Genetics Of Diabetes Ncbi

Genetics Of Type 1 Diabetes: What's Next?

Genetics of Type 1 Diabetes: What's Next? 1Department of Genome Biology, Hagedorn Research Institute, Gentofte, Denmark; 2Clinical Research Center (CRC), University of Lund, Malm, Sweden; 3Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland; 4Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia; 5Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia; 7Institut National de la Sant et de la Recherche Mdicale (INSERM) U730, Centre National de Gnotypage, Evry, France; 8Centre for Diabetes Research, The Western Australian Institute for Medical Research, University of Western Australia, Perth, Australia; 10Department of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K.; 4Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia; 11Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. 1Department of Genome Biology, Hagedorn Research Institute, Gentofte, Denmark; 2Clinical Research Center (CRC), University of Lund, Malm, Sweden; 3Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland; 4Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia; 5Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia; 6Roche Molecular Systems, Pleasanton, California; 7Instit Continue reading >>

Genetics Of Diabetes Complications

We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. A large body of evidence indicates that the risk of developing chronic diabetic complications is under the control of genetic factors. Previous studies using a candidate gene approach have uncovered a number of genetic loci that may shape this risk, such as the VEGF gene for retinopathy, the ELMO1 gene for nephropathy, and the ADIPOQ gene for coronary artery disease. Recently, a new window has opened on identifying these genes through genome-wide association studies. Such systematic approach has already led to the identification of a major locus for coronary artery disease on 9p21 as well three potential genes for nephropathy on 7p, 11p, and 13q. Further insights are expected from a broader application of this strategy. It is anticipated that the identification of these genes will provide novel insights on the etiology of diabetic complications, with crucial implications for the development of new drugs to prevent the adverse effects of diabetes. Keywords: Diabetic nephropathy, Diabetic retinopathy, Coronary artery disease, Atherosclerosis, Polymorphisms, Candidate genes, Genome-wide association studies Long-term complications affecting the eyes, the kidneys, and the cardiovascular system are the principal cause of morbidity and mortality among diabetic subjects ( 1 ). Because of the high prevalence of diabetes, these complications are significant public health problems, being resp Continue reading >>

The Genetics Of Type 2 Diabetes: What Have We Learned From Gwas?

The genetics of type 2 diabetes: what have we learned from GWAS? 1 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 3 Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 1 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 3 Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 4 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 1 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 3 Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 4 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts Correspondence: Jose C. Florez, M.D., Ph.D. Center for Human Genetic Research Simches Research Building, CPZN 5.250 Massachusetts General Hospital 185 Cambridge Street Boston, MA 02114 [email protected] The publisher's final edited version of this article is available at Ann N Y Acad Sci See other articles in PMC that cite the published article. Type 2 diabetes mellitus has been at the forefront of human diseases and phenotypes studied by new genetic analyses. Thanks to genome-wide association studies, we have made substantial progress in elucidating the genetic basis of type 2 diabetes. This review summarizes the concept, history, and recent discoveries produced by genome-wide association Continue reading >>

Genetic Epidemiology Of Diabetes

M. Alan Permutt ,1 Jonathon Wasson ,1 and Nancy Cox 2 1Department of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA. 1Department of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA. 1Department of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA. 1Department of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA. Address correspondence to: M. Alan Permutt, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8127, St. Louis, Missouri 63110-1010, USA. Phone: (314) 362-8680; Fax: (314) 747-2692; E-mail: [email protected] . Copyright 2005, American Society for Clinical Investigation This article has been cited by other articles in PMC. Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we Continue reading >>

Genetic Factors In Type 2 Diabetes - The Genetic Landscape Of Diabetes - Ncbi Bookshelf

Official name: ATP-binding cassette, sub-family C, member 8 The protein encoded by the ABCC8 gene is a member of the ATP-binding cassette transporters. These proteins use energy in the form of ATP to drive the transport of various molecules across cell membranes. ABCC8 belongs to a subfamily of transporters that contains the chloride channel that is mutated in cystic fibrosis (CFTR) and also the proteins that are involved in multi-drug resistance. Read more: The Human ATP-Binding Cassette (ABC) Transporter Superfamily The ABCC8 protein is also known as the sulfonylurea urea receptor (SUR). SUR is one of the proteins that composes the ATP-sensitive potassium channel (KATP channel) found in the pancreas ( 1 ). The other protein, called Kir6.2, forms the core of the channel and is encoded by the KCNJ11 gene . KATP channels play a central role in glucose-induced insulin secretion by linking signals derived from glucose metabolism (a rise in ATP) to membrane depolarization (due to KATP channels closing) and the secretion of insulin. The activity of the KATP channel regulates the release of insulin. The sulfonylureas are drugs that can modulate KATP channel activity and are used in the treatment of type 2 diabetes. By binding to SUR, they inhibit the channel and stimulate the release of insulin. This leads to a lowering of blood glucose levels. The activity of the KATP channel is also modulated by the subtype of SUR (SUR, also known as SUR1, is encoded by ABCC8; or SUR2A and SUR2B, which are encoded by ABCC9). In the pancreas, most KATP channels are thought to be a complex of four SUR1 proteins and four Kir6.2 proteins. Mutations in either ABCC8 or KCNJ11 can result in up-regulated insulin secretion, a condition termed familial persistent hyperinsulinemic hypoglycemia of inf Continue reading >>

The Genetics Of Type 2 Diabetes

Go to: Introduction Of the various subtypes of diabetes, type 2 diabetes has the greatest impact on health worldwide. Around 150 million people have type 2 diabetes, and the prevalence will rise by 40% by 2010 [1]. Type 2 diabetes and its complications already consume 5–10% of health budgets in many countries [2]. Yet, despite the manifest importance of this condition, and many years of detailed metabolic study, understanding of the basic aetiological mechanisms remains fragmentary [3]. This contrasts with the other major subtype of diabetes, type 1, where it is well-established that the major aetiological process involves autoimmune destruction of the insulin-secreting pancreatic beta-cells. Type 2 diabetes displays a clear association with obesity, and the clustering of type 2 diabetes, hypertension, dyslipidaemia and macrovascular disease within individuals and families, indicates that reduced sensitivity to the peripheral actions of insulin (i.e. insulin resistance) plays a key role in disease pathogenesis [4]. However, since many individuals with marked insulin resistance still manage to maintain normal glucose homeostasis, variation in the compensatory capacity of the pancreatic beta-cell must be an equal partner in disease progression [5]. Efforts to characterize further the crucial intermediate metabolic steps in the development of full-blown type 2 diabetes have largely foundered on the rocks of individual heterogeneity and the complicating effects of hyperglycaemia (and its treatment) on the very intermediate traits that investigators might wish to measure. Improved glycaemic control has been clearly shown to reduce the burden of diabetic complications [6]. Since currently available treatments rarely achieve the goal of lifelong restoration of normoglycaemia Continue reading >>

The Search For Genetic Risk Factors Of Type 2 Diabetes Mellitus

The Search for Genetic Risk Factors of Type 2 Diabetes Mellitus Department of Internal Medicine and Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine and Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Korea. Corresponding author: Kyong Soo Park. Department of Internal Medicine, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul 110-744, Korea. [email protected] Author information Copyright and License information Disclaimer Copyright 2011 Korean Diabetes Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Type 2 diabetes mellitus (T2DM) is caused by complex interplay between multiple genetic and environmental factors. The three major approaches used to identify the genetic susceptibility include candidate gene approach, familial linkage analysis and genome- wide association analysis. Recent advance in genome-wide association studies have greatly improved our understanding of the pathophysiology of T2DM. As of the end of 2010, there are more than 40 confirmed T2DM-associated genetic loci. Most of the T2DM susceptibility genes were implicated in decreased -cell function. However, these genetic variations have a modest effect and their combination only explains less than 10% of the T2DM heritability. With the advent of the next-generation sequencing technology, we will soon identify rare variants Continue reading >>

The Genetic Architecture Of Type 1 Diabetes

The Genetic Architecture of Type 1 Diabetes Barts and the London School of Medicine and Dentistry, QMUL, London E1 2AT, UK; [email protected] *Correspondence: [email protected] ; Tel.: +44-207-8823645 Received 2017 May 12; Accepted 2017 Aug 16. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( ). Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that geneenvironment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D. Keywords: Type 1, diabetes, genetic, genes The aetiology of Type 1 diabetes (T1D), like most common chronic diseases, is complex and results fr Continue reading >>

The Role Of Genetics In Susceptibility To Diabetic Retinopathy

The Role of Genetics in Susceptibility to Diabetic Retinopathy We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. The Role of Genetics in Susceptibility to Diabetic Retinopathy Gerald Liew, MD, MPH, Ronald Klein, MD, MPH, and Tien Y. Wong, MD, PhD Diabetic retinopathy remains the leading cause of blindness in working-aged adults.( 1 ) Over 4 million adults 40 years and older in the United States are estimated to have diabetic retinopathy, of whom 1 out of every 12 has advanced vision-threatening retinopathy ( 2 ). With the projected increase in the world-wide prevalence of diabetes to 380 million people by 2025,( 3 ; 4 ) of whom 40% are expected to have some form of diabetic retinopathy,( 2 ) there is a clearly a need to develop strategies to identify persons at risk of diabetic retinopathy, allowing prevention and early intervention. There is already strong evidence that longer duration of diabetes, poorer control of blood glucose and elevated blood pressure are the major factors responsible for the onset and progression of diabetic retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a population-based cohort study of diabetes in which participants were first examined in 1980-82, showed that in persons with type 1 diabetes, the prevalence of diabetic retinopathy ranged from 17% in those with diabetes for less than 5 years to almost 100% in those with diabetes for over 15 years.( 5 ) The corresponding fi Continue reading >>

Genetics Of Type 2 Diabetes

Omar Ali, Medical College of Wisconsin, Milwaukee, WI 53226, United States Author contributions: Ali O reviewed the published literature and wrote the article in its entirety. Correspondence to: Omar Ali, MD, Medical College of Wisconsin, Milwaukee, 8701 W Watertown Plank Rd, WI 53226, United States. [email protected] Telephone: +1-414-2666750 Fax: +1-414-2666749 Received 2013 Mar 3; Revised 2013 Jun 1; Accepted 2013 Jul 18. Copyright 2013 Baishideng Publishing Group Co., Limited. All rights reserved. This article has been cited by other articles in PMC. Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this missing heritability, including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed. Keywords: Type 2 diabetes, Genetics, TCF7L2, Genome-wide association studies, Heritability Core tip: We review the history and the current state of knowledge regarding the genetic component of type 2 diabetes risk. Genes like TCF7L2 that have been replicated in multiple studies are discussed in detail. The signi Continue reading >>

Genetics Of Type 2 Diabetespitfalls And Possibilities

Genetics of Type 2 DiabetesPitfalls and Possibilities Rashmi B. Prasad 1,* and Leif Groop 1,2,* 1Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Lund University, CRC, Skne University Hospital SUS, SE-205 02 Malm, Sweden 2Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki 00014, Finland *Authors to whom correspondence should be addressed; E-Mails: [email protected] (R.B.P.); [email protected] (L.G.). Received 2014 Dec 9; Accepted 2015 Feb 27. Copyright 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( ). This article has been cited by other articles in PMC. Type 2 diabetes (T2D) is a complex disease that is caused by a complex interplay between genetic, epigenetic and environmental factors. While the major environmental factors, diet and activity level, are well known, identification of the genetic factors has been a challenge. However, recent years have seen an explosion of genetic variants in risk and protection of T2D due to the technical development that has allowed genome-wide association studies and next-generation sequencing. Today, more than 120 variants have been convincingly replicated for association with T2D and many more with diabetes-related traits. Still, these variants only explain a small proportion of the total heritability of T2D. In this review, we address the possibilities to elucidate the genetic landscape of T2D as well as discuss pitfalls with current strategies to identify the elusive unknown heritability including the possibility that our definition of diabetes and its subgroups is imprecise and thereby makes the identification of g Continue reading >>

The Genetic Basis Of Type 2 Diabetes

We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Type 2 Diabetes results from a complex physiologic process that includes the pancreatic beta cells, peripheral glucose uptake in muscle, the secretion of multiple cytokines and hormone-like molecules from adipocytes, hepatic glucose production, and likely the central nervous system. Consistent with the complex web of physiologic defects, the emerging picture of the genetics will involve a large number of risk susceptibility genes, each individually with relatively small effect (odds ratios below 1.2 in most cases). The challenge for the future will include cataloging and confirming the genetic risk factors, and understanding how these risk factors interact with each other and with the known environmental and lifestyle risk factors that increase the propensity to type 2 diabetes. Type 2 Diabetes Mellitus (T2DM) is a complex heterogeneous group of metabolic condition characterized by elevated levels of serum glucose, caused mainly by impairment in both insulin action and insulin secretion. T2DM exerts a huge toll in human suffering and economy. A recent evaluation using a computerized generic formal disease model (DisMod II) revealed that excess global mortality due to diabetes in the year 2000 was equivalent to 5.2% of all deaths and diabetes is likely to be the fifth leading cause of death, similar in magnitude to numbers reported for HIV/AIDS ( 1 ). The prevalence of diabetes for Continue reading >>

Genetics Of Type 1 Diabetes.

1. Clin Chem. 2011 Feb;57(2):176-85. doi: 10.1373/clinchem.2010.148221. Epub 2011Jan 4. (1)Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045-6511, USA. [email protected] BACKGROUND: Type 1 diabetes, a multifactorial disease with a strong geneticcomponent, is caused by the autoimmune destruction of pancreatic cells. Themajor susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.CONTENT: Although HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smallereffects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and otherrecently discovered loci. Genomewide association studies performed withhigh-density single-nucleotide-polymorphism genotyping platforms have providedevidence for a number of novel loci, although fine mapping and characterizationof these new regions remain to be performed. Children born with the high-riskgenotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiisletautoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can befurther stratified by selection of children with susceptible genotypes at otherdiabetes genes, by selection of children with a multiple family history ofdiabetes, and/or by selection of relatives that are HLA identical to the proband.SUMMARY: Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have afamily history of type 1 diabetes have more than a 1 in 5 risk for developingislet autoantibodies during childhood, and children with the same HLA-riskgenotype but no family history have approximately a 1 in 20 risk. Determiningextreme genetic risk is a prerequisite for the implement Continue reading >>

Is Genetic Testing Useful To Predict Type 2 Diabetes?

Is Genetic testing useful to predict type 2 diabetes? We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Is Genetic testing useful to predict type 2 diabetes? Jason L. Vassy, MD, MPH, Clinical and Research Fellow and James B. Meigs, MD, MPH, Associate Professor The early identification of individuals at risk for type 2 diabetes (T2D) enables prevention. Recent genome-wide association studies (GWAS) have added at least 40 genetic variants to the list of already well characterized T2D risk predictors, including family history, obesity, and elevated fasting plasma glucose levels. Although these variants can significantly predict T2D alone and as a part of genotype risk scores, they do not yet offer clinical discrimination beyond that achieved with common clinical measurements. Future progress on at least two research fronts may improve the predictive performance of genotype information. First, expanded GWAS efforts in non-European populations will allow targeted sequencing of risk loci and the identification of true causal variants. Second, studies with longer prediction time horizons may demonstrate that genotype information performs better than clinical risk predictors over a longer period of the life course. At present, however, genetic testing cannot be recommended for clinical T2D risk prediction in adults. Keywords: type 2 diabetes genetics, risk prediction models, genotype risk scores The Human Genome Project listed among its b Continue reading >>

Personalized Medicine For Diabetes: Genetics Factors Contributing To Type 2 Diabetes Across Ethnicities

Genetics Factors Contributing to Type 2 Diabetes across Ethnicities University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas Correspondence to: Steven C. Elbein, M.D., Veterans Hospital, Endocrinology 111J/LR, 4300 West 7th Street, Little Rock, AR 72205; email address [email protected] Funding: This work was supported by NIH/NIDDK DK039311 and the Research Service of the Department of Veterans Affairs. Copyright 2009 Diabetes Technology Society This article has been cited by other articles in PMC. Type 2 diabetes mellitus (T2DM) is among the many common diseases with a strong genetic component, but until recently, the variants causing this disease remained largely undiscovered. With the ability to interrogate most of the variation in the genome, the number of genetic variants has grown from 2 to 19 genes, many with multiple variants. An additional three genes are associated primarily with fasting glucose rather than T2DM. Despite the plethora of new markers, the individual effect is uniformly small, and the cumulative effect explains little of the genetic risk for T2DM. Furthermore, the success is largely restricted to European populations. Despite success in mapping genes in Asian populations, success in United States minorities, particularly African Americans, has been limited. The genetic findings highlight the role of the cell in diabetes pathogenesis, but much remains to be discovered before genetic prediction and individualized medicine can become a reality for this disease. Keywords: genome-wide association scan, insulin action, insulin secretion, type 2 diabetes Type 2 diabetes mellitus (T2DM) has long been viewed as a disease with a substantial genetic contribution. This vie Continue reading >>