self-reactive T cells in T1D. However, the early deleterious events that occur in β cells, underpinning islet autoimmunity, are not known. We hypothesized that epigenetic modifications induced in β cells by inflammatory mediators play a key role in initiating the autoimmune response. We analyzed DNA methylation (DNAm) patterns and gene expression in human islets exposed to IFN-α, a cytokine associated with T1D development. We found that IFN-α triggers DNA demethylation and increases expression of genes controlling inflammatory and immune pathways. We then demonstrated that DNA demethylation was caused by upregulation of the exoribonuclease, PNPase old-35 (PNPT1), which caused degradation of miR-26a. This in turn promoted the upregulation of ten-eleven translocation 2 (TET2) enzyme and increased 5-hydroxymethylcytosine levels in human islets and pancreatic β cells. Moreover, we showed that specific IFN-α expression in the β cells of IFNα-INS1CreERT2 transgenic mice led to development of T1D that was preceded by increased islet DNA hydroxymethylation through a PNPT1/TET2-dependent mechanism. Our results suggest a new mechanism through which IFN-α regulates DNAm in β cells, leading to changes in expression of genes in inflammatory and immune pathways that can initiate islet autoimmunity in T1D.
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Affiliation(s)
- Mihaela Stefan-Lifshitz
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | | | - Lingguang Cui
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | - Abora Ettela
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
| | - Zhengzi Yi
- Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Weijia Zhang
- Department of Medicine Bioinformatics Core, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yaron Tomer
- Division of Endocrinology and the Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York, USA
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15
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Mothers' experiences of masculinity in the context of child obesity in Mexico. WOMENS STUDIES INTERNATIONAL FORUM 2018. [DOI: 10.1016/j.wsif.2018.07.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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16
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Lecamwasam A, Sexton-Oates A, Carmody J, Ekinci EI, Dwyer KM, Saffery R. DNA methylation profiling of genomic DNA isolated from urine in diabetic chronic kidney disease: A pilot study. PLoS One 2018; 13:e0190280. [PMID: 29462136 PMCID: PMC5819761 DOI: 10.1371/journal.pone.0190280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 12/09/2017] [Indexed: 11/18/2022] Open
Abstract
Aim To characterise the genomic DNA (gDNA) yield from urine and quality of derived methylation data generated from the widely used Illuminia Infinium MethylationEPIC (HM850K) platform and compare this with buffy coat samples. Background DNA methylation is the most widely studied epigenetic mark and variations in DNA methylation profile have been implicated in diabetes which affects approximately 415 million people worldwide. Methods QIAamp Viral RNA Mini Kit and QIAamp DNA micro kit were used to extract DNA from frozen and fresh urine samples as well as increasing volumes of fresh urine. Matched buffy coats to the frozen urine were also obtained and DNA was extracted from the buffy coats using the QIAamp DNA Mini Kit. Genomic DNA of greater concentration than 20μg/ml were used for methylation analysis using the HM850K array. Results Irrespective of extraction technique or the use of fresh versus frozen urine samples, limited genomic DNA was obtained using a starting sample volume of 5ml (0–0.86μg/mL). In order to optimize the yield, we increased starting volumes to 50ml fresh urine, which yielded only 0–9.66μg/mL A different kit, QIAamp DNA Micro Kit, was trialled in six fresh urine samples and ten frozen urine samples with inadequate DNA yields from 0–17.7μg/mL and 0–1.6μg/mL respectively. Sufficient genomic DNA was obtained from only 4 of the initial 41 frozen urine samples (10%) for DNA methylation profiling. In comparison, all four buffy coat samples (100%) provided sufficient genomic DNA. Conclusion High quality data can be obtained provided a sufficient yield of genomic DNA is isolated. Despite optimizing various extraction methodologies, the modest amount of genomic DNA derived from urine, may limit the generalisability of this approach for the identification of DNA methylation biomarkers of chronic diabetic kidney disease.
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Affiliation(s)
- Ashani Lecamwasam
- Clinical and Disease Epigenetics Group, Murdoch Childrens Research Institute, Victoria, Australia
- Department of Endocrinology, Austin Health, Victoria, Australia
- School of Medicine, Faculty of Health Deakin University, Victoria, Australia
- * E-mail:
| | - Alexandra Sexton-Oates
- Clinical and Disease Epigenetics Group, Murdoch Childrens Research Institute, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Victoria, Australia
| | - Jake Carmody
- Clinical and Disease Epigenetics Group, Murdoch Childrens Research Institute, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Victoria, Australia
| | - Elif I. Ekinci
- Department of Endocrinology, Austin Health, Victoria, Australia
| | - Karen M. Dwyer
- School of Medicine, Faculty of Health Deakin University, Victoria, Australia
| | - Richard Saffery
- Clinical and Disease Epigenetics Group, Murdoch Childrens Research Institute, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Victoria, Australia
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17
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Mitochondrial mothers of a fat nation: Race, gender and epigenetics in obesity research on Mexican mestizos. BIOSOCIETIES 2017. [DOI: 10.1057/s41292-017-0078-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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18
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Blossom SJ, Gilbert KM. Epigenetic underpinnings of developmental immunotoxicity and autoimmune disease. CURRENT OPINION IN TOXICOLOGY 2017; 10:23-30. [PMID: 30613805 DOI: 10.1016/j.cotox.2017.11.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The concordance rate for developing autoimmune disease in identical twins is around 50% demonstrating that gene and environmental interactions contribute to disease etiology. The environmental contribution to autoimmune disease is a wide-ranging concept including exposure to immunotoxic environmental chemicals. Because the immune system is immature during development suggests that adult-onset autoimmunity may originate when the immune system is particularly sensitive. Among the pollutants most closely associated with inflammation and/or autoimmunity include Bisphenol-A, mercury, TCDD, and trichloroethylene. These toxicants have been shown to impart epigenetic changes (e.g., DNA methylation) that may alter immune function and promote autoreactivity. Here we review these autoimmune-promoting toxicants and their relation to immune cell epigenetics both in terms of adult and developmental exposure.
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Affiliation(s)
- Sarah J Blossom
- University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR 72202, USA
| | - Kathleen M Gilbert
- University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR 72202, USA
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19
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Belot MP, Nadéri K, Mille C, Boëlle PY, Benachi A, Bougnères P, Fradin D. Role of DNA methylation at the placental RTL1 gene locus in type 1 diabetes. Pediatr Diabetes 2017; 18:178-187. [PMID: 27174469 DOI: 10.1111/pedi.12387] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 02/22/2016] [Accepted: 03/17/2016] [Indexed: 12/13/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified more than 40 T1D loci associated with type 1 diabetes (T1D). How these polymorphisms interact with environmental factors to trigger T1D is unknown, but recent evidence suggests that epigenetic mechanisms could play a role. To begin to explore the contribution of epigenetics to T1D, we have examined DNA methylation in a pilot study of whole blood cells DNA from 10 young T1D patients and 10 young controls. Through the study of >900 000 CG loci across a diverse set of functionally relevant genomic regions using a custom DNA methylation array, we identified 250 T1D-differentially methylated region (DMR) at p < 0.05 and 1 DMR using next a permutation-based multiple testing correction method. This DMR is located in an imprinted region previously associated with T1D on the chromosome 14 that encompasses RTL1 gene and 2 miRNAs (miR136 and miR432). Using pyrosequencing-based bisulfite PCR, we replicated this association in a different and larger set of T1D patients and controls. DNA methylation at this DMR was inversely correlated with RTL1 gene expression and positively correlated with miR136 expression in human placentas. The DMR identified in this study presents suggestive evidence for altered methylation site in T1D and provide a promising new candidate gene. RTL1 is essential for placental permeability function in the mid-to-late fetal stages. We suggest that hypo-methylation could increase the fetal exposure to environmental factors in T1D susceptibility.
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Affiliation(s)
- Marie-Pierre Belot
- INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
| | - Kambiz Nadéri
- INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
| | - Clémence Mille
- INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
| | - Pierre-Yves Boëlle
- Université Pierre et Marie Curie, Service de Biostatistique - INSERM U707, Paris, France
| | - Alexandra Benachi
- Department of Obstetric and Gynecology, Antoine Béclère Hospital, Paris Sud University, Clamart, France
| | - Pierre Bougnères
- INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.,Department of Pediatric Endocrinology, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
| | - Delphine Fradin
- INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
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20
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Luna P, Guarner V, Farías JM, Hernández-Pacheco G, Martínez M. Importance of Metabolic Memory in the Development of Vascular Complications in Diabetic Patients. J Cardiothorac Vasc Anesth 2016; 30:1369-78. [DOI: 10.1053/j.jvca.2016.02.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Indexed: 02/07/2023]
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21
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Mulder CL, Zheng Y, Jan SZ, Struijk RB, Repping S, Hamer G, van Pelt AMM. Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases. Hum Reprod Update 2016; 22:561-73. [PMID: 27240817 PMCID: PMC5001497 DOI: 10.1093/humupd/dmw017] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/28/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Subfertility affects approximately 15% of all couples, and a severe male factor is identified in 17% of these couples. While the etiology of a severe male factor remains largely unknown, prior gonadotoxic treatment and genomic aberrations have been associated with this type of subfertility. Couples with a severe male factor can resort to ICSI, with either ejaculated spermatozoa (in case of oligozoospermia) or surgically retrieved testicular spermatozoa (in case of azoospermia) to generate their own biological children. Currently there is no direct treatment for azoospermia or oligozoospermia. Spermatogonial stem cell (SSC) autotransplantation (SSCT) is a promising novel clinical application currently under development to restore fertility in sterile childhood cancer survivors. Meanwhile, recent advances in genomic editing, especially the clustered regulatory interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) system, are likely to enable genomic rectification of human SSCs in the near future. OBJECTIVE AND RATIONALE The objective of this review is to provide insights into the prospects of the potential clinical application of SSCT with or without genomic editing to cure spermatogenic failure and to prevent transmission of genetic diseases. SEARCH METHODS We performed a narrative review using the literature available on PubMed not restricted to any publishing year on topics of subfertility, fertility treatments, (molecular regulation of) spermatogenesis and SSCT, inherited (genetic) disorders, prenatal screening methods, genomic editing and germline editing. For germline editing, we focussed on the novel CRISPR-Cas9 system. We included papers written in English only. OUTCOMES Current techniques allow propagation of human SSCs in vitro, which is indispensable to successful transplantation. This technique is currently being developed in a preclinical setting for childhood cancer survivors who have stored a testis biopsy prior to cancer treatment. Similarly, SSCT could be used to restore fertility in sterile adult cancer survivors. In vitro propagation of SSCs might also be employed to enhance spermatogenesis in oligozoospermic men and in azoospermic men who still have functional SSCs albeit in insufficient numbers. The combination of SSCT with genomic editing techniques could potentially rectify defects in spermatogenesis caused by genomic mutations or, more broadly, prevent transmission of genomic diseases to the offspring. In spite of the promising prospects, SSCT and germline genomic editing are not yet clinically applicable and both techniques require optimization at various levels. WIDER IMPLICATIONS SSCT with or without genomic editing could potentially be used to restore fertility in cancer survivors to treat couples with a severe male factor and to prevent the paternal transmission of diseases. This will potentially allow these couples to have their own biological children. Technical development is progressing rapidly, and ethical reflection and societal debate on the use of SSCT with or without genomic editing is pressing.
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Affiliation(s)
- Callista L Mulder
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Yi Zheng
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Sabrina Z Jan
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Robert B Struijk
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Sjoerd Repping
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Geert Hamer
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Ans M M van Pelt
- Center for Reproductive Medicine, Amsterdam Research Institute Reproduction and Development, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
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22
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Abstract
With the impressive advancement in high-throughput 'omics' technologies over the past two decades, epigenetic mechanisms have emerged as the regulatory interface between the genome and environmental factors. These mechanisms include DNA methylation, histone modifications, ATP-dependent chromatin remodeling and RNA-based mechanisms. Their highly interdependent and coordinated action modulates the chromatin structure controlling access of the transcription machinery and thereby regulating expression of target genes. Given the rather limited proliferative capability of human cardiomyocytes, epigenetic regulation appears to play a particularly important role in the myocardium. The highly dynamic nature of the epigenome allows the heart to adapt to environmental challenges and to respond quickly and properly to cardiac stress. It is now becoming evident that histone-modifying and chromatin-remodeling enzymes as well as numerous non-coding RNAs play critical roles in cardiac development and function, while their dysregulation contributes to the onset and development of pathological cardiac remodeling culminating in HF. This review focuses on up-to-date knowledge about the epigenetic mechanisms and highlights their emerging role in the healthy and failing heart. Uncovering the determinants of epigenetic regulation holds great promise to accelerate the development of successful new diagnostic and therapeutic strategies in human cardiac disease.
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Affiliation(s)
- José Marín-García
- The Molecular Cardiology and Neuromuscular Institute, 75 Raritan Ave., Highland Park, NJ, 08904, USA,
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23
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Di Ciaula A. Type I diabetes in paediatric age in Apulia (Italy): Incidence and associations with outdoor air pollutants. Diabetes Res Clin Pract 2016; 111:36-43. [PMID: 26527558 DOI: 10.1016/j.diabres.2015.10.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 10/01/2015] [Accepted: 10/14/2015] [Indexed: 02/06/2023]
Abstract
AIM This study aimed to explore Type 1 diabetes (T1D) incidence and possible relations with specific air pollutants in a large population of children, during a wide time period. METHODS T1D rates and trends were examined (2001-2013, GAM and Joinpoint Regression analysis) by data on the first hospitalization in all children (0-14 years) living in Apulia (Southern Italy, average yearly population aged 0-14 years in the examined period: 631,275 subjects), and linked with levels of PM10, NOx, CO and ozone. RESULTS A total of 1501 children were first discharged in the selected area with a diagnosis of T1D. Incidence decreased from 48.5 (95% CI 43.3; 54.0, 2001) to 16.9 per 100,000 (95% CI 13.7; 20.6, 2013), with differences according to age at onset (constant at 0-4 years, continuously decreasing at 5-9 years, decreasing until 2003 at 10-14 years), and with a positive relation with PM10--but not ozone, NOx and CO average air levels. The OR was 1.037 (1.002; 1.074) in the high tertile of PM10 concentrations, and mean incidence was higher with PM10 levels in the highest, than in the medium/reference tertile. Mean age at T1D onset was linked with yearly PM10 and ozone air levels. CONCLUSIONS On a wide period, a stable or decreased incidence of T1D was evident in children with early- or later onset of disease, respectively. PM10 exposure significantly affects the incidence of T1D, which might be considered, at least in part, a preventable condition.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine, Hospital of Bisceglie (ASL BAT), Bisceglie, Italy; International Society of Doctors for Environment (ISDE), Arezzo, Italy.
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24
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Dos Santos JM, Moreli ML, Tewari S, Benite-Ribeiro SA. The effect of exercise on skeletal muscle glucose uptake in type 2 diabetes: An epigenetic perspective. Metabolism 2015; 64:1619-28. [PMID: 26481513 DOI: 10.1016/j.metabol.2015.09.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 09/09/2015] [Accepted: 09/19/2015] [Indexed: 02/08/2023]
Abstract
Changes in eating habits and sedentary lifestyle are main contributors to type 2 diabetes (T2D) development, and studies suggest that epigenetic modifications are involved with the growing incidence of this disease. Regular exercise modulates many intracellular pathways improving insulin resistance and glucose uptake in skeletal muscle, both early abnormalities of T2D. Mitochondria dysfunction and decreased expression of glucose transporter (GLUT4) were identified as main factors of insulin resistance. Moreover, it has been suggested that skeletal muscle of T2D subjects have a different pattern of epigenetic marks on the promoter of GLUT4 and PGC1, main regulator of mitochondrial function, compared with nondiabetic individuals. Recent studies have proposed that regular exercise could improve glucose uptake by the attenuation of such epigenetic modification induced at GLUT4, PGC1 and its downstream regulators; however, the exact mechanism is still to be understood. Herein we review the known epigenetic modifications on GLUT4 and mitochondrial proteins that lead to impairment of skeletal muscle glucose uptake and T2D development, and the effect of physical exercise at these modifications.
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Affiliation(s)
| | | | - Shikha Tewari
- Dr. Ram Manohar Lohia, Institute of Medical Science, Lucknow, India
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25
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Hansen MP, Matheis N, Kahaly GJ. Type 1 diabetes and polyglandular autoimmune syndrome: A review. World J Diabetes 2015; 6:67-79. [PMID: 25685279 PMCID: PMC4317318 DOI: 10.4239/wjd.v6.i1.67] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 11/11/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome.
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26
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Yip L, Fathman CG. Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis. Immunol Res 2015; 58:340-50. [PMID: 24682832 DOI: 10.1007/s12026-014-8501-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals. The emphasis placed on genome-wide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets. Using the nonobese diabetic (NOD) mouse model of T1D and the non-disease prone congenic NOD.B10 mice, our laboratory demonstrated striking tissue-specific and age-dependent changes in gene expression during disease progression. We established a "roadmap" of differential gene expression and used this to identify candidate genes in mice (and human orthologs) that play a role in disease pathology. Here, we describe two genes, Deformed epidermal autoregulatory factor 1 (Deaf1) and Adenosine A1 receptor (Adora1), that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominant-negative non-functional isoforms. Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance, while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes. Remarkably, both genes were also alternatively spliced in the same tissues of auto-antibody positive prediabetic patients, and these splicing events resulted in similar downstream effects as those seen in NOD mice. These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1D.
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Affiliation(s)
- Linda Yip
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, CCSR Room 2225, Stanford, CA, 94305-5166, USA
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Ferjeni Z, Bouzid D, Fourati H, Stayoussef M, Abida O, Kammoun T, Hachicha M, Penha-Gonçalves C, Masmoudi H. Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study. Immunol Lett 2014; 163:1-7. [PMID: 25448703 DOI: 10.1016/j.imlet.2014.11.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 10/30/2014] [Accepted: 11/10/2014] [Indexed: 11/28/2022]
Abstract
Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2.782; p=0.005) of TCRβ gene. We also demonstrated that rs10918706 in the intron of the CD3z gene was associated with increased risk of T1D (Z score 2.137; p=0.032). In the same region, rs2949655 (Z score=2.101; p=0.035) and rs1214611 (Z score=4.036; p=0.00005) showed a genotype association with the risk of T1D. When haplotypes were constructed, GAA haplotype displayed significant association with T1D (Z score=2.135; p=0.032), while GGA haplotype (Z score=-1.988; p=0.046) was negatively associated with the disease. We also identified an association with rs3181096 (Z score=2.177; p=0.029), rs17695937 (Z score =2.111; p=0.034) and rs2488457 (Z score=2.219; p=0.026), respectively of CD28, ZAP70 and PTPN22 genes. In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively. While, the GTCT (Z score=-2.114, p=0.034) and CTAGG (Z score=-2.121, p=0.033) haplotypes of CD28 and PTPN22 genes, may confer protection against T1D. These findings confirm the role of PTPN22 and CD28 involved in the T cell activation pathway in the development of T1D in Tunisian families. Interestingly, ZAP70 and TCRβ/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
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Affiliation(s)
- Zouidi Ferjeni
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
| | - D Bouzid
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
| | - H Fourati
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
| | - M Stayoussef
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
| | - O Abida
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
| | - T Kammoun
- Pediatric Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia
| | - M Hachicha
- Pediatric Department, Hedi Chaker Hospital, University of Sfax, Sfax, Tunisia
| | | | - H Masmoudi
- Immunology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia
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Gloria-Bottini F, Saccucci P, Meloni GF, Manca-Bitti ML, Coppeta L, Neri A, Magrini A, Egidio B. Study of factors influencing susceptibility and age at onset of type 1 diabetes: A review of data from Continental Italy and Sardinia. World J Diabetes 2014; 5:557-561. [PMID: 25126401 PMCID: PMC4127590 DOI: 10.4239/wjd.v5.i4.557] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 03/06/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the role of protein tyrosin phosphatase 22 (PTPN22), maternal age at conception and sex on susceptibility and age at onset of type 1 diabetes (T1D) in Continental Italy and Sardinian populations.
METHODS: Three hundred seventy six subjects admitted consecutively to the hospital for T1D and 1032 healthy subjects as controls were studied in Continental Italy and 284 subjects admitted consecutively to the hospital for T1D and 5460 healthy newborns were studied in Sardinia. PTPN22 genotype was determined by DNA analysis. Maternal age at conception and age at onset of disease were obtained from clinical records. χ2 test of independence, student t test for differences between means and odds ratio analysis were carried out by SPSS programs. Three way contingency table analysis was carried out according to Sokal and Rohlf.
RESULTS: The pattern of association between PTPN22 and T1D is similar in Continental Italy and Sardinia: the proportion of *T allele carriers is 13.6% in T1D vs 6.7% in controls in Continental Italy while in Sardinia is 7.3% in T1D vs 4.4% in controls. The association between T1D and maternal age at conception is much stronger in Sardinia than in Italy: the proportion of newborn from mother aging more than 32 years is 89.3% in T1D vs 32.7% in consecutive newborn in Sardinia (P < 10-6) while in Continental Italy is 32.2% in T1D vs 19.1% in consecutive newborns (P = 0.005). This points to an important role of ethnicity. A slight prevalence of T1D males on T1D females is observed both in Continental Italy and Sardinia. PTPN22 genotype does not exert significant effect on the age at onset neither in Continental Italy nor and Sardinia. Maternal age does not influence significantly age at onset in Italy (8.2 years in T1D infants from mothers aging 32 years or less vs 7.89 years in T1D infants from mothers aging more than 32 years: P = 0.824) while in Sardinia a border line effect is observed (5.75 years in T1D infants from mothers aging 32 years or less vs 7.54 years in T1D infants from mothers aging more than 32 years: P = 0.062). No effect of sex on age at onset is observed in Continental Italy while in Sardinia female show a lower age at onset of T1D as compared to males (8.07 years in males vs 6.3 years in females: P = 0.002).
CONCLUSION: The present data confirm the importance of ethnicity on susceptibility and on the age at onset of T1D.
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Wegner M, Neddermann D, Piorunska-Stolzmann M, Jagodzinski PP. Role of epigenetic mechanisms in the development of chronic complications of diabetes. Diabetes Res Clin Pract 2014; 105:164-75. [PMID: 24814876 DOI: 10.1016/j.diabres.2014.03.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 03/13/2014] [Accepted: 03/22/2014] [Indexed: 12/24/2022]
Abstract
There is growing evidence that epigenetic regulation of gene expression including post-translational histone modifications (PTHMs), DNA methylation and microRNA (miRNA)-regulation of mRNA translation could play a crucial role in the development of chronic, diabetic complications. Hyperglycemia can induce an abnormal action of PTHMs and DNA methyltransferases as well as alter the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal cells. These epigenetic abnormalities result in changes in the expression of numerous genes contributing to effects such as development of chronic inflammation, impaired clearance of reactive oxygen species (ROS), endothelial cell dysfunction and/or the accumulation of extracellular matrix in the kidney, which causing the development of retinopathy, nephropathy or cardiomyopathy. Some epigenetic modifications, for example PTHMs and DNA methylation, become irreversible over time. Therefore, these processes have gained much attention in explaining the long-lasting detrimental consequences of hyperglycaemia causing the development of chronic complications even after improved glycaemic control is achieved. Our review suggests that the treatment of chronic complications should focus on erasing metabolic memory by targeting chromatin modification enzymes and by restoring miRNA levels.
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Affiliation(s)
- Malgorzata Wegner
- Lipid Metabolism Laboratory, Chair of Chemistry and Clinical Biochemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland.
| | - Daniel Neddermann
- Novartis Pharma AG, Drug Metabolism and Pharmacokinetics, Postfach, 4002 Basel, Switzerland
| | - Maria Piorunska-Stolzmann
- Department of Clinical Biochemistry and Laboratory Medicine, Chair of Chemistry and Clinical Biochemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland
| | - Pawel P Jagodzinski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 6 Swiecickiego Street, 60-781 Poznan, Poland
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Stankov K, Benc D, Draskovic D. Genetic and epigenetic factors in etiology of diabetes mellitus type 1. Pediatrics 2013; 132:1112-22. [PMID: 24190679 DOI: 10.1542/peds.2013-1652] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D.
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Affiliation(s)
- Karmen Stankov
- Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Hajduk Veljkova 1, 21000 Novi Sad, Serbia.
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Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y. DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun 2013; 50:33-7. [PMID: 24210274 DOI: 10.1016/j.jaut.2013.10.001] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 10/07/2013] [Accepted: 10/13/2013] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins. Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.
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Affiliation(s)
- Mihaela Stefan
- Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA; James J. Peters Veterans Administration Medical Center, Bronx, NY 10468, USA
| | - Weijia Zhang
- Department of Medicine Bioinformatics Core, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Erlinda Concepcion
- Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Zhengzi Yi
- Department of Medicine Bioinformatics Core, Mount Sinai School of Medicine, New York, NY 10029, USA
| | - Yaron Tomer
- Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA; James J. Peters Veterans Administration Medical Center, Bronx, NY 10468, USA.
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Duygu B, Poels EM, da Costa Martins PA. Genetics and epigenetics of arrhythmia and heart failure. Front Genet 2013; 4:219. [PMID: 24198825 PMCID: PMC3812794 DOI: 10.3389/fgene.2013.00219] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 10/08/2013] [Indexed: 12/21/2022] Open
Abstract
Heart failure (HF) is the end stage of several pathological cardiac conditions including myocardial infarction, cardiac hypertrophy and hypertension. Various molecular and cellular mechanisms are involved in the development of HF. At the molecular level, the onset of HF is associated with reprogramming of gene expression, including downregulation of the alpha-myosin heavy chain (α-MHC) gene and sarcoplasmic reticulum Ca 2+ ATPase genes and reactivation of specific fetal cardiac genes such as atrial natriuretic factor and brain natriuretic peptide. These deviations in gene expression result in structural and electrophysiological changes, which eventually progress to HF. Cardiac arrhythmia is caused by altered conduction properties of the heart, which may arise in response to ischemia, inflammation, fibrosis, aging or from genetic factors. Because changes in the gene transcription program may have crucial consequences as deteriorated cardiac function, understanding the molecular mechanisms involved in the process has become a priority in the field. In this context, various studies besides having identified different DNA methylation patterns in HF patients, have also focused on specific disease processes and their underlying mechanisms, also introducing new concepts such as epigenomics. This review highlights specific genetic mutations associated with the onset and progression of HF, also providing an introduction to epigenetic mechanisms such as histone modifications, DNA methylation and RNA-based modification, and highlights the relation between epigenetics, arrhythmogenesis and HF.
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Affiliation(s)
- Burcu Duygu
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Maastricht, Netherlands
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Abstract
There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1 diabetes. Autoimmune type 1 diabetes is rare in those diagnosed before 6 months of age, but endogenous autoantibodies predictive of future type 1 diabetes may be detectable by 6-12 months of age, suggesting that environmental factors may operate before this age in some cases. Indirect evidence of a protective effect for the intrauterine environment comes from the observation that mothers with type 1 diabetes are less likely than affected fathers to transmit diabetes to their offspring, although the precise role (if any) is unclear. The risk of childhood-onset type 1 diabetes increases with maternal age at delivery, and with high birthweight, but these associations are weak and heterogeneous, and these factors are unlikely to be directly causally related to type 1 diabetes. No firm conclusion can be drawn from studies of maternal enteroviral infection or from various nutritional exposures. The birth process itself may play a role, as suggested by the slightly increased risk in children born by Caesarean section; lack of contact with maternal bacteria is one suggested mechanism. In sum, there is circumstantial evidence, but no proof of principle, that maternal or intrauterine conditions may modulate genetic risk of type 1 diabetes. The disease process culminating in type 1 diabetes typically begins in early life, but it is not clear whether the trail begins before or after birth.
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Affiliation(s)
- L C Stene
- Division of Epidemiology, Norwegian Institute of Public Health, PO Box 4404 Nydalen, NO-0403 Oslo, Norway.
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Achenbach P, Hummel M, Thümer L, Boerschmann H, Höfelmann D, Ziegler AG. Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children. Diabetologia 2013; 56:1615-22. [PMID: 23539116 DOI: 10.1007/s00125-013-2896-y] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Accepted: 03/06/2013] [Indexed: 10/27/2022]
Abstract
AIMS/HYPOTHESIS Islet autoantibody-positive children progress to type 1 diabetes at variable rates. In our study, we asked whether characteristic autoantibody and/or gene profiles could be defined for phenotypes showing extreme progression. METHODS Autoantibodies to insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured in follow-up sera, and genotyping for type 1 diabetes susceptibility genes (HLA-DR/HLA-DQ, INS variable number of tandem repeats [VNTR] and single nucleotide polymorphisms at PTPN22, PTPN2, ERBB3, IL2, SH2B3, CTLA4, IFIH1, KIAA0350 [also known as CLEC16A], CD25, IL18RAP, IL10, COBL) was performed on the DNA samples of children born to a parent with type 1 diabetes and prospectively followed from birth for up to 22 years. RESULTS Of the 1,650 children followed, 23 developed multiple autoantibodies and progressed to diabetes within 3 years (rapid progressors), while 24 children developed multiple autoantibodies and remained non-diabetic for more than 10 years from seroconversion (slow progressors). Rapid and slow progressors were similar with respect to HLA-DR/HLA-DQ genotypes, development of IAA, GADA and ZnT8A, and progression to multiple autoantibodies. In contrast, IA-2A development was considerably delayed in the slow progressors. Furthermore, both groups were effectively distinguished by the combined presence or absence of type 1 diabetes susceptibility alleles of non-HLA genes, most notably IL2, CD25, INS VNTR, IL18RAP, IL10, IFIH1 and PTPN22, and discrimination was improved among children carrying high-risk HLA-DR/HLA-DQ genotypes. CONCLUSIONS/INTERPRETATION Our data suggest that genotypes of non-HLA type 1 diabetes susceptibility genes influence the likelihood or rate of diabetes progression among children with multiple islet autoantibodies.
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Adolescent
- Autoantibodies/immunology
- CTLA-4 Antigen/genetics
- Cation Transport Proteins/immunology
- Child
- Child, Preschool
- DEAD-box RNA Helicases/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Female
- Genetic Predisposition to Disease/genetics
- Genotype
- HLA-DQ Antigens/genetics
- Humans
- Infant
- Infant, Newborn
- Insulin/immunology
- Interferon-Induced Helicase, IFIH1
- Interleukin-10/genetics
- Interleukin-18 Receptor beta Subunit/genetics
- Interleukin-2 Receptor alpha Subunit/genetics
- Intracellular Signaling Peptides and Proteins
- Lectins, C-Type/genetics
- Male
- Microfilament Proteins/genetics
- Monosaccharide Transport Proteins/genetics
- Polymorphism, Single Nucleotide/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Proteins/genetics
- Receptor, ErbB-3/genetics
- Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology
- Zinc Transporter 8
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Affiliation(s)
- P Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
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Bodin J, Bølling AK, Samuelsen M, Becher R, Løvik M, Nygaard UC. Long-term bisphenol A exposure accelerates insulitis development in diabetes-prone NOD mice. Immunopharmacol Immunotoxicol 2013; 35:349-58. [PMID: 23496298 DOI: 10.3109/08923973.2013.772195] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Exposure to the endocrine disruptor (ED) bisphenol A (BPA) used in polycarbonate plastic and epoxy resins appears ubiquitous since BPA can be found in over 90% of analyzed urine samples from all age groups. There is a parallel occurrence of increased prevalence in type 1 diabetes mellitus (T1DM) and an increased exposure to EDs the last decades. T1DM is caused by insulin deficiency due to autoimmune destruction of insulin producing pancreatic beta cells and has been suggested to be induced by various environmental factors acting together with a genetic predisposition. The objective of the present study was to investigate the effect of BPA (0, 1 and 100 mg/l BPA in the drinking water) on T1DM development in nonobese diabetic (NOD) mice, spontaneously developing T1DM. Histological evaluation of pancreas from 12-weeks-old female mice revealed significantly increased insulitis in mice exposed to 1 mg/l BPA, while the insulitis was less severe at the higher BPA exposure. Serum glucose levels in the 1 mg/ml BPA group tended to be hyperglycaemic, also indicating an accelerated onset of T1DM. The high BPA exposure seemed to counteract the diabetes development in females and also in male NOD mice for both BPA concentrations. Prior to insulitis, both BPA concentrations resulted in increased apoptosis and reduced numbers of tissue resident macrophages in pancreatic islets. In conclusion, long-term BPA exposure at a dose three times higher than the tolerable daily intake of 50 µg/kg, appeared to accelerate spontaneous insulitis and diabetes development in NOD mice.
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Affiliation(s)
- Johanna Bodin
- Department of Food, Water and Cosmetics, Norwegian Institute of Public Health, Oslo, Norway.
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Koziol AG, Loit E, McNulty M, MacFarlane AJ, Scott FW, Altosaar I. Seed storage proteins of the globulin family are cleaved post-translationally in wheat embryos. BMC Res Notes 2012; 5:385. [PMID: 22838494 PMCID: PMC3434096 DOI: 10.1186/1756-0500-5-385] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 07/09/2012] [Indexed: 01/26/2023] Open
Abstract
Background The 7S globulins are plant seed storage proteins that have been associated with the development of a number of human diseases, including peanut allergy. Immune reactivity to the wheat seed storage protein globulin-3 (Glo-3) has been associated with the development of the autoimmune disease type 1 diabetes in diabetes-prone rats and mice, as well as in a subset of human patients. Findings The present study characterized native wheat Glo-3 in salt-soluble wheat seed protein extracts. Glo-3-like peptides were observed primarily in the wheat embryo. Glo-3-like proteins varied significantly in their molecular masses and isoelectric points, as determined by two dimensional electrophoresis and immunoblotting with anti-Glo-3A antibodies. Five major polypeptide spots were identified by mass spectrometry and N-terminal sequencing as belonging to the Glo-3 family. Conclusions These results in combination with our previous findings have allowed for the development of a hypothetical model of the post-translational events contributing to the wheat 7S globulin profile in mature wheat kernels.
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Affiliation(s)
- Adam G Koziol
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
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Abstract
Classical genetic studies established a link between Type 1 diabetes, a common childhood autoimmune disease and genes that encode MHC antigens and several immune-related determinants. The mechanisms by which these genes contribute to the initiation and perpetuation of Type 1 diabetes remain enigmatic. Emerging data indicate a role for epigenetic mechanisms involving hyperacetylation of histones in the differential gene expression and amelioration of autoimmune diabetes in a mouse model. In this article the implications of these and other epigenetic mechanisms including ncRNA-mediated gene regulation in the abrogation of autoimmune diabetes are discussed. Concerted efforts to decipher the epigenetics of Type 1 diabetes may provide novel perspectives on autoimmune diabetogenesis.
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Affiliation(s)
- Sundararajan Jayaraman
- Deptartment of Medicine, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
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Mathis D, Benoist C. The influence of the microbiota on type-1 diabetes: on the threshold of a leap forward in our understanding. Immunol Rev 2012; 245:239-49. [PMID: 22168424 DOI: 10.1111/j.1600-065x.2011.01084.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The last several years have seen breakthroughs in techniques to track the symbiont communities that normally colonize mammals (the microbiota) and in cataloguing the universe of the genes they carry (the microbiome). Applying these methods to human patients and corresponding murine models should allow us to decipher just how the microbiota impacts type-1 diabetes, i.e. which particular microbes are responsible and the cellular and molecular processes that are involved. Here, at its threshold, we set the stage for what promises to be an exciting rejuvenated area of investigation.
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Affiliation(s)
- Diane Mathis
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
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40
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Hasham A, Tomer Y. The recent rise in the frequency of type 1 diabetes: who pulled the trigger? J Autoimmun 2011; 37:1-2. [PMID: 21641185 DOI: 10.1016/j.jaut.2011.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 04/21/2011] [Indexed: 12/17/2022]
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Affiliation(s)
- Toni I Pollin
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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Association analysis of proopiomelanocortin (POMC) haplotypes in type 1 diabetes in a UK population. DIABETES & METABOLISM 2011; 37:298-304. [PMID: 21723177 DOI: 10.1016/j.diabet.2010.11.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Revised: 10/31/2010] [Accepted: 11/03/2010] [Indexed: 12/16/2022]
Abstract
AIM To assess the association of POMC haplotype-tagged single nucleotide polymorphisms (htSNPs) with the development of type 1 diabetes (T1D) in a Caucasian population. METHODS All exons, intron 1, and approximately 6-kb upstream and 3-kb downstream of the POMC gene were bidirectionally resequenced to identify DNA polymorphisms in 30 individuals. Allele frequencies were determined (60 chromosomes) and efficient htSNPs were selected using the htSNP2 programme. Genotyping was performed in 390 cases, 339 controls and 245 T1D parent-offspring trios, using Taqman, Sequenom and direct-sequencing technologies. RESULTS Thirteen polymorphisms (two novel) with a minor allele frequency greater than 1% were identified. Six POMC htSNPs (rs3754863 G>A, ss161151662 A>G, rs3754860 C>T, rs1009388 G>C, rs3769671 A>C, rs1042571 G>A) were identified. Allele and haplotype frequencies were similar between case and control groups (P>0.60 by permutation test), and assessment of allele transmission distortion from informative parents to affected offspring also failed to find any association. Stratification of these analyses for age-at-onset and HLA-DR risk group (DR3/DR4) revealed no significant associations. A haplotype block of 9.86-kb from rs3754863 to rs1042571 was identified, encompassing the POMC gene. Comparison of haplotype frequencies identified the GGCGAG haplotype as protective against T1D in 12.9% of cases vs. 18.3% of controls: χ(2)=8.18, Pc=0.03 by permutation test. CONCLUSION The POMC SNP haplotype GGCGAG may have a protective effect against T1D in the UK population. However, this finding needs to be replicated, and the cellular and molecular processes influenced by this POMC haplotype determined to fully appreciate its impact.
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Abstract
INTRODUCTION Epigenetics describes the phenomenon of heritable changes in gene regulation governed by non-Mendelian processes, primarily through biochemical modifications to chromatin that occur during cell differentiation and development. Abnormal levels of DNA and/or histone modifications are observed in patients with a wide variety of chronic diseases. Drugs that target the proteins controlling these chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents with single target pharmacologies that are susceptible to biochemical pathway degeneracy. AREAS COVERED This article reviews research characterizing dysregulation of epigenetic processes in cancer, immuno-inflammatory, psychiatric, neurological, metabolic and virology disease areas, and summarizes recent developments in identifying small molecule modulators that are being used to inform target discovery and initiate drug discovery projects. EXPERT OPINION There are numerous potential opportunities for epigenetic modulators in treating a wide range of chronic diseases; however, the field is complex, involving > 300 proteins, and much work is still required to provide tools to unravel the functions of individual proteins, particularly in vivo. This groundwork is essential to allow the drug discovery community to focus on those epigenetic proteins most likely to be suitable targets for safe, efficacious new therapies.
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Affiliation(s)
- Tom D Heightman
- Astex Therapeutics Ltd., 436 Cambridge Science Park, Cambridge CB4 0QA, UK.
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44
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Fernández-Morera JL, Calvanese V, Rodríguez-Rodero S, Menéndez-Torre E, Fraga MF. Epigenetic regulation of the immune system in health and disease. ACTA ACUST UNITED AC 2011; 76:431-9. [PMID: 21058938 DOI: 10.1111/j.1399-0039.2010.01587.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Epigenetics comprises various mechanisms that mold chromatin structures and regulate gene expression with stability, thus defining cell identity and function and adapting cells to environmental changes. Alteration of these mechanisms contributes to the inception of various pathological conditions. Given the complexity of the immune system, one would predict that a higher-order, supragenetic regulation is indispensable for generation of its constituents and control of its functions. Here, we summarize various aspects of immune system physiology and pathology in which epigenetic pathways have been implicated. Increasing knowledge in this field, together with the development of specific tools with which to manipulate epigenetic pathways, might form a basis for new strategies of immune function modulation, both to optimize immune therapies for infections or cancer and to control immune alterations in aging or autoimmunity.
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Affiliation(s)
- J L Fernández-Morera
- Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Oviedo, Spain
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45
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Abstract
Genomic imprinting refers to a class of transmissible genetic effects in which the expression of the phenotype in the offspring depends on the parental origin of the transmitted allele. The DNA from one parent may be epigenetically modified so that only a single allele of the imprinted gene is expressed in the offspring. Although imprinting has an important role in the regulation of growth and development through its role in regulating gene expression, its contribution to susceptibility to common complex disorders is not well understood. We summarize current views on the role of imprinting in diabetes and in particular chromosome 6q24-related transient neonatal diabetes mellitus, the best known example of an imprinted genetic disorder that leads to diabetes.
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Affiliation(s)
- Braxton D Mitchell
- Division of Endocrinology, Diabetes and Nutrition, University of Maryland, 6601 West Redwood Street, Baltimore, MD 21201, USA.
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2010; 17:384-93. [PMID: 20588116 DOI: 10.1097/med.0b013e32833c4b2b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Genetic Predisposition for Type 1 Diabetes Mellitus - The Role of Endoplasmic Reticulum Stress in Human Disease Etiopathogenesis. J Med Biochem 2010. [DOI: 10.2478/v10011-010-0016-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Genetic Predisposition for Type 1 Diabetes Mellitus - The Role of Endoplasmic Reticulum Stress in Human Disease EtiopathogenesisThe increasing incidence of diabetes mellitus worldwide has prompted a rapid growth in the pace of scientific discovery of the mechanisms involved in the etiopathogenesis of this multifactorial disease. Accumulating evidence suggests that endoplasmic reticulum stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta cell loss and insulin resistance. Wolfram syndrome is an autosomal recessive neurodegenerative disorder accompanied by insulin-dependent diabetes mellitus and progressive optic atrophy. The pathogenesis of this rare neurodegenerative genetic disease is unknown. A Wolfram gene (WFS1 locus) has recently been mapped to chromosome 4p16.1, but there is evidence for locus heterogeneity, including the mitochondrial genome deletion. Recent positional cloning led to identification of the second WFS locus, a mutation in the CISD2 gene, which encodes an endoplasmic reticulum intermembrane small protein. Our results were obtained by the analysis of a families belonging to specific population, affected by Wolfram syndrome. We have identified the newly diagnosed genetic alteration of WFS1 locus, a double non-synonymous and frameshift mutation, providing further evidence for the genetic heterogeneity of this syndrome. Newly identified mutations may contribute to the further elucidation of the pathogenesis of Wolfram syndrome, as well as of the complex mechanisms involved in diabetes mellitus development.
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Rowe PA, Campbell-Thompson ML, Schatz DA, Atkinson MA. The pancreas in human type 1 diabetes. Semin Immunopathol 2010; 33:29-43. [PMID: 20495921 PMCID: PMC3022158 DOI: 10.1007/s00281-010-0208-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Accepted: 04/13/2010] [Indexed: 11/24/2022]
Abstract
Type 1 diabetes (T1D) is considered a disorder whose pathogenesis is autoimmune in origin, a notion drawn in large part from studies of human pancreata performed as far back as the 1960s. While studies of the genetics, epidemiology, and peripheral immunity in T1D have been subject to widespread analysis over the ensuing decades, efforts to understand the disorder through analysis of human pancreata have been far more limited. We have reviewed the published literature pertaining to the pathology of the human pancreas throughout all stages in the natural history of T1D. This effort uncovered a series of findings that challenge many dogmas ascribed to T1D and revealed data suggesting the marked heterogeneity in terms of its pathology. An improved understanding and appreciation for pancreatic pathology in T1D could lead to improved disease classification, an understanding of why the disorder occurs, and better therapies for disease prevention and management.
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Affiliation(s)
- Patrick A Rowe
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA
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49
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Todd JA. Etiology of type 1 diabetes. Immunity 2010; 32:457-67. [PMID: 20412756 DOI: 10.1016/j.immuni.2010.04.001] [Citation(s) in RCA: 366] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Revised: 03/24/2010] [Accepted: 03/31/2010] [Indexed: 12/11/2022]
Abstract
Recent genetic mapping and gene-phenotype studies have revealed the genetic architecture of type 1 diabetes. At least ten genes so far can be singled out as strong causal candidates. The known functions of these genes indicate the primary etiological pathways of this disease, including HLA class II and I molecules binding to preproinsulin peptides and T cell receptors, T and B cell activation, innate pathogen-viral responses, chemokine and cytokine signaling, and T regulatory and antigen-presenting cell functions. This review considers research in the field of type 1 diabetes toward identifying disease mechanisms using genetic approaches. The expression and functions of these pathways, and, therefore, disease susceptibility, will be influenced by epigenetic and environmental factors. Certain inherited immune phenotypes will be early precursors of type 1 diabetes and could be useful in future clinical trials.
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Affiliation(s)
- John A Todd
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
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