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Yu G, Tam HCH, Huang C, Shi M, Lim CKP, Chan JCN, Ma RCW. Lessons and Applications of Omics Research in Diabetes Epidemiology. Curr Diab Rep 2024; 24:27-44. [PMID: 38294727 PMCID: PMC10874344 DOI: 10.1007/s11892-024-01533-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 02/01/2024]
Abstract
PURPOSE OF REVIEW Recent advances in genomic technology and molecular techniques have greatly facilitated the identification of disease biomarkers, advanced understanding of pathogenesis of different common diseases, and heralded the dawn of precision medicine. Much of these advances in the area of diabetes have been made possible through deep phenotyping of epidemiological cohorts, and analysis of the different omics data in relation to detailed clinical information. In this review, we aim to provide an overview on how omics research could be incorporated into the design of current and future epidemiological studies. RECENT FINDINGS We provide an up-to-date review of the current understanding in the area of genetic, epigenetic, proteomic and metabolomic markers for diabetes and related outcomes, including polygenic risk scores. We have drawn on key examples from the literature, as well as our own experience of conducting omics research using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank, as well as other cohorts, to illustrate the potential of omics research in diabetes. Recent studies highlight the opportunity, as well as potential benefit, to incorporate molecular profiling in the design and set-up of diabetes epidemiology studies, which can also advance understanding on the heterogeneity of diabetes. Learnings from these examples should facilitate other researchers to consider incorporating research on omics technologies into their work to advance the field and our understanding of diabetes and its related co-morbidities. Insights from these studies would be important for future development of precision medicine in diabetes.
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Affiliation(s)
- Gechang Yu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Henry C H Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Chuiguo Huang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Mai Shi
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Cadmon K P Lim
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
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Ansari MA, Chauhan W, Shoaib S, Alyahya SA, Ali M, Ashraf H, Alomary MN, Al-Suhaimi EA. Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions. Int J Obes (Lond) 2023; 47:1179-1199. [PMID: 37696926 DOI: 10.1038/s41366-023-01369-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/04/2023] [Accepted: 08/17/2023] [Indexed: 09/13/2023]
Abstract
Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.
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Affiliation(s)
- Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia.
| | - Waseem Chauhan
- Department of Hematology, Duke University, Durham, NC, 27710, USA
| | - Shoaib Shoaib
- Department of Biochemistry, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Sami A Alyahya
- Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia
| | - Mubashshir Ali
- USF Health Byrd Alzheimer's Center and Neuroscience Institute, Department of Molecular Medicine, Tampa, FL, USA
| | - Hamid Ashraf
- Rajiv Gandhi Center for Diabetes and Endocrinology, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohammad N Alomary
- Advanced Diagnostic and Therapeutic Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia.
| | - Ebtesam A Al-Suhaimi
- King Abdulaziz & his Companions Foundation for Giftedness & Creativity, Riyadh, Saudi Arabia.
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Nabi AHMN, Ebihara A, Shekhar HU. Impacts of SARS-CoV-2 on diabetes mellitus: A pre and post pandemic evaluation. World J Virol 2023; 12:151-171. [PMID: 37396707 PMCID: PMC10311579 DOI: 10.5501/wjv.v12.i3.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/24/2023] [Accepted: 04/13/2023] [Indexed: 06/21/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the novel beta coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) crippled the whole world and has resulted in large number of morbidity and mortality. The origin of the SARS-CoV-2 is still disputed. The risk of infection with SARS-CoV-2 is dependent on several risk factors as observed in many studies. The severity of the disease depends on many factors including the viral strain, host immunogenetics, environmental factors, host genetics, host nutritional status and presence of comorbidities like hypertension, diabetes, Chronic Obstructive Pulmonary Disease, cardiovascular disease, renal impairment. Diabetes is a metabolic disorder mainly characterized by hyperglycemia. Diabetic individuals are intrinsically prone to infections. SARS-CoV-2 infection in patients with diabetes result in β-cell damage and cytokine storm. Damage to the cells impairs the equilibrium of glucose, leading to hyperglycemia. The ensuing cytokine storm causes insulin resistance, especially in the muscles and liver, which also causes a hyperglycemic state. All of these increase the severity of COVID-19. Genetics also play pivotal role in disease pathogenesis. This review article focuses from the probable sources of coronaviruses and SARS-CoV-2 to its impacts on individuals with diabetes and host genetics in pre- and post-pandemic era.
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Affiliation(s)
- A H M Nurun Nabi
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Akio Ebihara
- Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan
| | - Hossain Uddin Shekhar
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
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Goyal S, Rani J, Bhat MA, Vanita V. Genetics of diabetes. World J Diabetes 2023; 14:656-679. [PMID: 37383588 PMCID: PMC10294065 DOI: 10.4239/wjd.v14.i6.656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/13/2023] [Accepted: 04/17/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic, epigenetic, and environmental variables. It is one of the world's fastest-growing diseases, with 783 million adults expected to be affected by 2045. Devastating macrovascular consequences (cerebrovascular disease, cardiovascular disease, and peripheral vascular disease) and microvascular complications (like retinopathy, nephropathy, and neuropathy) increase mortality, blindness, kidney failure, and overall quality of life in individuals with diabetes. Clinical risk factors and glycemic management alone cannot predict the development of vascular problems; multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications. In the twenty-first century, technological advancements (genome-wide association studies, next-generation sequencing, and exome-sequencing) have led to the identification of genetic variants associated with diabetes, however, these variants can only explain a small proportion of the total heritability of the condition. In this review, we address some of the likely explanations for this "missing heritability", for diabetes such as the significance of uncommon variants, gene-environment interactions, and epigenetics. Current discoveries clinical value, management of diabetes, and future research directions are also discussed.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Jyoti Rani
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Mohd Akbar Bhat
- Department of Ophthalmology, Georgetown University Medical Center, Washington DC, DC 20057, United States
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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Newman JRB, Concannon P, Ge Y. UBASH3A Interacts with PTPN22 to Regulate IL2 Expression and Risk for Type 1 Diabetes. Int J Mol Sci 2023; 24:ijms24108671. [PMID: 37240014 DOI: 10.3390/ijms24108671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
UBASH3A is a negative regulator of T cell activation and IL-2 production and plays key roles in autoimmunity. Although previous studies revealed the individual effects of UBASH3A on risk for type 1 diabetes (T1D; a common autoimmune disease), the relationship of UBASH3A with other T1D risk factors remains largely unknown. Given that another well-known T1D risk factor, PTPN22, also inhibits T cell activation and IL-2 production, we investigated the relationship between UBASH3A and PTPN22. We found that UBASH3A, via its Src homology 3 (SH3) domain, physically interacts with PTPN22 in T cells, and that this interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22. Furthermore, our analysis of RNA-seq data from T1D cases showed that the amounts of UBASH3A and PTPN22 transcripts exert a cooperative effect on IL2 expression in human primary CD8+ T cells. Finally, our genetic association analyses revealed that two independent T1D risk variants, rs11203203 in UBASH3A and rs2476601 in PTPN22, interact statistically, jointly affecting risk for T1D. In summary, our study reveals novel interactions, both biochemical and statistical, between two independent T1D risk loci, and suggests how these interactions may affect T cell function and increase risk for T1D.
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Affiliation(s)
- Jeremy R B Newman
- Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL 32610, USA
- Genetics Institute, University of Florida, Gainesville, FL 32610, USA
| | - Patrick Concannon
- Genetics Institute, University of Florida, Gainesville, FL 32610, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Yan Ge
- Genetics Institute, University of Florida, Gainesville, FL 32610, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
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Pang H, Lin J, Luo S, Huang G, Li X, Xie Z, Zhou Z. The missing heritability in type 1 diabetes. Diabetes Obes Metab 2022; 24:1901-1911. [PMID: 35603907 PMCID: PMC9545639 DOI: 10.1111/dom.14777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/04/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1D are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1D, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called 'missing heritability' phenomenon. While the gap between known heritability and true heritability in T1D is small compared with that in other complex traits and disorders, further elucidation of T1D genetics has the potential to bring novel insights into its aetiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants and structural variants) and interactions (gene-gene and gene-environment interactions; e.g. epigenetic effects). In the following review, we introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1D.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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Bartolomé A. Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction. Int J Mol Sci 2022; 23:501. [PMID: 35008927 PMCID: PMC8745644 DOI: 10.3390/ijms23010501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.
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Affiliation(s)
- Alberto Bartolomé
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain
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Houeiss P, Luce S, Boitard C. Environmental Triggering of Type 1 Diabetes Autoimmunity. Front Endocrinol (Lausanne) 2022; 13:933965. [PMID: 35937815 PMCID: PMC9353023 DOI: 10.3389/fendo.2022.933965] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
- *Correspondence: Christian Boitard,
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Yukina MY, Larina AA, Vasilyev EV, Troshina EA, Dimitrova DA. Search for Genetic Predictors of Adult Autoimmune Polyendocrine Syndrome in Monozygotic Twins. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2021; 14:11795514211009796. [PMID: 33953634 PMCID: PMC8058797 DOI: 10.1177/11795514211009796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/18/2021] [Indexed: 11/20/2022]
Abstract
Autoimmune polyendocrine syndromes (APS) are a heterogeneous group of diseases characterized by the presence of autoimmune dysfunction of 2 or more endocrine glands and other non-endocrine organs. The components of the syndrome can manifest throughout life: in childhood—APS type 1 (the juvenile type) and in adulthood—APS type 2, 3, and 4 (the adult types). Adult types of APS are more common in clinical practice. It is a polygenic disease associated with abnormalities in genes encoding key regulatory proteins of the major histocompatibility complex (MHC). The search of for candidate genes responsible for mutations in adult APS is continuing. Genetic predisposition is insufficient for the manifestation of the APS of adults, since the penetrance of the disease, even among monozygotic twins, does not approach 100% (30–70%). The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.
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Yukina M, Erofeeva T, Nuralieva N, Andreeva T, Savvateeva E, Dudko N, Troshina E, Rogaev E, Melnichenko G. Novel Gene Mutations Regulating Immune Responses in Autoimmune Polyglandular Syndrome With an Atypical Course. J Endocr Soc 2021; 5:bvab077. [PMID: 34235359 PMCID: PMC8252644 DOI: 10.1210/jendso/bvab077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Indexed: 11/19/2022] Open
Abstract
Context Autoimmune polyglandular syndrome (APS) is a cluster of endocrine disorders arising from immune dysregulation, often combined with damage to nonendocrine organs. There are 2 types of APS: type 1 and type 2 (APS-1 and APS-2, respectively). In clinical practice, an atypical course of APS is often observed. Objective This work aims to find a novel genetic predictor of APS. Methods We performed exome sequencing in 2 patients with an atypical clinical APS picture and members of their families. Patient A presented with a manifestation of APS-2 in early childhood and patient B with a late manifestation of the main components of APS-1. Results In patient B, we identified inherited compound mutations as a novel combination of the c.769C > T and c.821delG alleles of AIRE and genetic variation in the CIITA gene. No homozygous or compound mutations in AIRE were found in patient A, but we did reveal mutations in genes encoding regulatory proteins of innate and acquired immunity in this patient. Conclusion Our data revealed novel combination of mutations in the AIRE gene in atypical APS and imply that mutations in immune-related genes may modify the clinical manifestation of APS in AIRE-mutation carriers and contribute to the development of autoimmune pathology in non-AIRE carriers with atypical APS.
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Affiliation(s)
- Marina Yukina
- Endocrinology Research Centre, Moscow 117036, Russia
| | - Taisia Erofeeva
- Laboratory of Evolutionary genomics, Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia
| | | | - Tatiana Andreeva
- Laboratory of Evolutionary genomics, Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia.,Center for Genetics and Genetic Technologies, Faculty of Biology, Lomonosov Moscow State University, Moscow 119192, Russia
| | - Elena Savvateeva
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Natalia Dudko
- Laboratory of Evolutionary genomics, Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia
| | | | - Evgeny Rogaev
- Laboratory of Evolutionary genomics, Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia.,Center for Genetics and Genetic Technologies, Faculty of Biology, Lomonosov Moscow State University, Moscow 119192, Russia.,Center for Genetics and Life Science, Sirius University of Science and Technology, Sochi 354340, Russia.,Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA
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Pang H, Xia Y, Luo S, Huang G, Li X, Xie Z, Zhou Z. Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus. J Med Genet 2021; 58:289-296. [PMID: 33753534 PMCID: PMC8086251 DOI: 10.1136/jmedgenet-2020-107350] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 01/06/2021] [Accepted: 01/10/2021] [Indexed: 12/12/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%–85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ying Xia
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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12
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Armitage LH, Wallet MA, Mathews CE. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol 2021; 12:636618. [PMID: 33717184 PMCID: PMC7946861 DOI: 10.3389/fimmu.2021.636618] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/18/2021] [Indexed: 01/18/2023] Open
Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
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Affiliation(s)
- Lucas H. Armitage
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
| | - Mark A. Wallet
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
- Immuno-Oncology at Century Therapeutics, LLC, Philadelphia, PA, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
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13
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Abstract
Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.
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Affiliation(s)
- Joanne B Cole
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA
| | - Jose C Florez
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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14
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Diedisheim M, Carcarino E, Vandiedonck C, Roussel R, Gautier JF, Venteclef N. Regulation of inflammation in diabetes: From genetics to epigenomics evidence. Mol Metab 2020; 41:101041. [PMID: 32603690 PMCID: PMC7394913 DOI: 10.1016/j.molmet.2020.101041] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.
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Affiliation(s)
- Marc Diedisheim
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Elena Carcarino
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Claire Vandiedonck
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Ronan Roussel
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France; Bichat-Claude Bernard, Hospital, AP-HP, Diabetology Department, Université de Paris, Paris, France
| | - Jean-François Gautier
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France; Lariboisière Hospital, AP-HP, Diabetology Department, Université de Paris, Paris, France
| | - Nicolas Venteclef
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France.
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15
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Thaler FS, Bangol B, Biljecki M, Havla J, Schumacher AM, Kümpfel T. Possible link of genetic variants to autoimmunity in GAD-antibody-associated neurological disorders. J Neurol Sci 2020; 413:116860. [PMID: 32388243 DOI: 10.1016/j.jns.2020.116860] [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: 11/19/2019] [Revised: 04/07/2020] [Accepted: 04/26/2020] [Indexed: 12/31/2022]
Abstract
OBJECTIVE In patients with GAD-antibody (ab) associated neurological disorders coexistence of other autoimmune disorders is observed. METHODS In this exploratory study we analysed variations in 33 candidate genes involved in autoimmunity or representing immunological check-points using next-generation sequencing. We performed haplotype-analysis of HLA-DRB1 and HLA-DQB1. Additionally, we analysed levels of sFasL, IL10, and IL18 in serum of patients and healthy controls. RESULTS 19 patients (3 males, 16 females; mean age at onset: 46.4 years) with positive GAD-ab and the following neurological phenotypes were included: n = 8 cerebellar ataxia, n = 6 limbic encephalitis, n = 4 stiff person syndrome, n = 1 demyelinating CNS disease with recurrent optic neuritis. 15 patients exhibited at least one other autoimmune disorder and/or showed other auto-ab. We identified several variations in genes linked to autoimmunity or representing check-point proteins. Most frequently (14/19 patients, allele frequency: 42.1%), we observed an amino acid exchange in the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene. Two of the observed variants are known to cause alterations of protein function (Y446C in caspase-10, K750N in protein-tyrosin-phosphatase, non-receptor type 22). These latter variants were detected in two related patients (mother and daughter) who both present with GAD-ab-associated neurological disorders but with different clinical phenotypes. The rare haplotype DRB1*15:01:01 ~ DQA1*01:02:01 ~ DQB1*05:02:01 previously described in patients with GAD-ab-associated neurological disorders was not observed in any of our patients. No elevated serum levels of sFasL, IL18 or IL10 were observed in patients indicating no typical phenotype of autoimmune lymphoproliferate syndrome. CONCLUSIONS These findings suggest genetic risk factors in patients with GAD-ab-associated neurological disorders.
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Affiliation(s)
- Franziska S Thaler
- Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany.
| | - Barbara Bangol
- Center for Human Genetics and Laboratory Diagnostics, Martinsried, Germany
| | - Michelle Biljecki
- Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Joachim Havla
- Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Adrian-Minh Schumacher
- Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Tania Kümpfel
- Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany
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16
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A Multi-Omics Perspective of Quantitative Trait Loci in Precision Medicine. Trends Genet 2020; 36:318-336. [PMID: 32294413 DOI: 10.1016/j.tig.2020.01.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/05/2020] [Accepted: 01/21/2020] [Indexed: 02/07/2023]
Abstract
Quantitative trait loci (QTL) analysis is an important approach to investigate the effects of genetic variants identified through an increasing number of large-scale, multidimensional 'omics data sets. In this 'big data' era, the research community has identified a significant number of molecular QTLs (molQTLs) and increased our understanding of their effects. Herein, we review multiple categories of molQTLs, including those associated with transcriptome, post-transcriptional regulation, epigenetics, proteomics, metabolomics, and the microbiome. We summarize approaches to identify molQTLs and to infer their causal effects. We further discuss the integrative analysis of molQTLs through a multi-omics perspective. Our review highlights future opportunities to better understand the functional significance of genetic variants and to utilize the discovery of molQTLs in precision medicine.
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17
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Ge Y, Paisie TK, Chen S, Concannon P. UBASH3A Regulates the Synthesis and Dynamics of TCR-CD3 Complexes. THE JOURNAL OF IMMUNOLOGY 2019; 203:2827-2836. [PMID: 31659016 DOI: 10.4049/jimmunol.1801338] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 09/27/2019] [Indexed: 01/14/2023]
Abstract
The TCR-CD3 complex is a multicomponent membrane receptor, the expression of which is tightly regulated in thymocytes, as well as in mature T cells both at steady state and upon stimulation. In this study, we report novel roles for UBASH3A in TCR-CD3 synthesis and turnover. UBASH3A is a negative regulator of T cell function and plays a broad role in autoimmunity. We show that modulation of UBASH3A levels in unstimulated Jurkat cells leads to altered amounts of total cellular CD3 chains and of cell-surface TCR-CD3 complexes; in contrast, UBASH3A does not affect the level of cell-surface CD28, an important T cell costimulatory receptor. Upon TCR engagement, UBASH3A enhances the downmodulation of cell-surface TCR-CD3. Mass spectrometry and protein-protein interaction studies uncover novel associations between UBASH3A and components of several cellular pathways involved in the regulation of TCR-CD3 turnover and dynamics, including endoplasmic reticulum-associated protein degradation, cell motility, endocytosis, and endocytic recycling of membrane receptors. Finally, we demonstrate that the SH3 domain of UBASH3A mediates its binding to CBL-B, an E3 ubiquitin ligase that negatively regulates CD28-mediated signaling and, hence, T cell activation. In summary, this study provides new mechanistic insights into how UBASH3A regulates T cell activation and contributes to autoimmunity. The interaction between UBASH3A and CBL-B may synergistically inhibit T cell function and affect risk for type 1 diabetes, as both genes have been shown to be associated with this autoimmune disease.
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Affiliation(s)
- Yan Ge
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610; .,Genetics Institute, University of Florida, Gainesville, FL 32610
| | - Taylor K Paisie
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610.,Genetics Institute, University of Florida, Gainesville, FL 32610.,Genetics and Genomics Graduate Program, University of Florida, Gainesville, FL 32610
| | - Sixue Chen
- Genetics Institute, University of Florida, Gainesville, FL 32610.,Genetics and Genomics Graduate Program, University of Florida, Gainesville, FL 32610.,Department of Biology, University of Florida, Gainesville, FL 32611.,Plant Molecular and Cellular Biology Program, University of Florida, Gainesville, FL 32611; and.,Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32610
| | - Patrick Concannon
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610; .,Genetics Institute, University of Florida, Gainesville, FL 32610
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18
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.Robertson CC, Rich SS. Genetics of type 1 diabetes. Curr Opin Genet Dev 2018; 50:7-16. [DOI: 10.1016/j.gde.2018.01.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/20/2018] [Accepted: 01/25/2018] [Indexed: 01/14/2023]
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19
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Alswat KA, Nasr A, Al Dubayee MS, Talaat IM, Alsulaimani AA, Mohamed IAA, Allam G. The Potential Role of PTPN-22 C1858T Gene Polymorphism in the Pathogenesis of Type 1 Diabetes in Saudi Population. Immunol Invest 2018; 47:521-533. [PMID: 29611765 DOI: 10.1080/08820139.2018.1458109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Recent investigations have reported an association between protein tyrosine phosphatase non-receptor type-22 (PTPN-22) gene polymorphism and susceptibility to the development of type 1 diabetes (T1D) in some populations and not in others. In this study, we aimed to investigate the association of PTPN-22 C1858T polymorphism with T1D in Saudi children. METHODS A cohort of 372 type 1 diabetic children and 372 diabetes-free subjects was enrolled in the current investigation. The PTPN-22 C1858T polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS Our data showed that the frequency of CT and TT genotypes of PTPN-22 C1858T was higher in T1D children (17.7% and 4.3%, respectively) compared to healthy controls (4.8% and 1.6%, respectively), and both genotypes were statistically associated with T1D patients (OR = 4.4, 95% CI: 2.55-7.58, p < 0.001; and OR = 3.2, 95% CI: 1.23-8.28, p = 0.017, respectively). Moreover, the 1858T allele was significantly associated with T1D patients compared to the C allele (OR = 3.2, 95% CI: 1.59-6.88, p < 0.001). In addition, the T allele was significantly associated with elevated levels of HbA1c, anti-GAD, and anti-insulin antibodies (p < 0.001) and a lower concentration of C-peptide (p < 0.001) in T1D children. CONCLUSION The data presented here suggests that the T allele of PTPN-22 C1858T polymorphism might be a risk factor for T1D development in Saudi children.
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Affiliation(s)
- Khaled A Alswat
- a Department of Internal Medicine , College of Medicine, Taif University , Taif , Saudi Arabia.,b Diabetic Center , Prince Mansour Military Community Hospital , Taif , Saudi Arabia
| | - Amre Nasr
- c King Saud bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia.,d King Abdullah International Medical Research Center KAIMRC , Riyadh , Saudi Arabia
| | - Mohammed S Al Dubayee
- c King Saud bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia.,d King Abdullah International Medical Research Center KAIMRC , Riyadh , Saudi Arabia.,e King Abdulaziz Medical City , Saudi Arabia
| | - Iman M Talaat
- f Department of Pediatrics, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Adnan A Alsulaimani
- b Diabetic Center , Prince Mansour Military Community Hospital , Taif , Saudi Arabia.,g Department of Pediatrics , College of Medicine, Taif University , Taif , Saudi Arabia
| | - Imad A A Mohamed
- h Department of Microbiology, Faculty of Veterinary Medicine , Zagazig University , Sharkia , Egypt.,i Department of Microbiology and Immunology , College of Medicine, Taif University , Taif , Saudi Arabia
| | - Gamal Allam
- i Department of Microbiology and Immunology , College of Medicine, Taif University , Taif , Saudi Arabia.,j Immunology Section, Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
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20
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Wright F, Fessele K. Primer in Genetics and Genomics, Article 5-Further Defining the Concepts of Genotype and Phenotype and Exploring Genotype-Phenotype Associations. Biol Res Nurs 2018; 19:576-585. [PMID: 28920489 DOI: 10.1177/1099800417725190] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
As nurses begin to incorporate genetic and genomic sciences into clinical practice, education, and research, it is essential that they have a working knowledge of the terms foundational to the science. The first article in this primer series provided brief definitions of the basic terms (e.g., genetics and genomics) and introduced the concept of phenotype during the discussion of Mendelian inheritance. These terms, however, are inconsistently used in publications and conversations, and the linkage between genotype and phenotype requires clarification. The goal of this fifth article in the series is to elucidate these terms, provide an overview of the research methods used to determine genotype-phenotype associations, and discuss their significance to nursing through examples from the current nursing literature.
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Affiliation(s)
- Fay Wright
- 1 Yale School of Nursing, Orange CT, USA
| | - Kristen Fessele
- 2 Scientific Project Leader, Flatiron Health, New York, NY, USA.,3 Post-doctoral Research Fellow, University of Utah College of Nursing, Salt Lake City, UT, USA
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21
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Newman JRB, Conesa A, Mika M, New FN, Onengut-Gumuscu S, Atkinson MA, Rich SS, McIntyre LM, Concannon P. Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res 2017; 27:1807-1815. [PMID: 29025893 PMCID: PMC5668939 DOI: 10.1101/gr.217984.116] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 09/13/2017] [Indexed: 12/22/2022]
Abstract
Genome-wide association studies (GWAS) have identified multiple, shared allelic associations with many autoimmune diseases. However, the pathogenic contributions of variants residing in risk loci remain unresolved. The location of the majority of shared disease-associated variants in noncoding regions suggests they contribute to risk of autoimmunity through effects on gene expression in the immune system. In the current study, we test this hypothesis by applying RNA sequencing to CD4+, CD8+, and CD19+ lymphocyte populations isolated from 81 subjects with type 1 diabetes (T1D). We characterize and compare the expression patterns across these cell types for three gene sets: all genes, the set of genes implicated in autoimmune disease risk by GWAS, and the subset of these genes specifically implicated in T1D. We performed RNA sequencing and aligned the reads to both the human reference genome and a catalog of all possible splicing events developed from the genome, thereby providing a comprehensive evaluation of the roles of gene expression and alternative splicing (AS) in autoimmunity. Autoimmune candidate genes displayed greater expression specificity in the three lymphocyte populations relative to other genes, with significantly increased levels of splicing events, particularly those predicted to have substantial effects on protein isoform structure and function (e.g., intron retention, exon skipping). The majority of single-nucleotide polymorphisms within T1D-associated loci were also associated with one or more cis-expression quantitative trait loci (cis-eQTLs) and/or splicing eQTLs. Our findings highlight a substantial, and previously underrecognized, role for AS in the pathogenesis of autoimmune disorders and particularly for T1D.
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Affiliation(s)
- Jeremy R B Newman
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA
| | - Ana Conesa
- Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, Florida 32610, USA
- Genetics Institute, University of Florida, Gainesville, Florida 32610, USA
| | - Matthew Mika
- Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Felicia N New
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA
| | - Suna Onengut-Gumuscu
- Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Mark A Atkinson
- Diabetes Institute, University of Florida, Gainesville, Florida 32610, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida 32610, USA
| | - Stephen S Rich
- Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA
| | - Lauren M McIntyre
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA
- Genetics Institute, University of Florida, Gainesville, Florida 32610, USA
| | - Patrick Concannon
- Genetics Institute, University of Florida, Gainesville, Florida 32610, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida 32610, USA
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22
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Ge Y, Paisie TK, Newman JRB, McIntyre LM, Concannon P. UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling. Diabetes 2017; 66:2033-2043. [PMID: 28607106 PMCID: PMC5482087 DOI: 10.2337/db16-1023] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 03/20/2017] [Indexed: 01/19/2023]
Abstract
Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus-UBASH3A, which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in UBASH3A have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associations is unresolved. Our study reveals a previously unrecognized role of UBASH3A in human T cells: UBASH3A attenuates the NF-κB signal transduction upon T-cell receptor (TCR) stimulation by specifically suppressing the activation of the IκB kinase complex. We identify novel interactions of UBASH3A with nondegradative polyubiquitin chains, TAK1 and NEMO, suggesting that UBASH3A regulates the NF-κB signaling pathway by an ubiquitin-dependent mechanism. Finally, we show that risk alleles at rs11203203 and rs80054410, two T1D-associated variants in UBASH3A, increase UBASH3A expression in human primary CD4+ T cells upon TCR stimulation, inhibiting NF-κB signaling via its effects on the IκB kinase complex and resulting in reduced IL2 gene expression.
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Affiliation(s)
- Yan Ge
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
- Genetics Institute, University of Florida, Gainesville, FL
| | - Taylor K Paisie
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
- Genetics Institute, University of Florida, Gainesville, FL
- Genetics & Genomics Graduate Program, University of Florida, Gainesville, FL
| | - Jeremy R B Newman
- Genetics Institute, University of Florida, Gainesville, FL
- Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL
| | - Lauren M McIntyre
- Genetics Institute, University of Florida, Gainesville, FL
- Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, FL
| | - Patrick Concannon
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
- Genetics Institute, University of Florida, Gainesville, FL
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23
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Roep BO, Kracht MJ, van Lummel M, Zaldumbide A. A roadmap of the generation of neoantigens as targets of the immune system in type 1 diabetes. Curr Opin Immunol 2016; 43:67-73. [PMID: 27723537 DOI: 10.1016/j.coi.2016.09.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/16/2016] [Accepted: 09/28/2016] [Indexed: 01/08/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of the insulin-producing beta cells. Beta cell dysfunction caused by an inflammatory microenvironment is believed to trigger the peripheral activation of CD4 and CD8 autoreactive T cells. This review will compile post-transcriptional and post-translational modifications (PTM) involved in the generation of beta cell neoantigens and proposes a reconstruction of the sequence of events connecting environmental changes and autoimmunity.
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Affiliation(s)
- Bart O Roep
- Department of Diabetes Immunology, Diabetes and Metabolism Research Institute at the Beckman Research Institute of the City of Hope, Duarte, CA, USA; Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
| | - Maria Jl Kracht
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Menno van Lummel
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Arnaud Zaldumbide
- Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
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